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”.

5. SJS-TEN

6. 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

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

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

9. M/C DRUGS CAUSING SJS/TEN

10. 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.

11. 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

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

13. Purpuric macules coalescing and blistering.

14. Atypical targets on palms
and soles with blistering.

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

16. Confluent erythema with
negligible
blistering/epidermal
detachment.

17. Denuded skin - large areas of exposed dermis.

18. Detached epidermis.

19. 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.

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

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

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

23. DIFFERENTIAL DIAGNOSIS

24. 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.

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

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

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

28. COMPLICATIONS (CONTD.)
‣ M/C life threatening: septicemia
‣ M/C disabling: ocular

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

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

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

32. TESTS NEEDED AT PRESENTATION

33. ‣ 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

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

35. 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

36. 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.

37. 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.

38. 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)

39. 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

40. 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

41. 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)

42. 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

43. 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.

44. DRESS

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

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

47. 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)

48. M/C DRUGS CAUSING DRESS

49. 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.

50. 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

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

52. Morbilliform eruption

53. Widespread exfoliative erythema

54. Erythema multiforme‐like phenotype

55. CLINICAL FEATURES - MUCOUS
MEMBRANE
‣ Mucous membrane involvement is rare (should call the
diagnosis of DRESS into question)
‣ But cheilitis - common finding.

56. 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

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

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

59. 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.

60. 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.

61. 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

62. INVESTIGATIONS

63. INVESTIGATIONS

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

65. 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.

66. 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)

67. 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.

68. AGEP

69. 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

70. EPIDEMIOLOGY
‣ 1–5 per million per year
‣ Adult females

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

72. M/C DRUGS CAUSING AGEP

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

74. 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.

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

76. Pustules with erythema at the knee flexure.

77. Eruption resolving with postpustular desquamation.

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

79. 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)

81. DIAGNOSTIC CRITERIA

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

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

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

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

86. GED

87. 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)

88. M/C DRUGS CAUSING GED

89. 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

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

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

92. DIFFERENTIAL DIAGNOSIS
‣ Other causes of erythroderma

93. 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

94. 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.

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

96. ANAPHYLA
XIS

97. 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.

98. ETIOLOGY
‣ Medications, foods, insect stings, idiopathic.

99. 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.

100. 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

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

102. 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

103. 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/