m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 6 9 ( 2 0 1 3 ) 3 7 5 e3 8 3

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Review Article

Severe cutaneous adverse drug reactions

Col Rajesh Verma a, Lt Col Biju Vasudevan b,*, Lt Col Vijendran Pragasam b
a
b

Professor & HOD, Department of Dermatology, Command Hospital (Southern Command), Pune 40, India
Classified Specialist, Department of Dermatology, Command Hospital (Southern Command), Pune 40, India

article info

abstract

Article history:

Severe cutaneous drug reactions are one of the commonest medical challenges presenting

Received 3 July 2012

to an emergency room in any hospital. The manifestations range from maculopapular rash

Accepted 1 January 2013

to severe systemic symptoms like renal failure and cardiovascular compromise. Toxic

Available online 17 March 2013

epidermal necrolysis, erythroderma, drug rash with eosinophilia and systemic symptoms,
acute generalised exanthematous pustulosis and drug induced vasculitis are the common

Keywords:

cutaneous drug reactions which can have severe morbidity and even mortality. Careful

Cutaneous drug reaction

history taking of the lag period after drug intake and associated symptoms, along with

Toxic epidermal necrolysis

detailed examination of the skin, mucosa and various systems, help in early diagnosis of

Erythroderma

these reactions. Early stoppage of the incriminating drug, specific therapy including cor-

DRESS

ticosteroids, cyclosporine and intravenous immunoglobulin depending on the case along

Vasculitis

with supportive therapy and local measures help in salvaging most patients. An overview
of these important cutaneous drug reactions along with their management is being
reviewed in this article.
2013, Armed Forces Medical Services (AFMS). All rights reserved.

Introduction
Adverse drug reactions (ADR) are rated as the fifth leading
cause of death among all diseases. Approximately 5e8% of all
hospitalisation worldwide is due to ADR. Cutaneous adverse
drug reactions (CADR) are the commonest ADR (30e45%) and
responsible for about 2% of hospital admissions.1 Approximately 2e7% of these may be severe.2 In India, CADR account
for 2e5% of all inpatients, while it affects 2.6% of outpatients.3
CADRs are defined as undesirable changes in either structure
or functions of skin, the appendages or the mucous membranes due to a drug. They range from minor exanthematous
skin rashes to severe, life threatening ones like Toxic
epidermal necrolysis. It can affect all ages and is a global
phenomenon. Female sex, increasing age, more number of
drugs, immunosuppressed patients and autoimmune

disorders are implicated risk factors. We herein describe the

common severe cutaneous adverse drug reactions (SCAR)
seen in clinical practice. It is important that all medical fraternity be aware of these adverse reactions to correctly
diagnose them at an early stage and prevent complications
and thereby improve morbidity and mortality due to these
conditions.

Toxic epidermal necrolysis [TEN] (Lyells

syndrome)
It is a rare, severe, life threatening idiosyncratic exfoliative
disease involving skin and mucosa and was first described by
Lyell in 1956. It is a part of a spectrum of disorders including
StevenseJohnson syndrome (SJS). SJS is defined as epidermal

* Corresponding author. Tel.: 91 7798225557 (mobile).

E-mail address: [email protected] (B. Vasudevan).
0377-1237/$ e see front matter 2013, Armed Forces Medical Services (AFMS). All rights reserved.
http://dx.doi.org/10.1016/j.mjafi.2013.01.007

376

m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 6 9 ( 2 0 1 3 ) 3 7 5 e3 8 3

detachment < 10%, while SJS/TEN overlap is epidermal

detachment between 10 and 30% and TEN is defined as
epidermal detachment of >30% body surface area. TEN can
start denovo or by progression from SJS. The incidence varies
between 0.4 and 1.2 cases/million/year worldwide with mortality varying between 14% and 70%.4

Aetiology
It is mostly caused by drugs (80e95%). The drugs commonly
implicated are antibacterials, anticonvulsants, non-steroidal
anti-inflammatory drugs and allopurinol [Table 1]. Rarely
infections (especially Mycoplasma pneumonia), graft versus
host disease (GVHD) and vaccinations have been reported to
cause this condition. Risk factors include concomitant Human
immunodeficiency virus (HIV) infection, radiotherapy, lymphomas, leukaemias and systemic lupus erythematosus. HIV
patients are three times more prone to develop TEN compared
to the normal population. Women are more affected than men
for unspecified reasons (61e64%). The mean age for occurrence is 46e63 years.

