Adverse Cutaneous Drug Reactions – Drug reaction with eosinophilia and systemic symptoms(DRESS) ; Acute generalized

exanthematous pustulosis(AGEP).

Dr.Rohit Kr. SinghResident ,Dermatology

Base Hospital .Lko

Introduction Classification of drug reactions Risk factors Mechanism of drug reactions Drug reaction with eosinophilia and systemic features(DRESS) Acute generalized exanthematous pustulosis(AGEP) Comparison b/w DRESS,SJS/TEN ,AGEP Conclusion References

Contents

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.

Introduction

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 rash.

Around 2.5% of the children receiving medication ( 12 % if on antibiotics)

Some facts about prevalence of drug reactions .

1. Non –immunological 2. Immunological

Predictable Unpredictable Overdose Intolerance Side effects Idiosyncrasy Cumulation Delayed toxicity Facultative effects Drug interactions Metabolic alterations Teratogenicity Non –immunological activation of effector pathways Exacerbation of disease Drug induced chromosomal damage

Classification of drug reactions

Immunological 1. IgE-dependent drug reactions2. Immune-complex –dependent drug reaction3. Cytotoxicity –induced reactions 4. Cell – mediated reactions.

Women > men Elderly patient (>65 yrs)Obese ( BMI > 30)Inappropriate medicationsImmunosuppressed patient Patients with Sjogren’s syndromeAntiphospholipid syndromeDysthyroidism

Risk factors for ADRs

Various mechanisms for drug reaction1. Immune mediated mechanisms2. Metabolic idiosyncrasies3. Other mechanisms

Mechanisms of drug reactions

Immune mediated

Immediate hypersensitivity

1. Urticaria, 2. Angioedema, 3. Anaphylaxis

Immune complex disease

1. Cutaneous small vessel vasculitis2. Serum sickness3. Lupus erythematosus

Delayed hypersensitivity(cell-mediated immunity)

1. Allergic contact dermatitis2. Systemic allergic contact dermatitis

Drug / Reactive drug metabolite

Hapten

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 dependent way

Immune mediated mechanism

Metabolic idiosyncrasies

Epoxide hydroxylase defficiency

1. Anti – convulsant hypersensitivity syndrome

Slow acetylators 1.Lupus erythematosus

Other mechanisms

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 lymphocytes/mononucleosis (40%)],

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 papulopustular3. Exanthematous rash 4. Exfoliative dermatitis

organ % of patient involvement

Liver 80

Kidney 40

Pulmonary 33

Cardiac(myocarditis)

15

Pancreas 5

Hypothyroidism <5

CNS(encephalitis)

<5

Incidence of organ involvment in DRESS

Liver damage by eosinophilic infiltration.

Other features include:1. Fever(>38 ºcelcius).2. Lymphadenopathy(benign lymphoid hyperplasia) .3. Malaise4. Pharyngitis and mucosal involvement5. Facial oedema ( anticonvulsant induced reactions)

Periorbital edema

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.Genetic predispositionProgress to SJS or TEN.Mortality is about 10%

Progression of the DRESS Clinical symptoms can worsen even after

withdrawal of the offending drug.

Step by step development of several organ failure.

Late sequel-Encephalitis ,type 1 DM and delayed hypothyroidism ,SIADH, long after discontinuation of the drug.

Dysfunction in drug metabolism and detoxification Slow acetylatorsRelated to Epoxide Hydroxylase defficiency

Leads to accumulation of toxic metabolite

ARENE OXIDES

Trigger immunological response

Pathophysiology of DRESS

Generation of drug specific T-cell recognition

Endothelial damage 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.

Cont…

Intercurrent infection (URTI or UTI) in cases of maculopapular eruption in 58 % of cases.

Mechanism

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

Anti-convulsants Sulphonamides Phenytoin Anti-microbial agents Carbamazepine Dapsone Phenobarbital Sulfasalazine

Anticonvulsants Sulphonamides and related drugsCabamazepine DapsoneLamotrigine SulfasalazinePhenobarbital Sulfonamide antibioticsPhenytoin

Antiretroviral agents Miscellaneous drugsIndinavir AllopurinolNevirapine ValdecoxibOther antibacterial agents Traditional chinese medicinesMinocycline Nitrofurantoin vancomycin

Other Drugs causing DRESS

•Toxic metabolites(ARENE OXIDES)•Viral associations like HHV-6 reactivation

Anticonvulsants

•Glutathione def. patientsSulfonamide antibiotics

•Hydroxylamines reactive metabolites•After 4 or more weeksDapsone

•Reactive iminoquinone derivativeMinocycline

•HHV-6 reactivation•HLA-B 5801Allopurinol

•CD-4 status •HLA-B 0101Nevirapine

Cutaneous drug eruption Hematologic abnormalities Eosinophilia > 1500/dl or Presence of atypical lymphocytes Systemic involvement Adenopathies > 2 cm in a diameter Hepatitis (transaminases > 2N) or Interstitial pneumonitis or Interstitial nephritis or Carditis

Proposed criteria of a diagnosis for drug rash with DRESS(Bocquet et al)

RegiSCAR inclusion criteria for DRESS( 3 required)

1 Hospitalization

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

6 Leukocytosis

7 Atypical leukocytosis ( > 5%)

8 Lymphadenopathy

9 HHV-6 reactivation

1. Drug induced pseudolymphoma .2. Other cutaneous drug reactions with

systemic features.3. Idiopathic hypereosinophilic syndrome4. Lymphoma. 5. Acute viral infections( EBV,CMV,Hepatitis

virus, influenza virus).

