Severe Cutaneous Adverse Reactions to Drugs

This is a PPT on severe drug reactions in emergency dermatology.

1. SEVERE CUTANEOUS ADVERSE REACTIONS TO DRUGS Dr. Jerriton brewin FINAL YEAR DVL PG, SVMCH, PONDY. 08.06.2020

2. INTRODUCTION Cutaneous reactions to drugs - 2% of OP and 5% of the IP admissions. Approximately 2% of all drug-induced skin reactions are considered “serious” according to the WHO definition: “If it results in death, requires hospitalization or prolongation of existing hospital stay, results in persistent or significant disability/incapacity, or is life-threatening”.

3. SJS-TEN

4. DEFINITION Severe mucocutaneous reaction Usually to drugs Characterized by blistering and epithelial sloughing. Two terms - single severity spectrum SJS is the less extensive TEN is the more extensive

5. EPIDEMIOLOGY One to two cases per million per year. Elderly females. Increased risk of SJS/TEN in HIV‐infected individuals. Possible association with SLE.

6. etiology Drug - 85% Non-drug: 15% Infections (some) - Mycoplasma pneumoniae (children) Genes: - HLA‐B*1502 (carbamazepine‐induced) - HLA‐B*5801 (allopurinol-induced)

7. M/C DRUGS CAUSING SJS/TEN

8. PATHOPHYSIOLOGY MHC class I‐restricted drug presentation leads to clonal expansion of CD8+ CTLs. TNF‐α, IFN‐γ, and inducible nitric oxide synthase, link drug‐induced immune responses to keratinocyte damage. Soluble Fas ligand (basis for IVIG), perforin, granzyme and granulysin (M/I) have all been implicated in triggering keratinocyte death.

9. CLINICAL FEATURES - CUTANEOUS Latency: 7-10 days (5-28 days) Prodrome: malaise, fever, URI symptoms (few days) Rash: - Atypical targets / purpuric macules - Starts on face & chest, then disseminates - Vesicles or fluid‐filled blisters develop within lesional skin Large areas of confluent erythema may develop Nikolsky sign - gentle lateral pressure causes lesional epidermis to slide over the dermis

10. Atypical target - red macules – each has a darker centre and a slightly paler outer ring.

11. Purpuric macules coalescing and blistering.

12. Atypical targets on palms and soles with blistering.

13. Blisters forming both vesicles, and large flaccid bullae.

14. Confluent erythema with negligible blistering/epidermal detachment.

15. Denuded skin - large areas of exposed dermis.

16. Detached epidermis.

17. CLINICAL FEATURES - MUCOUS MEMBRANES Eye: Pain, visual impairment, chemosis, conjunctivitis, pseudomembrane formation and corneal and conjunctival epithelial defects. Mouth: - Painful mucosal erythema with subsequent blistering and ulceration and hemorrgahic crusting. - Tongue & hard palate are common sites. Can extend to oropharynx, larynx, respiratory tract and oesophagus. Uro-genital tract: Dysuria, urine retention, mucosal erythema, blistering and erosions. Lungs: Dyspnoea, increased respiratory rate and bronchial hypersecretion.

18. Eyelid oedema, conjunctivitis and keratitis, purulant discharge (green material is exudate stained by fluorescein dye)

19. Lip involvement. Severe cheilitis has produced thick haemorrhagic crusts.

20. Confluent erythema of the scrotum and discrete lesions on the glans penis.

21. DIFFERENTIAL DIAGNOSIS

22. severity classification Based on lesional morphology and extent of epidermal detachment: 1. SJS - epidermal detachment less than 10% BSA, plus widespread purpuric macules or flat atypical targets. 2. SJS-TEN overlap - detachment of 10–30% BSA, plus widespread purpuric macules or flat atypical targets. 3. TEN with spots - detachment greater than 30% BSA, plus wide- spread purpuric macules or flat atypical targets. 4. TEN without spots - detachment greater than 30% BSA, with loss of large epidermal sheets without purpuric macules or target lesions.

23. ACUTE complications Hypothermia Anemia and leucopenia Fluid-electrolyte imbalance Acute renal shutdown High output cardiac failure Dyspnoea, hemoptysis Septicemia

24. CHRONIC complications Skin Post‐inflammatory dyspigmentation Eruptive melanocytic naevi Permanent anonychia Telogen effluvium Eye Corneal and conjunctival ulceration and scarring, dry eye, entropion, trichiasis.

