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Adverse Cutaneous Drug Reactions – Drug
reaction with eosinophilia and systemic
symptoms(DRESS) ; Acute generalized
Dr.Rohit Kr. Singh
Base Hospital .Lko
Classification of drug reactions
Mechanism of drug reactions
Drug reaction with eosinophilia and systemic features(DRESS)
Acute generalized exanthematous pustulosis(AGEP)
Comparison b/w DRESS,SJS/TEN ,AGEP
Definition of adverse drug reaction:
Undesirable clinical manifestations resulting from
administration of a particular drug ; this includes
reactions due to overdose ,predictable side effects
and unanticipated adverse manifestations.
Skin is the most common site of drug reactions.
Adverse cutaneous drug reactions constitute from 24%
to 29% of all ADRs .
2 – 3 % of all hospitalized patients experience drug rash.
Upto 5 % of all patients on antibiotics experience drug
Around 2.5% of the children receiving medication ( 12 % if
Some facts about prevalence of drug
1. Non –immunological 2. Immunological
Side effects Idiosyncrasy
Non –immunological activation of effector pathways
Exacerbation of disease
Drug induced chromosomal damage
Classification of drug reactions
1. IgE-dependent drug reactions
2. Immune-complex –dependent drug reaction
3. Cytotoxicity –induced reactions
4. Cell – mediated reactions.
Women > men
Elderly patient (>65 yrs)
Obese ( BMI > 30)
Patients with Sjogren’s syndrome
Risk factors for ADRs
Various mechanisms for drug reaction
1. Immune mediated mechanisms
2. Metabolic idiosyncrasies
3. Other mechanisms
Mechanisms of drug reactions
Immediate hypersensitivity 1. Urticaria,
Immune complex disease 1. Cutaneous small vessel vasculitis
2. Serum sickness
3. Lupus erythematosus
1. Allergic contact dermatitis
2. Systemic allergic contact dermatitis
Drug / Reactive drug metabolite
Acts as antigen for the T-cells activation
Drug specific CD4+ and CD8 + T-cells
Recognize drugs through their T-cell receptors in an MHC
Immune mediated mechanism
1. Anti – convulsant hypersensitivity
Slow acetylators 1.Lupus erythematosus
Direct mast cell degranulation Aspirin ,NSAIDS,codeine-or
radiocontrast –induced urticaria
Protein c deficiency (heterozygotes) Warfarin –induced necrosis
Defination: is a severe cutaneous event characterized by a
Triad of :
1. Skin eruptions ,
2. Hematologic abnormalities[hypereosinophilia(80%) and atypical
3. Internal organ involvement( Acute and Late sequelae) .
Heterogenesity of the initial presentation leads to it’s
misdiagnosis as infection .
Drug reaction with eosinophilia and
systemic symptoms (DRESS).
Skin lesions can be :
1. Infiltrated papules(follicular
or non – follicular)
2. Generalized papulopustular
3. Exanthematous rash
4. Exfoliative dermatitis
organ % of patient
Incidence of organ involvment in
Liver damage by eosinophilic
Other features include:
1. Fever(>38 ºcelcius).
2. Lymphadenopathy(benign lymphoid hyperplasia) .
4. Pharyngitis and mucosal involvement
5. Facial oedema ( anticonvulsant induced reactions)
Can occur with 1st exposure to drug.
In case of previous exposure – symptoms develop
within 1 day .
Onset : b/w 3 wks and 2 months.
Probability ranges : 1:1000 to 1:10,000.
Progress to SJS or TEN.
Mortality is about 10%
Progression of the DRESS
Clinical symptoms can worsen even after withdrawal of the
Step by step development of several organ failure.
Late sequel-Encephalitis ,type 1 DM and delayed
hypothyroidism ,SIADH, long after discontinuation of the
Dysfunction in drug metabolism and detoxification
Related to Epoxide Hydroxylase defficiency
Leads to accumulation of toxic metabolite
Trigger immunological response
Pathophysiology of DRESS
Generation of drug specific T-cell recognition
Reactivation of HHV-6,7; EBV, CMV, Hepatitis C virus
A multiorgan T cell response ( TNF-α ,INF -γ ,IL-2)
Increase in IL-5 Eosinophilia
During the acute phase of DRESS ,regulatory Tcells
(T-regs) are expanded and functionally more robust.