Differential diagnosis

At present : CBC with differential . LFT. S.creatinine 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 TSH. 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

1. Dyskeratosis 2. Basal vacuolation 3. Lymphocyte exocytosis4. Dermal oedema5. Superficial perivascular inflammation

Histopathology of DRESS

Stop the offending drug .General management – hypothermia and fluid lossPrednisone 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 .Topical steroid. Antihistamines.

Management of DRESS

Continuing management for systemic symptoms Eye care Oral care Pulmonary care 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.

Abrupt onset.

Acute generalized exanthematous pustulosis(AGEP)

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 mucosa.

After 2 weeks – generalized desquamation occurs after pustules subside.

Clinical features of AGEP

Additional skin lesion : 1.Petechial purpura 2.Erythema multiforme like target lesion 3.Vesicles or blister

Fever. Malaise.Lymphadenopathy. 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 neutrophilsOther 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 include1. Amoxicillin 2. Ampicillin 3. Fluoroquinolones4. Hyroxychloroquine 5. Terbinafine6. Sulfonamides

Drugs causing AGEP

Anticonvulsants Beta-lactam antibiotics other antibioticsCARBAMAZEPINE AMOXYCILLIN/AMPICILLIN CIPROFLOXACINPHEYTOIN CEFACLOR DOXYCYCLINEAntifungal CEFUROXIME ISONIAZIDEITRACONAZOLE CEPHALEXIN STREPTOMYCINTERBINAFINE PENICILLIN SULPHONAMIDES

Antimalarial agents MACROLIDE other drugs HYDROXYCHLOROQUINE AZITHROMYCIN ACETAMINOPHEN CALCIUM CHANNEL BLOCKERS ERYTHROMYCIN ALLOPURINOLDILTIAZEM SPIRAMYCIN DICLOFENACNIFEDIPINE PRISTINAMYCIN MERCURY

Other Drugs causing AGEP

1. Pustular psoriasis 2. Bacterial folliculitis3. Localized pustular contact dermatitis4. Dermatophyte infection5. Pyoderma vegetans6. Varicella 7. Kaposi’s varicelliform eruption 8. Sweet’s syndrome9. Behcet’s syndrome10.Infantile chronic acropustulosis

Differential diagnosis of AGEP

AGEP Pustular psoriasis

History of psoriasis Possible Mostly

Duration pattern Predominant in the folds

More generalized

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 intraepidermal pustules,papillary edema,lymphohistiocytic infiltrate

Subcorneal and /or intraepiderma pustules,papillomatosis,acanthosis

Hematological investigations – Leukocytosis Neutrophilic(90%)Eosinophilia in 30% casesLFT and KFT can be abnormal.Patch test Lymphocyte transformation tests- suggest

involvement of T cells in AGEP.Re-administration (re-challange) is not advised.Skin biopsy

Lab. Diagnosis of AGEP

Subcorneal or Intraepidermal pustules Papillary oedema Lymphohistiocytic infiltrate with some eosinophils and neutrophils

Histopathology of AGEP

Contd…

Subcorneal pustule

Diffuse spongiosis

Neutrophilic infiltration

MORPHOLOGY

1.PUSTULES Typical 2

Compatible 1

Insufficient 0

2.ERYTHEMA Typical 2

Compatible 1

insufficient 0

3.DISTRIBUTION Typical 2

Compatible 1

Insufficient 0

Validation Scoring system in AGEP by EuroSCAR study group

A.

4.POST –PUSTULAR DESQUAMATION

Yes 1

No 0

COURSE

1.MUCOSAL INVOLVEMENT

Yes 2

No 0

2.ACUTE ONSET (10 days)

Yes 0

no 2

3.RESOLUTION(15 days)

Yes 0

No 4

4.FEVER ( 38ºcelcius) Yes 1

No 0

5.PMNs (7000/mm3) Yes 1

No 0

B.

HISTOLOGY

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 papillary edema

2

4.Spongiform subcorneal and/or intraepidermal pustules with papillary edema

3

C.

INTERPRETATION

0 No AGEP

1 – 4 Possible

5 – 7 Probable

8 - 12 Definite chance of AGEP

Interpretation of the validation score

Stop the offending drugSupportive treatmentTopical steroid Antihistamines Systemic steroid can also be givenSevere cases – Infliximab ; etanerceptCyclosporine 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

+++ +++ +

Histological pattern

DRESS SJS/TEN AGEP

Histological pattern of the skin

Lymphocytic infiltrate

Epidermal necrolysis

Subcorneal pustules

Histology of lymphnode

Lymphoid hyperplasia ,pseudolymphoma

NA NA

LAB. values DRESS SJS/TEN AGEP

Hepatitis +++ + +

Neutrophils Normal or increase

Decrease +++

Eosinophil +++ Normal +

Atypical lymphocytes

++ - +

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 non-pharmacological additives.More focus on immune – mediated

cutaneous drug reaction that can cause systemic complications.

Conclusion

1. FITZPATRICK’S DERMATOLOGY IN GENERAL MEDICINE2. ROOK’S TEXTBOOK OF DERMATOLOGY 3. IADVAL TEXTBOOK AND ATLAS OF DERMATOLOGY BY R.G AND

AMEET VALIA4. DERMATOLOGICAL SIGNS OF INTERNAL DISEASE BY JEAN L

BOLOGNIA5. COMPREHENSIVE DERMATOLOGIC DRUG THERAPY BY STEPHEN

E . WOLVERTON6. JOURNAL IN CUTANEOUS PATHOLOGY( EUROPIAN JOURNAL)7. ARCHIVES JOURNAL( JAMA)

References

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