1. Adverse Cutaneous Drug Reactions – Drug
reaction with eosinophilia and systemic
symptoms(DRESS) ; Acute generalized
exanthematous pustulosis(AGEP).
Dr.Rohit Kr. Singh
Resident ,Dermatology
Base Hospital .Lko
2. 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
3. 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
4. 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 .
5. 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
6. Immunological
1. IgE-dependent drug reactions
2. Immune-complex –dependent drug reaction
3. Cytotoxicity –induced reactions
4. Cell – mediated reactions.
7. Women > men
Elderly patient (>65 yrs)
Obese ( BMI > 30)
Inappropriate medications
Immunosuppressed patient
Patients with Sjogren’s syndrome
Antiphospholipid syndrome
Dysthyroidism
Risk factors for ADRs
8. Various mechanisms for drug reaction
1. Immune mediated mechanisms
2. Metabolic idiosyncrasies
3. Other mechanisms
Mechanisms of drug reactions
10. 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
12. Other mechanisms
Direct mast cell degranulation Aspirin ,NSAIDS,codeine-or
radiocontrast –induced urticaria
Protein c deficiency (heterozygotes) Warfarin –induced necrosis
13. 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).
14. Skin lesions can be :
1. Infiltrated papules(follicular
or non – follicular)
2. Generalized papulopustular
3. Exanthematous rash
4. Exfoliative dermatitis
15. 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.
16. Other features include:
1. Fever(>38 ºcelcius).
2. Lymphadenopathy(benign lymphoid hyperplasia) .
3. Malaise
4. Pharyngitis and mucosal involvement
5. Facial oedema ( anticonvulsant induced reactions)
Periorbital edema
17.
18. 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 predisposition
Progress to SJS or TEN.
Mortality is about 10%
19. 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.
20. Dysfunction in drug metabolism and detoxification
Slow acetylators
Related to Epoxide Hydroxylase defficiency
Leads to accumulation of toxic metabolite
ARENE OXIDES
Trigger immunological response
Pathophysiology of DRESS
21. 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
22. 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…
23. 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
24. Most common drugs causing DRESS
Anti-convulsants Sulphonamides
Phenytoin Anti-microbial agents
Carbamazepine Dapsone
Phenobarbital Sulfasalazine
25. Anticonvulsants Sulphonamides and related drugs
Cabamazepine Dapsone
Lamotrigine Sulfasalazine
Phenobarbital Sulfonamide antibiotics
Phenytoin
Antiretroviral agents Miscellaneous drugs
Indinavir Allopurinol
Nevirapine Valdecoxib
Other antibacterial agents Traditional chinese medicines
Minocycline
Nitrofurantoin
vancomycin
Other Drugs causing DRESS
26.
27.
28. 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)
29. 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)
30. 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
31. 1. Drug induced pseudolymphoma .
2. Other cutaneous drug reactions with systemic
features.
3. Idiopathic hypereosinophilic syndrome
4. Lymphoma.
5. Acute viral infections( EBV,CMV,Hepatitis virus,
influenza virus).
Differential diagnosis
32. 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
35. 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 .
Topical steroid.
Antihistamines.
Management of DRESS
36. Continuing management for systemic symptoms
Eye care
Oral care
Pulmonary care
And other organs involved
37. 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)
38. 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
39.
40. Additional skin lesion :
1.Petechial purpura
2.Erythema multiforme
like target lesion
3.Vesicles or blister
Fever.
Malaise.
Lymphadenopathy.
No internal organ involvement .
41. Risk of superinfection can be life threatening in old
and immunocompromised patient.
Lethality is about 1%.
Over all good prognosis.
Progression of AGEP
42. 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
43. Most common offending drugs include
1. Amoxicillin
2. Ampicillin
3. Fluoroquinolones
4. Hyroxychloroquine
5. Terbinafine
6. Sulfonamides
Drugs causing AGEP
46. 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,lymphohisti
ocytic infiltrate
Subcorneal and /or intraepiderma
pustules,papillomatosis,
acanthosis
47. Hematological investigations – Leukocytosis
Neutrophilic(90%)
Eosinophilia in 30% cases
LFT 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
48. Subcorneal or
Intraepidermal pustules
Papillary oedema
Lymphohistiocytic infiltrate
with some eosinophils and
neutrophils
Histopathology of AGEP
52. 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.
53. 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.
54. INTERPRETATION
0 No AGEP
1 – 4 Possible
5 – 7 Probable
8 - 12 Definite
chance of
AGEP
Interpretation of the validation score
55. Stop the offending drug
Supportive treatment
Topical steroid
Antihistamines
Systemic steroid can also be given
Severe cases – Infliximab ; etanercept
Cyclosporine dose = 3-5 mg/kg/day.
Management of the AGEP
58. LAB. values DRESS SJS/TEN AGEP
Hepatitis +++ + +
Neutrophils Normal or
increase
Decrease +++
Eosinophil +++ Normal +
Atypical
lymphocytes
++ - +
59. 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
60. 1. FITZPATRICK’S DERMATOLOGY IN GENERAL MEDICINE
2. ROOK’S TEXTBOOK OF DERMATOLOGY
3. IADVAL TEXTBOOK AND ATLAS OF DERMATOLOGY BY R.G AND
AMEET VALIA
4. DERMATOLOGICAL SIGNS OF INTERNAL DISEASE BY JEAN L
BOLOGNIA
5. COMPREHENSIVE DERMATOLOGIC DRUG THERAPY BY STEPHEN E
. WOLVERTON
6. JOURNAL IN CUTANEOUS PATHOLOGY( EUROPIAN JOURNAL)
7. ARCHIVES JOURNAL( JAMA)
References