In late phase T-regs become functionally defficient as
DRESS resolves ,perhaps allowing for the development
of autoimmune disease.
Intercurrent infection (URTI or UTI) in cases of maculopapular eruption in
58 % of cases.
Transient drug induced hypogammaglobinemia is susceptible individuals
creates an immunological environment that permits viral reactivation.
Compications of the viral reactivation
1. The sequential reactivation of these virus may be responsible for the
delayed onset ,paradoxical worsening of clinical features ,long after
discontinuation of drug.
2. Sodium valproate directly induce HHV-6 replication.
Viral reactivation theory
Most common drugs causing DRESS
Phenytoin Anti-microbial agents
Anticonvulsants Sulphonamides and related drugs
Phenobarbital Sulfonamide antibiotics
Antiretroviral agents Miscellaneous drugs
Other antibacterial agents Traditional chinese medicines
Other Drugs causing DRESS
Cutaneous drug eruption
Eosinophilia > 1500/dl or
Presence of atypical lymphocytes
Adenopathies > 2 cm in a diameter
Hepatitis (transaminases > 2N) or
Interstitial pneumonitis or
Interstitial nephritis or
Proposed criteria of a diagnosis for
drug rash with DRESS(Bocquet et al)
RegiSCAR inclusion criteria for DRESS( 3 required)
2 Reaction suspected to be drug related
3 Acute rash
4 Fever > 38 celcius
5 Lymphadenopathy ( at 2 sites)
6 Internal organ involvement ( at least one )
7 Blood counts abnormality (lymphopenia or lymphocytosis
,eosinophilia , thrombocytopenia)
Japanese consensus group diagnostic criteria for DRESS(7 needed
or first 5 required)
1 Maculo-papular rash after >3 wks of starting of the drug
2 Prolonged clinical symptom 2wk after stopping suspected drug
3 Fever > 38 celcius
4 ALT > 100 U/L (liver or any other organ involvement )
5 Leukocyte abnormality
7 Atypical leukocytosis ( > 5%)
9 HHV-6 reactivation
1. Drug induced pseudolymphoma .
2. Other cutaneous drug reactions with systemic
3. Idiopathic hypereosinophilic syndrome
5. Acute viral infections( EBV,CMV,Hepatitis virus,
At present :
CBC with differential .
Other like – chest x rays etc for systemic investigation.
Baseline thyroid function tests (eg..TSH).
At < 3 weeks
Repeat abnormal tests.
At 3 weeks
Repeat blood work /investigation as clinically warranted.
At 3 months
Review warnings about cross-reacting drugs.
Skin biopsy: if blistering or pustular eruption.
Patch test : specially in case anticonvulsant-induced drug rash.
Investigations for DRESS
Atypical lymphocyte 63 %
Eosinophilia (>1500/dl) 52 %
Lymphocytopenia 45 %
Thrombocytopenia 25 %
Lymphocytosis 25 %
Incidence of hemtologic abnormality in DRESS syndrome
2. Basal vacuolation
3. Lymphocyte exocytosis
4. Dermal oedema
5. Superficial perivascular
Histopathology of DRESS
Stop the offending drug .
General management – hypothermia and fluid loss
Prednisone at dose of 1-2 mg/kg daily if symptoms are
severe ,with a slow taper , often over wks to months.
IVIg dose = 0.4g/kg/day .
Plamapheresis in combination with Rituximab.
Cyclosporine dose = 3-5 mg/kg per day p.o or IV .
Management of DRESS
Continuing management for systemic symptoms
And other organs involved
Def: is characterized by a fever (>38 celcius) and a
cutaneous eruption with non-follicular sterile pustules on
an edematous erythematous background.
Onset of symptoms :
within 2days to 2-3 weeks.
Acute generalized exanthematous
Scarletiniform eruptions starting from intertriginous areas, or face
then spread to trunk and lower limbs.
Burning and itching sensation present.
Multiple small pinhead sized , 5mm non – follicular sterile pustules
arise at the site of the rash.
Mucous membrane is involvement ( 20%) usually mild limited to oral
After 2 weeks – generalized desquamation occurs after pustules
Clinical features of AGEP
Additional skin lesion :
like target lesion
3.Vesicles or blister
No internal organ involvement .
Risk of superinfection can be life threatening in old
and immunocompromised patient.
Lethality is about 1%.
Over all good prognosis.