Pathogenesis
It is an immune mediated, HLA class I restricted drug hypersensitivity reaction. The drugs or its toxic metabolites act as
haptens providing antigenic stimulus. The stimulated cytotoxic CD8 T-cells clonally expand and along with the help of
perforins, granzyme B, granulysins and cytokines (especially
TNFa) mediate the keratinocyte apoptosis leading to
epidermal necrosis.5 TNFa upregulates Fas (death receptors)
on effector cells and Fas ligand (FasL) on the keratinocytes
leading to their interactions: thus amplifying the apoptotic
pathway. Certain specific HLA genotypes have been implicated in TEN caused by carbamazepine and allopurinol,
namely HLA-B1502 (in Han Chinese/Asian population) and
HLA-B5801 respectively.6 HLA-B*5701 detected in abacavir
hypersensitivity is a recent development.7 People with altered
drug metabolism, especially slow-acetylators, leading to
deficient detoxification of intermediary drug metabolites may
be more prone to develop TEN.

Clinical features
The lag period (period between drug administration and onset
of clinical signs and symptoms) varies from 4 to 28 days

Table 1 e List of drugs commonly causing TEN.

Group
Antibacterials
Anticonvulsants
NSAIDs
ART drugs
ATT drugs
Anti-gout drug
Anti-malarials
Miscellaneous

usually. Rarely does it occur after 8 weeks. There is a prodromal phase (not always) of fever, cough, malaise, rhinitis and
arthralgia followed 2 weeks later by the skin rash. Stinging
sensation inside the eyes, conjunctivitis, oral ulcers,
dysphagia or genital lesions leading to painful micturition
may precede the rash by 1e2 days.
The initial skin rash may be erythematous maculopapular, urticarial, purpuric or targetoid and is specifically
tender [Fig. 1a]. They usually first appear on trunk and rapidly
spread over 3e4 days to involve the face, neck and extremities. The scalp is usually spared and the palms and soles
unlike other drug reactions are not often involved. Later
bullous lesions may develop. The lesions rapidly coalesce and
lead to sheets of skin peeling off [Fig. 1b]. They leave behind
erythematous, oozy, raw lesions which can easily become
infected. The Nikolskys sign is positive i.e gentle lateral
pressure on the normal appearing skin adjacent to the lesions
leads to epidermal separation.
Painful mucous membrane erosions can occur on the lips,
tongue, oral cavity, nasal cavity, pharynx, larynx, conjunctiva,
vagina, urethra, gastrointestinal tract and respiratory tract, if
the process is not halted. Rarely mucous membranes may not
be involved (TEN without spots).
Eye involvement occurs in 80% of patients.8 The gastrointestinal tract (GIT) can be extensively involved. GIT bleeding
and colonic perforation may occur. Upto 30% cases have respiratory involvement.9 Marked hypoxaemia, pneumonia and
sloughing of bronchial epithelium can arise. Other complications include liver function abnormalities, myocarditis, acute
tubular necrosis, glomerulonephritis, acute renal failure and
pulmonary oedema. Sepsis is the commonest cause of mortality and the main pathogens are Staphylococcus aureus and
Pseudomonas. ARDS can also occur.

Residual effects
Once disease progression is controlled the lesions usually heal
without scarring, unless there is secondary infection. Severe
mucous membrane involvement can result in fibrosis and
strictures of the oesophagus, urethra, vagina and anus. 35%
cases have chronic residual eye problems. Dry eyes, photophobia, synechiae and scarring are the common chronic
sequelae. Others include trichiasis, distichiasis, symblepharon, entropion, ankyloblepharon, lagophthalmos,
corneal ulceration leading to perforation and blindness.10
Patients may also have residual xerostomia or keratoconjunctivitis mimicking Sjogrens syndrome.