25. CHRONIC complications Lungs Bronchiolitis obliterans GIT Oesophageal stricture, intestinal ulceration Gynaecological Vaginal and introital adhesions Psychiatric Post‐traumatic stress disorder

26. complications (CONTD.) M/C life threatening: septicemia M/C disabling: ocular

27. SCORETEN Prognostic scoring system with 7 parameters (1 point for each) Increasing score = higher mortality

28. BODY MAPPING BSA calculated for extent of erythema & epidermal detachment Wallace rule of 9

29. INVESTIGATIONS Done to (a) substantiate the diagnosis (b) exclude other blistering dermatoses (c) identify any systemic complications

30. Tests needed at presentation

31. 2 skin biopsies: - HPE: Lesional skin adjacent to blister - DIF: Peri‐blister lesional skin Lesional skin swabs for bacterial culture CXR Tests needed at presentation

32. Parakeratosis, subepidermal cleft, civette bodies, superficial perivascular infiltrate.

33. MANAGEMENT OF SJS/TEN Meticulous care of lesional skin and mucous membrane + Intensive supportive care for the systemic complications Identify and stop offending drug Specific therapy

34. MANAGEMENT OF SJS/TEN > 10% BSA - managed in ICU / burns unit Barrier nursed in a side room on a pressure-relieving mattress Ambient temperature: 25-28 °C Requires multi-disciplinary team - dermatologist or burns surgeon, clinicians from intensive care, ophthalmology, skin care nursing, thoracic medicine, gastroenterology, gynaecology, urology, oral medicine, microbiology, dietetics, physiotherapy and pharmacy.

35. 1. CULPRIT DRUG D/C of the culprit drug is an essential and immediate intervention. All medicines taken by the patient over the previous 2 months.

36. 2a. care of skin / mucous membrane Detached skin: - Conservative approach: detached epidermis left in situ - Interventional approach: detached epidermis removed - Topical antibiotic ointment - only on sloughy / crusted areas - Silicone dressing of denuded skin, above which absorbent non-adherent dressing (to collect exudate and protect lesional skin) Intact skin: Gentle irrigation with warm saline water / chlorhexidine (1/5000) Whole skin: Frequent application of 50/50 WSP / LP (aerosolized formulation)

37. 2a. care of skin / mucous membrane Eye: - Cleaning, lubricant Q2H, antibiotic & steroid E/D - Amniotic membrane transplantation - extensive loss epithelia Mouth: Saline, antiseptic, mucoprotectant, steroid mouthwashs, anti-inflammatory oral rinse, frequent WSP application Uro-genital tract: Catheterization, frequent use of WSP ointment, silicone sheet dressings to eroded areas, TCS with antibiotic activity to non-eroded areas

38. 2B. SUPPORTIVE CARE Fluid replacement: - Parkland: IV crystalloid (RL) at 4 ml/kg / %BSA in first 24 hours. - Delivery of half the volume is in the first 8 hours, and the remaining volume given over the next 16 hours. - Urine output maintained at 0.5 ml / kg / hour Nutrition: - Enteral > parenteral nutrition - Naso-gastric feeding with silicone tube (20-25 kcal/kg/day) Analgesia: - Simple analgesia (+ opiates if needed) - 0.1 mg / kg morphine IV before dressing change / repositioning

39. 2B. SUPPORTIVE CARE Additional supportive medications: - rG-CSF (to resist infections) - PPI (for gastric protection) - LMWH (for risk of thromboembolism) Monitoring infections: - Blood culture, culture from sloughy / crusted sites - Monitor O2 saturation, urine output hypotension - No prophylactic antibiotics (can↑skin colonization)

40. 3. SPECIFIC THERAPY IVIG MOA: IG inhibits Fas-FasL interaction & thereby keratinocyte apoptosis (anti-Fas activity) Dose: ≥3 g/kg/day for 1 cycle Systemic corticosteroids MOA: switches off inflammation when used early Disadvantage: Risk of sepsis & delayed re-epithelialization IV Methylprednisolone 2 to 2.5 mg/kg daily in divided doses Ciclosporin MOA: Inhibits lymphocyte function 3 mg / kg / day

41. DISEASE COURSE & PROGNOSIS Acute phase increases over the first 5–7 days, then re‐epithelialization starts, heals by 2-3 weeks. In sepsis / systemic complications / culprit drug not removed - delayed would healing. Overall mortality: 22% Cause of death: septicaemia‐induced multiorgan failure.

42. DRESS

43. DEFINITION Idiosyncratic multisystem drug hypersensitivity disorder Characterized by skin rash plus Systemic upset (haematological and solid‐organ disturbances)

44. EPIDEMIOLOGY 1 in 1000 to 1 in 10 000 Average: 48 years Females > males

45. etiology Drug + infection (HHV‐6 [M/I], CMV, Epstein–Barr Virus (EBV) and HHV‐7) Genes: - HLA‐B*5701 (abacavir-induced) - HLA‐B*1502 & HLA‐B*3101 (carbamazepine induced; familial)

46. M/C DRUGS CAUSING DRESS

47. PATHOPHYSIOLOGY Haptenization theory - immunologically neutral molecule (drug) is rendered antigenic when bound to a protein. p‐i concept - pharmacological interaction of drugs with the immune receptor (MHC). Persistence of viral reactivation explains the ‘chronic’ phase of DRESS.