Progression of AGEP
1.T-cell mediated reaction.
2.Drug – specific CD-4+ T-cells.
IL-8 (CXCL8) produced by keratinocytes
Infiltration of the neutrophils
Other cytokines involved are IL-4,5 ;IFN-γ ;GM-CSF.
3.Viral infections(CMV,EBV) can also trigger the disease.
Pathogenesis of AGEP
Most common offending drugs include
Drugs causing AGEP
Anticonvulsants Beta-lactam antibiotics other antibiotics
CARBAMAZEPINE AMOXYCILLIN/AMPICILLIN CIPROFLOXACIN
PHEYTOIN CEFACLOR DOXYCYCLINE
Antifungal CEFUROXIME ISONIAZIDE
ITRACONAZOLE CEPHALEXIN STREPTOMYCIN
TERBINAFINE PENICILLIN SULPHONAMIDES
Antimalarial agents MACROLIDE other drugs
HYDROXYCHLOROQUINE AZITHROMYCIN ACETAMINOPHEN
CALCIUM CHANNEL BLOCKERS ERYTHROMYCIN ALLOPURINOL
DILTIAZEM SPIRAMYCIN DICLOFENAC
NIFEDIPINE PRISTINAMYCIN MERCURY
Other Drugs causing AGEP
1. Pustular psoriasis
2. Bacterial folliculitis
3. Localized pustular contact dermatitis
4. Dermatophyte infection
5. Pyoderma vegetans
7. Kaposi’s varicelliform eruption
8. Sweet’s syndrome
9. Behcet’s syndrome
10. Infantile chronic acropustulosis
Differential diagnosis of AGEP
AGEP Pustular psoriasis
History of psoriasis Possible Mostly
Duration pattern Predominant in the
Duration of pustules Shorter Longer
Duration of fever Shorter Longer
H/O drug reaction Usual Uncommon
Recent drug administration Very frequent Less frequent
Arthritis Rare 30%
Histology Subcorneal or
Subcorneal and /or intraepiderma
Hematological investigations – Leukocytosis
Eosinophilia in 30% cases
LFT and KFT can be abnormal.
Lymphocyte transformation tests- suggest
involvement of T cells in AGEP.
Re-administration (re-challange) is not advised.
Lab. Diagnosis of AGEP
with some eosinophils and
Histopathology of AGEP
1.PUSTULES Typical 2
2.ERYTHEMA Typical 2
3.DISTRIBUTION Typical 2
Validation Scoring system in AGEP by
EuroSCAR study group
1.MUCOSAL INVOLVEMENT Yes 2
2.ACUTE ONSET (10 days) Yes 0
3.RESOLUTION(15 days) Yes 0
4.FEVER ( 38ºcelcius) Yes 1
5.PMNs (7000/mm3) Yes 1
1.Other disease 0
2.Exocytosis of PMNs 1
3.Subcorneal and/or intraepidermal
non-spongioform or NOS
pustules(s) with papillary edema or
Subcorneal and/or intraepidermal
spongiform or NOS Pustules with
4.Spongiform subcorneal and/or
intraepidermal pustules with
0 No AGEP
1 – 4 Possible
5 – 7 Probable
8 - 12 Definite
Interpretation of the validation score
Stop the offending drug
Systemic steroid can also be given
Severe cases – Infliximab ; etanercept
Cyclosporine dose = 3-5 mg/kg/day.
Management of the AGEP
Clinical sign’s DRESS SJS/TEN AGEP
Onset of eruption 2-6 wks 1-3wks 48 hrs
Duration of eruption Several wks 1-3 wks < 1 wks
Fever +++ +++ +++
Infiltrated papules +++ - ++
Facial edema +++ - ++
Pustules + - +++
Blisters + +++ +
Atypical targets Chelitis +++ Rarely
Mucous membranes +++ +++ Rarely
Lymphadenopathy +++ - +
Other organ involvement +++ +++ +
DRESS SJS/TEN AGEP
pattern of the
LAB. values DRESS SJS/TEN AGEP
Hepatitis +++ + +
Neutrophils Normal or
Eosinophil +++ Normal +
++ - +
The identification of the responsible drug presents as
a major challenge.
Absence of any definitive diagnostic test.
Unpredictable outcome due to some cases due to
More focus on immune – mediated cutaneous drug
reaction that can cause systemic complications.
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