Differential diagnosis

Drugs
Sulphonamides, penicillins, cephalosporins,
quinolones, vancomycin
Phenytoin, carbamazepine, phenobarbitone,
valproate, lamotrigine
Phenylbutazone, piroxicam, aspirin, diclofenac
Nevirapine, protease inhibitors, abacavir
Isoniazid, ethambutol
Allopurinol
Chloroquine
Chlormezanone

Scalded skin syndrome, pemphigus (esp paraneoplastic) and

acute GVHD.

Assessment of severity
The severity and prognosis of TEN is assessed based on the
SCORTEN scale, first introduced by Bastuji, et al, in 2000.11,12
This scale uses seven independent factors which are as
given in Table 2. The assessment is done within 24 h of
admission of the patient.

m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 6 9 ( 2 0 1 3 ) 3 7 5 e3 8 3

377

Fig. 1 e Clinical presentation in Toxic epidermal necrolysis. (a) Purpuric lesions on face. (b) Peeling off of skin on the back.

Investigations

Treatment

The laboratory investigations are mostly non-specific. On

histopathology, initially there may be satellite cell necrosis
which later progresses to full thickness epidermal necrosis,
resulting in the sub epidermal separation [Fig. 2]. There is a
very sparse papillary dermal mononuclear cell infiltrate.
The definitive diagnosis is reappearance of the clinical
features after rechallenge with the drug. But that should
definitely not be undertaken because of the associated complications and high chances of mortality. Desensitisation is
also not recommended in this situation. Patch tests are not
useful. Lymphocyte transformation tests which measures
proliferation of T lymphocytes in vitro, if done within a week
of appearance of rash is a reliable technique to demonstrate
the causative agent.13 The in vitro lymphocyte toxicity assay
which measures activity of detoxification enzymes is a reliable test for research purposes.14

Though several treatment protocols exist, none have been

formalised by randomised controlled trials. The burns unit is
the ideal set up for management and if not available, the ICU.
Prompt and early diagnosis is the key to management as
disease progression can be prevented and complications can
be restricted. All specific treatment modalities also are successful only if started at the earliest sign of the disease. There
are three cornerstones for therapy namely (1) early withdrawal/elimination of drug (2) supportive therapy and (3)
specific therapy

Table 2 e SCORTEN assessment.

Factor

Score 0

Score 1

Age
% of BSA with epidermal detachment
Heart rate
Presence of malignancy
Blood urea nitrogen
Blood glucose (random)
Serum bicarbonate
Total

40 yrs
10%
120
No
28 mg/dl
252 mg/dl
20 mEq/L
0 points

>40 yrs
>10%
>120
Yes
>28 mg/dl
>252 mg/dl
>20 mEq/L
7 points

Score
0e1
2
3
4
5

Mortality rate
3%
12%
35%
58%
90%

Fig. 2 e Histopathology of early lesion of Toxic epidermal

necrolysis revealing spongiosis, basal cell vacuolisation
and satellite cell necrosis progressing to partial thickness
epidermal necrosis.[H & E stain e 403].

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m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 6 9 ( 2 0 1 3 ) 3 7 5 e3 8 3

Table 3 e General supportive therapy in TEN.

Factor
Prevent trauma to skin
Prevent hypothermia
Provide pain relief
Prevent infection

Nutrition

Fluid requirement

Supportive measures
1.
1.
2.
1.
1.
2.
3.
4.
5.
6.
7.
1.
2.
3.
1.
2.