48. CLINICAL FEATURES - skin Latency: 2 - 6 weeks (up to 3 months) Prodrome: asthenia, malaise and fatigue, fever Head and neck edema (important finding) Rash (4 types): 1. Urticarial papular exanthem 2. Morbilliform erythema 3. Exfoliative erythroderma 4. EM-like reaction

49. Most common clinical phenotype is widespread papules and plaques accompanied by cutaneous oedema.

50. Morbilliform eruption

51. Widespread exfoliative erythema

52. Erythema multiforme‐like phenotype

53. CLINICAL FEATURES - mucous membrane Mucous membrane involvement is rare (should call the diagnosis of DRESS into question) But cheilitis - common finding.

54. CLINICAL FEATURES - systemic Lymphadenopathy in at least two sites Liver -hepatocellular and obstructive patterns of hepatitis (M/I: phenytoin, minocycline and dapsone) Renal dysfunction (M/I: allopurinol) Cardiac: pericarditis and myocarditis GI: Bloody diarrhoea, oesophagitis Endocrine: Thyroid dysfunction, type 1 diabetes Lungs: pleural effusion, pleuritis or acute interstitial pneumonitis CNS: headache, seizures, cranial nerve palsies

55. DRESS OVERLAP SYNDROMES DRESS-overlap syndromes: SJS/TEN–DRESS and AGEP– DRESS

56. DIFFERENTIAL DIAGNOSIS Sepsis/infection Other SCAR syndromes (AGEP, SJS/TEN)

57. diagnostic criteria (RegiSCAR) Hepatitis A, B and C Mycoplasma/ chlamydia Antinuclear antibody <2 points: no case; 2–3 points: possible case; 4–5 points: probable case; >5 points: definite case.

58. POOR PROGNOSTIC MARKERS Blood markers: eosinophilia, pancytopenia and thrombocytopenia, lymphocytosis, raised ferritin and creatinine. Clinical markers: atypical targets [EM-like], purpura, tachypnoea, tachycardia, coagulopathy and gastrointestinal bleeding. High‐notoriety drugs (allopurinol and minocycline) may confer a higher risk of more severe hepatic involvement.

59. COMPLICATIONS Fulminant liver failure - most serious and M/C cause of death Interstitial nephritis Thyroid dysfunction Myocarditis Autoimmune phenomena may arise following DRESS (AA, SLE, Hashimoto) Protracted clinical course: chronic exfoliative dermatitis

60. INVESTIGATIONS

61. INVESTIGATIONS

62. SKIN BIOPSY Basal cell vacuolation, and several necrotic keratinocytes (EM like changes)

63. TREATMENT Identify and remove offending drug. Supportive care (intravenous fluids, thermoregulation, catheterization, supplemental oxygen) Surveillance for coexisting infection Management of organ-specific involvement sought from appropriate specialties.

64. TREATMENT - SPECIFIC First line: Oral prednisolone of 1 mg/kg/day with a tapering‐off period varying from 1 to 3 months. Second line: Ciclosporin, IVIG (due to fall in endogenous immunoglobulins seen in DRESS, which causes viral reactivation) Third line: Plasmapharesis, rituxumab, N‐acetylcysteine (in severe liver involvement)

65. DISEASE COURSE & PROGNOSIS Majority will recover fully, following withdrawal of the culprit drug and management of the acute episode. Organ‐specific chronic sequelae may arise after the acute phase. Number of autoimmune phenomena can arise after the acute phase.

66. AGEP

67. DEFINITION One of the SCAR syndromes Characterized by the rapid appearance of sheets of non‐follicular sterile pustules Usually localized to the major flexures Rapid in both onset and resolution Self‐limiting phenomenon

68. EPIDEMIOLOGY 1–5 per million per year Adult females

69. etiology Drug - 90% Non-drug - 10% Infections: Mycoplasma pneumoniae, coxsackievirus, parvovirus B19 and cytomegalovirus Others: Mercury exposure and spider bites

70. M/C DRUGS CAUSING AGEP

71. PATHOPHYSIOLOGY Drug‐specific CD4+ and CD8+ cell response High level of CXCL8 production IL-8 - neutrophil‐attracting chemokine IL36RN gene mutation

72. CLINICAL FEATURES - mucocutaneous Latency: 2-5 days Prodrome: burning or itching in the skin Rash: Sheets of hundreds of sterile non‐follicular pustules on a background of oedematous erythema in major flexures such as the neck, axillae and inframammary and inguinal folds. Other types: atypical targets, purpura, blisters and vesicles. Mucous membrane - rare, mild.

