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Drug hypersensitivity Prof Ghada Shousha, Assistant Professor of pediatrics, Immunology, Allergy and Rheumatology, Ain Shams University
Drug hypersensitivity Prof Ghada Shousha, Assistant Professor of pediatrics, Immunology, Allergy and Rheumatology, Ain Shams University How to diagnose, confirm and manage drug hypersensitivity?
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Drug hypersensitivity Prof Ghada Shousha, Assistant Professor of pediatrics, Immunology, Allergy and Rheumatology, Ain Shams University
- 1. Drug Hypersensitivity Reactions Ghada Shousha Asst.Prof. Pediatrics, Ain Shams University
- 2. 1) Drug Hypersensitivity:new classification 2024 2) Diagnostic tools 3) Scaling of drug reaction severity 4) Bradykinin angioedema 5) Examples for delayed drug reactions
- 5. Adverse drug reaction(ADR): A noxious and unintended reaction that occurs in addition to the intended effect of a drug, for which a causal relationship between the use of the drug and the adverse effect is suspected. ADRs can be both type A and type B: 1- Type A (“augmented” = pharmacological/toxic (on-target) drug effects): manifestations due to dose-dependent predictable pharmacological/toxic effects of a drug at the recommended dose (examples: sedative effect of older antihistamines, hair loss due to immunosuppressants) or increased dosage (intoxication). 2- Type B (“bizarre” = hypersensitivity (off-target) reactions): Individual, unpredictable clinical reaction to a drug, i.e., symptoms occur only in specially predisposed patients. Two forms can be distinguished: Definitions
- 6. –Drug allergy: Hypersensitivityis based on an immunological reaction (types I – IV). –Non-allergic drug hypersensitivity: An allergic mechanism is not detectable. Previously, this type of reaction was further divided into: >>Drug intolerance: Typical symptoms of pharmacological action (toxicity) develop even at low doses that are usually tolerated. >>Drug idiosyncrasy: The symptoms differ from the pharmacological substance effect. In cases where the symptoms are similar to an allergic reaction, the term pseudoallergy has also been used.
- 9. Mast cells ascentral effector cells on immediate drug hypersensitivity reactions (IDHRs). 1 and 2 are immunological mechanisms that need the drug binding to carrier molecules forming adducts; 3 and 4 are non-immunological mechanisms produced by the direct interaction of the drug to either receptors or enzymes.
- 12. # Adverse drugreactions (ADRs) to antibiotics are commonly reported among children, with some representing genuine drug allergies. # Drug provocation testing (DPT) is accepted as the gold standard investigation among children with suspected antibiotic allergy. # No evidence supports using skin prick, ID or in vitro diagnostic testing; indeed, the testing regimens, extracts and positivity criteria used are inconsistent.
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- 20. Test Dose Protocol:In hospital
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- 28. Drug Desensitization A processby which a patient’s immune response to a drug is modified to generate temporary tolerance, taking advantage of well characterized inhibitory pathways. Patients without evidence of IgE mechanism are good candidates for desensitization provided the phenotype of the drug reaction is a type I or a type IV like reaction without features of SJS/TEN.
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- 31. How to differentiatebetween Allergic and Hereditary AE? Family History? Urticaria? Anaphylaxis? Onset? Duration? Triggers?
- 32. Presentation Slowly progressiveover few hours Peak within 12-24 hrs Last for 2-5 days No urticaria or itching Sometimes, stretching of the skin is very painful. Abdulkarim A, Craig TM. Statpearls. 2023.
- 33. Erythema marginatum (EM)is a visible prodromal symptom which occasionally occurs prior to an angioedema attack; hence, recognizing the risk of an acute attack is important for early treatment.