Air fluidised beds e also prevents bed sores

Maintaining ambient temperature (30e32  C)
Warmed fluids
Adequate analgesia, anxiolytics (morphine, diazepam)
Repeated cultures from lesions and sites of catheters
Topical antibiotics and antibiotic dressings
Avoid invasive techniques e Use peripheral wide bore IV access and avoid central line whenever possible
Prophylactic antibiotics not indicated
Use antibiotics in culture proven sepsis, neutropenia or increase in single strain bacterial counts on swabs
Antibiotics given at higher doses than usual in view of large protein loss
Reverse isolation techniques of nursing
Early and continuous enteral nutrition reduces risk of stress ulcer
Albumin infusions if serum albumin is low
Calories e 1500 calories over first 24 h and increased gradually by 500 calories to about 3500e4000 calories/day
2/3rd of that of burns patients
4e6 L/day in the first few days when >35e40% BSA is affected. 0.5% NaCl is the fluid of choice

1. Elimination of drug e Prompt drug withdrawal is the most

important factor in limiting damage caused by the drug.
Studies claim a reduction of mortality from 26% to 5% in
drugs with short half-life (<24 h), if drug is withdrawn on
first appearance of skin lesions.15 Removal of both drug and
inducing cytokines by plasmaphaeresis is another method
of restricting progression of disease. Other filtration
methods like dialysis and other extracorporeal blood
purification techniques are useful especially in long acting
drugs. Another important mortality predictor is the time
interval between initial skin rash and admission to a specialised centre. It has been seen that 100% patients
admitted within 5 days of onset of symptoms survive, but
mortality increases with every passing day of delay.16
2. Supportive care
a. Dressings e Bland dressings like petrolatum gauze
are usually preferred. Biobrane, a temporary semisynthetic skin substitute dressing is associated with
reduced pain, decreased fluid loss and faster reepithelialisation.17 Biologic dressings like porcine
xenografts or human skin allografts can also be
used. Silver nitrate impregnated gauzes along with
topical antibiotics have been found to cover wounds
without risk of immune reactions and found to

maintain the moist wound environment, speeding up

re-epithelialisation and decreasing chance of infection. White petrolatum is ideal for lips while chlorhexidine mouth washes help in maintaining good oral
hygiene and preventing secondary infection. It is recommended that all intravenous and other invasive
lines be sutured at site without applying adhesive
tapes to prevent further skin damage.
b. Rest of the supportive therapy is as given in Tables 3
and 4.
3. Specific therapy e As the process is mainly considered to be
immunological, immunosuppressants are the specific
treatments available.
a. Corticosteroids e Nothing is more controversial than
the use of systemic corticosteroids in TEN.18 Few reports have shown improvement with steroid use19;
however, others show better prognosis in patients
treated without steroids compared to those treated
with steroids.20 Steroids have beneficial immunosuppressive, anti-inflammatory and antiapoptotic effects.
Their use is however risky due to increased chances of
severe infections, GI ulcers, prolonged wound healing
and masking of early signs of sepsis. If at all they are to
be used, they have to be started within first 48 h of

Table 4 e Systemic support therapy in TEN.

Factor
Care of the eye

Respiratory system
GI tract

Protective measures
1.
2.
3.
4.
5.

Use of glass rods daily for sweeping the fornices to break the forming adhesions
Lubricants, topical antibiotics and steroids should be used judiciously
Topical preparation similar pharmacologically to the incriminated drug should not be given
Amniotic membrane transplants- for damaged surfaces
Topical bevacizumab (humanised IgG monoclonal antibody) which binds to vascular endothelial growth
factor e for preventing chronic sequelae
6. Soft contact lenses e for persistent corneal defects
1. Use of aerosols and physiotherapy to prevent pneumonitis
2. If trachea and bronchi get involved e intubation and finally mechanical ventilation
Antacids e reduce chances of GI bleeding

m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 6 9 ( 2 0 1 3 ) 3 7 5 e3 8 3