73. Sheets of sterile non‐follicular pustules on the arm.

74. Pustules with erythema at the knee flexure.

75. Eruption resolving with postpustular desquamation.

76. CLINICAL FEATURES - SYSTEMIC Fever Neutrophilia Agranulocytosis Hepatic, renal and pulmonary dysfunction Resolves rapidly, within days, leaving postpustular desquamation

77. differential diagnosis Pustular psoriasis (Von Zumbusch) Subcorneal pustular dermatosis (flaccid pustules with hypopyon sign) DRESS (pustules will be less numerous, has more chance of systemic involvement) Candida infection (detection of yeast on microbiological samples)

78. DIAGNOSTIC CRITERIA

79. INVESTIGATIONS Baseline haematological investigations - neutrophilia and eosinophilia Biochemical investigations - renal and liver dysfunction ESR, CRP Septic screen

80. biopsy Marked spongiosis, intraepidermal pustules and vesicles, perivascular infiltrate, perivascular neutrophilic infiltrate, occasional eosinophils, infrequent necrotic keratinocytes.

81. TREATMENT Identify and withdraw culprit drug Supportive care in systemic involvement Oral corticosteroids Emollient - continued through postpustular desquamation phase

82. DISEASE COURSE & PROGNOSIS Has excellent prognosis and resolves quickly with discontinuation of the offending drug. Resolves without sequelae.

83. GED

84. DEFINITION Drug induced Generalized Exfoliative Dermatitis (GED) SCAR syndrome characterized by erythema and scaling affecting more than 90% of the body surface area Incidence: between 5 and 40% of all erythroderma HLA‐B*5801 (allopurinol-induced)

85. M/C DRUGS CAUSING ged

86. PATHOPHYSIOLOGY Increased epidermal turnover Decreased transit time Increased mitotic activity Th1‐ and Th2 response Upregulated of CD62L on keratinocytes (adhesion molecule) - recruits T cells and Langerhan cells

87. CLINICAL FEATURES - cutaneous Latency: Abrupt onset within days Erythroderma due to DRESS - upto 3 months Rash: Generalized scaling, erythema, pruritus

88. CLINICAL FEATURES - systemic Constitutional symptoms such as malaise, hypothermia or fever Lymphadenopathy, organomegaly High‐output cardiac failure.

89. DIFFERENTIAL DIAGNOSIS Other causes of erythroderma

90. investigations Routine investigations Peripheral smear - to r/o Sezary syndrome ESR / CRP Investigations for systemic involvement Patch testing with culprit drug Skin biopsy - to r/o other causes of erythroderma; presence of eosinophils

91. TREATMENT Identification and withdrawal of the offending drug. Supportive management for hypothermia, fluid and electrolyte imbalances and high‐output cardiac failure. Antibiotics for sepsis. Topical and systemic corticosteroids.

92. PROGNOSIS Has the best prognosis and improves with discontinuation of the offending drug.

93. ANAPHYLAXIS

94. DEFINITION Life-threatening acute Type 1 hypersensitivity reaction Rapidly-evolving, generalized, multi-system, allergic reaction. Includes anaphylactic and anaphylactoid reactions. Clinical state and treatment for each reaction are identical.

95. etiology Medications, foods, insect stings, idiopathic.

96. pathophysiology Release of numerous chemical mediators from degranulation of basophils and mast cells following re-exposure to a specific antigen. Histamine - increases vascular permeability, vasodilation leading to hypoperfusion of tissues. Prostaglandin D, leukotrienes, platelet activating factor - bronchoconstriction, cardiac and pulmonary vascular constriction, peripheral vasodilation, increased vascular permeability. TNF-alpha activates neutrophils and increases chemokine synthesis.

97. CLINICAL FEATURES - cutaneous Latency: Within 1 hour Presentation: - Respiratory - breathlessness, tachypnoea, dyspnoea, hoarseness, wheezing, and stridor - Cutaneous - flushing with pruritus and urticaria - CVS - hypotension and shock

98. DIAGNOSIS Clinical, with 2 or more involved systems, even in the absence of airway involvement or hypotension.

99. treatment ABC Inj Adrenaline 0.3 to 0.5 mL of 1:1000 IM (1:10,000 for IV) If requiring multiple injections, continuous infusion of 0.1 mg of 1:10,000 IV given over 5 to 10 minutes to be given. Adjuvants: - Methylprednisolone (80 to 125 mg IV) or hydrocortisone (250 to 500 mg IV) are the accepted treatments during the acute phase, after which oral treatment of prednisone (40 to 60 mg daily or divided twice per day) is continued for 3 to 5 days. - Antihistamines

100. REFERENCES Rooks Textbook of Dermatology Bolognia’s Dermatology Fitzpatrick’s Dermatology McLendon K, Sternard BT. Anaphylaxis. [Updated 2019 Dec 16]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482124/