- 34. Bradykinin-induced AE Mastcell mediated AE Slow (hours) Rapid (mins) Onset 48-72 hr or more Few hours Duration - ++ Urticaria + + Laryngeal edema +/- +++ Bronchospasm +++ + Abdominal Pain +/- +++ Hypotension - +++ Response to antihistamines, steroids or epinephrine Depetri F, et al. Eur J Intern Med. 2018; 59. DOI: 10.1016/j.ejim.2018.09.004
- 35. HAE Acquired AEMast cell mediated AE 1st -2nd decade 4th -6th decade Any Age of Onset Face, extremities, upper airway, GIT Lips, tongue, uvula, upper airway Face & neck Predominant site yes No No Family history Trauma, infections, emotional stress, estrogen, idiopathic Drugs Known or probable allergen Trigger Estrogens ACEI, ARBS, gliptins Antibiotics, NSAIDs, others Triggering drugs Not mandatory Not mandatory Always symmetrical Symmetry
- 36. Treatment of HAE Acuteattacks ( IV versus SQ ) C1INH: (IV) 1- Plasma derived: Cinryze 2- Recombinant (derived from rabbits) 1 - Bradykinin inhibitors (SQ): Icatibant 2 - Kallikrein inhibitor (SQ) Prophylaxis 1 - C1 INH: humanized SQ 2 - C1 INH: plasma derived 3 - Kallikrein inhibitor: Berotralstat oral 4 - Kallikrein monoclonal Ab: Lanadelumab SQ
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- 40. Steven Johnson Syndrome(SJS) Causes of death: Skin failure Electrolyte imbalance Hypothermia Sepsis
- 41. “Ruminski et al.,US Pharm 2013; 38(7):69-79”
- 42. Medications that caninduce SJS/TEN: Anti epileptics: Carbamazepine Lamotrigine Valproate Phenytoin Barbiturates Antimicrobials Allopurinol Anti-TNF Ab PPI SSRI NSAIDs
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- 44. Presentation Early Non specific symptoms: fever, myalgia,rhinitis 3-4 days later Blistering rash and erosions over the skin and mucous membranes Forms of rash Erythematous, targetoid, macules Flaccid bullae Large painful erosions Nikolsky-positive
- 45. TEN displays widespread tendererythroderma and erosions (with or without targetoid rash), whereas SJS is characterized more by targetoid rash, with fewer areas of denudation.
- 46. Mucosal ulcerationand erosions can involve lips, mouth, pharynx, esophagus and gastrointestinal tract, eyes, genitals, upper respiratory tract. About half of patients have involvement of three mucosal sites. Liver, kidneys, lungs, bone marrow, and joints may be affected.
- 48. Diagnostic criteria: theNiigata criteria 2025 • Severe mucosal lesions in extensive areas of the cutaneous–mucosal transition zone OR generalized erythema of the skin with necrotic lesions of the epidermis. • Fever (≥ 38.5 °C). • Necrotic changes of the epidermis are observed on histopathology. Main Items • Erythematous plaques are flat and show target lesions. • Pseudomembrane formation and ocular surface epithelial defects. • Autoimmune bullous disease (e.g. linear IgA bullous dermatosis), SSSS, TEN-like lupus erythematosus, generalized bullous fixed drug eruption and GVHD should be excluded. Supplementar y • All three of the main items are fulfilled, after consideration of supplementary items • TEN>> skin detachment exceeding 10% of body surface area is required. • Diagnosis according to the entire course of the disease, not just the initial stages. Diagnosis
- 49. Differential diagnosis: STEPSMADE DIG S: SSSS T: toxic shock syndrome E: erythema multiform P: Paraneoplastic pemphigus S: SLE M: Diffuse cutaneous mastocytosis A: Acute generalized exanthematous pustulosis D: DRESS syndrome E: Epidermolysis Bullosa D: Drug hypersensitivity reaction I: IgA bullous lesions The Hallmark Extensive Skin Detachment