appearance of rash and withdrawn in a total of 3e5

days.21 Short term supra-pharmacological doses of
steroids like Dexamethasone 1.5e2 mg/kg IV for 3
consecutive days and methylprednisolone are better
than prolonged dose of oral corticosteroids.
b. Cyclosporine e It is presently the drug found to have
maximum benefits in treatment of TEN. Its strong
immunosuppressive action by blocking T cell activation and tumour necrosis factor alpha (TNFa), as also
the antiapoptotic effect are probably the reason for its
increased benefits. The time taken to arrest disease
progression is 24e36 h and complete re-epithelialisation is also found to be faster.22 Doses of 3e5 mg/kg
daily IV or oral for a duration of 8e24 days (till reepithelialisation) followed by weaning off the dose in
another 2 weeks is recommended.23
c. Intravenous immunoglobulin (IVIG) e It blocks
FaseFasL interactions between effector cells and keratinocytes and prevents apoptosis of keratinocytes.
There are studies which report reduced mortality with
use of IVIg,24 but also reports which say that they do
not improve outcome.25 Despite these conflicting
reports, many clinicians worldwide are still using IVIg
as a first line treatment based on clinical and laboratorial evidence and also because of the good safety
profile. In patients where the disease is progressing, it
is advocated to use IVIg for halting progression and to
speed up re-epithelialisation. Doses of 0.2e0.75 g/kg
daily for 4 days is recommended, with the higher doses
being preferred nowadays. They should be avoided in
cases of renal insufficiency, cardiac abnormalities,
patients with risk of thromboembolism and in IgA
deficiency. They are the drugs of choice when TEN
occurs in HIV patients.
d. Other therapies e Cyclophosphamide, Infliximab,26 N
acetyl cysteine, Pentoxyphylline, Oral Zinc, Granulocyte colony stimulating factor (G-CSF) and many
other drugs have been tried in various studies,
though no concrete evidence for their use has been
proposed.

379

[Fig. 3]. Pruritus, lymphadenopathy, hepatosplenomegaly,

pedal and facial oedema, hypothermia, pneumonia, fluid,
protein and electrolyte loss and infection can occur. Basal
metabolic rate is usually high with increased catabolism. The
excessive protein loss by means of scaling and leakage through
skin, increased plasma volume causing haemodilution and
hypermetabolism, all contribute towards hypoalbuminemia
and therefore severe oedema. Increased cutaneous blood flow
leading to high output cardiac failure is a dreaded complication. The nails may be thick, dry, lustreless, and show ridging.
The rash takes 4e6 weeks to resolve even after withdrawal of
drug.
Common lab abnormalities are anaemia, leucocytosis
with eosinophilia, increased erythrocyte sedimentation rate,
decreased serum albumin levels and increased uric acid
levels. Increased IgE levels may be there. Biopsy reports are
nonspecific including hyperkeratosis, parakeratosis, acanthosis along with a chronic mainly perivascular inflammatory
infiltrate with few eosinophils [Fig. 4].
Emollients, maintenance of fluid and electrolyte balance,
nutritious protein-rich diet, and antihistamines for pruritus
are advised. Local skin care measures such as starch baths
and wet dressings for crusted sites followed by the application of bland emollients and low-potency corticosteroids are
in order. Secondary infections should be treated with antibiotics. The patient should be placed in a regulated environmental temperature to avoid cooling and overheating.
Systemic steroids are required when conservative therapy is
ineffective.

Drug induced erythroderma

It is characterised by widespread, generalised erythema and
desquamation extending to >90% of BSA. Compared to other
causes of erythroderma, the drug induced cases are sudden
in onset, rapidly progressive, and resolve faster.27 Drugs
commonly incriminated are sulphonamides, penicillin,
isoniazid, antimalarials, allopurinol, phenytoin, omeprazole,
captopril and vancomycin. Drug induced erythroderma is
seen twice more often in males than in females and is definitely more common among elderly.
The complex interaction between cytokines and cellular
adhesion molecules results in highly increased epidermal
turnover leading to reduced transit time of keratinocytes
through epidermis causing loss of cellular material from the
surface.
Lag period is 1e2 weeks. It begins as erythema and exudation in the flexures and progresses to generalised scaling

Fig. 3 e Extensive exfoliation of the skin in erythroderma.

380

m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 6 9 ( 2 0 1 3 ) 3 7 5 e3 8 3

Fig. 4 e Histopathology of drug induced erythroderma

revealing parakeratosis, hyperkeratosis and perivascular
dermal infiltrate. [H & E stain e 103].