- 51. Lines of Management 1st line •Corticosteroids: solumedrol 10-30 mg/kg/d • Ciclosporin A: considering the renal functions • Etanercept/Tocilizumab: add-on therapy • Supportive treatment 2nd line • IVIG: 1-2 gm/kg over 2 days • Plasmapheresis • Cyclophosphamide Promisin g • PC111: anti fas/fasL • Anti-annexin 1 • JAK inhibitors
- 52. DRESS is arare, potentially life-threatening, drug-induced hypersensitivity reaction. DRESS includes skin eruption, hematologic abnormalities, lymphadenopathy, and at least one internal organ involvement. DRESS is characterized by a long latency (2-8 wks) between drug exposure and disease onset, a prolonged course with frequent relapses, and reactivation of latent human herpesvirus infections. Treatment is supportive: Corticosteroids ± Cyclosporin A. Drug reaction with eosinophilia and systemic symptoms (DRESS)
- 53. Japanese consensus groupdiagnostic criteria for DRESS: 7or the first 5 criteria required (2010) Maculopapular rash developing > 3 weeks after the suspected drug Clinical symptoms 2 weeks after discontinuation of the drug Fever > 38 °C Liver or other organ involvement Leukocyte abnormalities Leukocytosis ( > 11 x 109 /l) Atypical lymphocytosis (>5%) Lymphadenopathy Human herpesvirus 6 reactivation
- 54. Incidence of organinvolvement in DRESS syndrome Organ Percent of patients Liver 80% Kidney 40% Pulmonary 33% Cardiac/muscular 15% Pancreas 5% Incidence of hematologic abnormalities in DRESS Abnormality Percent of patients Atypical lymphocyte 63% Eosinophilia 52% Lymphopenia 45% Thrombocytopenia 25% Lymphocytosis 25%
- 55. Serum Sickness Serum sicknessis an immune-complex-mediated hypersensitivity reaction that classically presents with fever, rash, polyarthritis or polyarthralgia. # The symptoms typically occur 1-2 weeks after exposure and resolve within several weeks of discontinuation. # It is a self-limited disease process with an excellent prognosis. # Medications containing heterologous antigens are the most common cause: vaccinations (i.e., Rabies), immune modulating agents (i.e., rituximab, infliximab) and anti-venoms.
- 56. # Serum sicknesslike reactions (SSLRs) are non-immune complex mediated reactions which are characterized by rash, fever, and polyarthralgia. SSLRs are triggered by viral infections, vaccines, and drugs, with many reported cases to penicillin, cephalosporins (most commonly cefaclor), sulfonamides, bupropion, fluoxetine and thiouracil. # The rash typically takes days to weeks to resolve once the offending agent is discontinued. # Arthralgias are more common than frank arthritis, but either may occur: peripheral > axial # Less common findings include edema, lymphadenopathy, headache or blurry vision, splenomegaly, anterior uveitis, peripheral neuropathy, nephropathy, and vasculitis. # The symptoms are less likely in serum sickness-like reaction, which is usually limited to fever, arthralgias, rash/urticaria, and pruritis.
- 57. Acute generalized exanthematouspustulosis # AGEP is an adverse cutaneous type IV hypersensitivity reaction, characterized by sterile pinpoint nonfollicular pustules atop an erythematous background. # It is drug induced>> antibiotics (B lactam, macrolides), hydroxychloroquine, antifungal, antiviral, and antiparasitic drugs, antineoplastic and antirheumatic agents, analgesics, anticonvulsants, and intravenous contrast media, and even corticosteroids. # Rapidly become generalized, followed by desquamation and resolution within about two weeks of discontinuing the offending trigger. # Severe cases are classified alongside other cutaneous adverse reactions such as SJS/TEN, and DRESS. # Treatment is supportive, and the prognosis is excellent.