Drug rash with eosinophilia and systemic

symptoms (DRESS)
Also called Drug hypersensitivity syndrome (DHS) or drug
induced delayed multiorgan hypersensitivity syndrome
(DIDMOHS), it is another severe idiosyncratic drug reaction
associated with multiorgan involvement. Incidence of DHS is
1/1000e1/10,000 drug exposures. The commonest cause is
anti- convulsants.28 Here cross reaction can occur between all
the aromatic anti- convulsants namely phenytoin, phenobarbitone, carbamazepine and lamotrigine. Other drugs
incriminated include dapsone, sulphonamides, allopurinol,
minocycline, terbinafine, azathioprine, captopril, nevirapine,
abacavir and sulfasalazine.29

Pathogenesis
The main pathogenesis in the anticonvulsant hypersensitivity
syndrome is the inability to detoxify intermediate drug metabolites and this is genetically determined. However there
may be other immune mechanisms in play which are not yet
fully determined. Reactivation of herpesvirus-6 may occur
during the course of the disease.30

rashes. However they may develop features of erythroderma

or blistering. Initially the face, upper extremities and upper
trunk are involved which generalisation in later stages. Facial
oedema is prominent. Lymphadenopathy is tender with initial
involvement of cervical nodes followed by generalised
lymphadenopathy. Hepatitis is present in about 50% cases.
The involvement can present as mild transaminitis to fulminant hepatic necrosis. It is a high risk factor for mortality.
Kidney (interstitial nephritis) and lungs (pneumonitis) are
involved in 10% cases each. 10% cases also develop hypothyroidism after reaction settles. Severe rhabdomyolysis, myopathy and pancreatitis have also been reported. Mortality is
about 10%.31 The skin rashes and systemic involvement can
last very long.
Differential diagnosis other than lymphomas includes
viral
exanthems,
hypereosinophilic
syndrome
and
pseudolymphomas.
Investigations- Eosinophilia is a prominent diagnostic
feature. Atypical lymphocytes present in the peripheral
blood smear create a diagnostic confusion with lymphomas.
Neutropenia, thrombocytopaenia, agranulocytosis and haemolytic anaemia can occur. Histopathology is nonspecific
with a dense lymphocytic infiltrate in the superficial dermis
associated with dermal oedema. The lymphocyte toxicity
assay is probably the only specific test available for diagnosis.
There are mainly two diagnostic criteria for DHS, the
RegiSCAR and the Japanese. In the RegiSCAR, three out of
5 criteria are required [Table 5] while in the Japanese scale, if
all seven criteria are present, it is a classical DHS and if atleast
5 criteria are present, it is an atypical DHS [Table 6].32

Treatment
Oral Prednisolone in a dose of 1e2 mg/kg is drug of choice, but
it is to be continued for a prolonged period of 2e3 months.
Valproic acid, benzodiazepine and gabapentin are ideal
replacement for drugs causing anticonvulsant hypersensitivity syndrome. Haematological, hepatic and renal parameters
must be monitored. Supportive care with accurate fluid and
electrolyte balance is a must. Topical steroids are helpful for
cutaneous manifestations as are antihistamines. Patient
should not be prescribed the same or related drug. First degree
relatives should be counselled about increased risk. A
lymphocyte toxicity assay can be done for relatives to confirm
increased susceptibility.

Clinical features
A characteristic triad of fever, rash and internal organ
involvement is considered diagnostic. The symptoms develop
2e6 weeks after intake of drug, much later than other drug
reactions. However Dapsone can cause early reactions. When
re-exposed to same drug, the reaction can occur as early as
within 24 h.
The sequence is usually fever followed by skin rash, then
lymphadenopathy, pharyngitis and finally systemic involvement. Fever is high grade, ranging from 38 to 40  C and is
persistent. The skin lesions are in the form of maculopapular

Table 5 e RegiSCAR criteria for DRESS absolute criteria e

1. hospitalisation 2. reaction suspected to be drug related.
Sr no
1
2
3
4

Feature
Acute skin rash
Atleast one internal organ involvement
Lymph node enlargement of atleast 2 sites
One of the following blood count abnormalities
a. Lymphocytosis/lymphopenia
b. Eosinophilia
c. Thrombocytopaenia
Fever > 38  C

m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 6 9 ( 2 0 1 3 ) 3 7 5 e3 8 3

381

Table 6 e Diagnostic features of DRESS: Japanese scale.