- 58. EuroSCAR criteria: ascore of 0 or below rules out the possibility of AGEP. A score of 1 to 4 cannot rule out AGEP, whereas a score of 5 to 7 indicates that AGEP is probable. A score of 8 to 12 is considered to diagnose AGEP definitively. Exanthem Features No pustules or unable to determine (0), Pustules present and equivocal (+1), Pustules present in significant number, nonfollicular, and minuscule/"pinhead" < 5 mm size, can be confluent (+2). No erythema or unable to determine (0), Erythema present and equivocal (+1), Erythema present and widespread as a base upon which the pustules are located (+2). Unable to determine distribution pattern (0), Distribution pattern equivocal (+1), Distribution begins in intertriginous regions or face with rapid spread to trunk and limbs (+2). No post-pustular desquamation or unable to determine (0), Post-pustular desquamation (+1).
- 59. EuroSCAR criteria: ascore of 0 or below rules out the possibility of AGEP. A score of 1 to 4 cannot rule out AGEP, whereas a score of 5 to 7 indicates that AGEP is probable. A score of 8 to 12 is considered to diagnose AGEP definitively. Other Features Mucosal involvement (- 2), no mucosal involvement (0). Onset > 10 days (-2), onset <= 10 days (0). Resolution > 15 days (-4), resolution <= 15 days (0) Temperature < 38° C (0), Fever >- 38° C (+1). WBC < 7,000 cells/mm^3 (0), WBC >= 7,000 cells/mm^3 (+1)
- 60. EuroSCAR criteria: ascore of 0 or below rules out the possibility of AGEP. A score of 1 to 4 cannot rule out AGEP, whereas a score of 5 to 7 indicates that AGEP is probable. A score of 8 to 12 is considered to diagnose AGEP definitively. Histologic Features Consistent with another diagnosis (-10). Not representative or no histology (0). Peripheral neutrophil exocytosis (+1). Non-spongiform subcorneal and/or intraepidermal or nonspecified pustules with papillary edema (+2), Spongiform subcorneal and/or intraepidermal or nonspecific pustules without papillary edema (+2). Spongiform subcorneal and/or intraepidermal pustules with papillary edema (+3).
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- 62. Drug or classSkin prick test Intradermal test 8 Patch test Beta-lactam antibiotics Benzylpenicilloyl-octa-L-lysine 8.6 × 10-5 mol/L 8.6 × 10-5 mol/L NA Sodium benzylpenilloate 1.5 × 10-3 mol/L 1.5 × 10-3 mol/L NA Benzylpenicillin 10,000 UI/mL 10,000 UI/mL 5% Amoxicillin 20 mg/mL 20 mg/mL 5% Ampicillin 20 mg/mL 20 mg/mL 5% Cephalosporins 20 mg/mL10 20 mg/mL10 5% Anticoagulants Heparins1 Undiluted8 1/10 diluted Undiluted8 Heparinoids2 Undiluted8 1/10 diluted Undiluted8 Platinum salts Carboplatin 10 mg/mL 1 mg/mL NA Oxaliplatin 1 mg/mL 0.1 mg/mL NA Cisplatin 1 mg/mL 0.1 mg/mL NA NSAID Pyrazolone3 Suspension9 0.1 – 1 mg/mL 10% Coxibe4 Suspension9 10% Other NSAIDs5 Suspension9 0.1 – 1 mg/mL 10% Biologics Adalimumab 50 mg/mL 50 mg/mL Undiluted8 Etanercept 25 mg/mL 5 mg/mL NA Infliximab 10 mg/mL 10 mg/mL NA Omalizumab 1.25 µg/mL 1.25 µg/mL NA Other Local anesthetics Undiluted8 1/10 diluted Undiluted8 X-ray contrast agent Undiluted8 1/10 diluted Undiluted8 Gadolinium chelates Undiluted8 1/10 diluted NA Patent blue Undiluted 1/10 diluted NA Methylene blue Undiluted 1/100 diluted NA Fluorescein Undiluted8 1/10 diluted Undiluted8 Proton pump inhibitors6 Undiluted9 40 mg/mL 10% Anticonvulsants7 NA NA 10% Chlorhexidine digluconate 5 mg/mL 0.002 mg/mL 1%
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