Sr
no
1
2
3
4
5

6
7

Feature
Maculopapular rash atleast 3 weeks after starting drug
Clinical symptoms lasting atleast 2 weeks after
discontinuation of drug
Fever > 38  C
Raised LFT (Serum ALT > 100 IU/L)
Abnormal blood counts, atleast one of:
a. WBC count > 11,000/mm3
b. Atypical lymphocytes > 5%
c. Eosinophilia > 1500/mm3
Lymphadenopathy
HHV-6/EBV/CMV reactivation

Acute generalised exanthematous pustulosis

(AGEP)
First described in 1968 by Baker and Ryan, it is characterised
by an acute febrile illness with a rapidly progressive generalised pustular skin eruption. The most striking feature of AGEP
is the short interval between the drug administration and the
onset of the disease.33 The presence of eosinophils in the inflammatory infiltrate is a helpful pointer to a drug cause.
Incidence is 1e5 cases/million/year. The main pathogenesis is
a hypersensitivity reaction. It is postulated that initial vesiculation may be mediated by keratinolytic cytokines like perforins, granzymes and FasL, all produced by the drug specific
CD4 T-cells infiltrating epidermis. These cells further express IL-8, which leads to subsequent infiltration by neutrophils and causes pustule formation. Activation of protein
kinases also induces keratinocyte apoptosis and inflammation through independent signalling pathways. Certain viral
infections like parvovirus are also implicated.34 The drugs
causing AGEP are aminopenicillins, macrolides, quinolones,
terbinafine, carbamazepine, diltiazem and antimalarials.35
The characteristic features of AGEP are:
a. Skin rash- Small non follicular pustules on background of
erythema appearing mainly in folds namely neck, axilla
and groin and also trunk and upper extremities. There is
associated burning sensation and generalised oedema,
especially on face.
b. Fever > 38 appearing on same day of rash
c. Increased neutrophil count
d. Histopathology shows subcorneal pustules, papillary
dermal oedema and perivascular polymorphic infiltrate
[Fig. 5].
e. Spontaneous resolution in <15 days
The lag period is less than 48 h. The disease is usually selflimiting with fever and pustules lasting 7e10 days, followed
later by desquamation. Mucosal involvement is reported in
only 20% cases and is usually restricted to a single mucosa.
Leucocytosis and neutrophilia are present in 90% patients.
Transient renal failure, hepatitis, eosinophilia and hypocalcemia can occur. Patch testing is more informative in AGEP
than in other severe cutaneous reactions. Topical steroids and

Fig. 5 e Histopathology of drug induced AGEP lesion

revealing loss of stratum corneum and subcorneal necrotic
material along with neutrophils. [H & E stain e 403].

oral antihistaminics are the drugs of choice in mild cases.

Systemic corticosteroids and Methotrexate are the preferred
drugs of choice for treatment of severe cases.

Drug induced angioedema

It is a type I hypersensitivity reaction characterised by dermal
and subcutaneous oedema due to increased vascular permeability and fluid leakage secondary to vascular reaction. It can
be accompanied by urticaria. Face (esp eyelids and lips), oral
mucosa, pharynx, larynx and genitalia can also be affected.
When submucosa is also involved, it can be dangerous.
Involvement of the respiratory tract can cause acute respiratory distress and airway obstruction, sometimes even death.
NSAIDs, ACE inhibitors, angiotensin receptor blockers and
penicillins are the commonest drugs implicated.36 It is seen in
various studies that angioedema occurs in approximately
2e10 of every 10,000 naive ACE inhibitor users. The reaction
occurs mostly during first week of therapy, usually within
hours of initial dose, but late reactions can also occur. Pathogenesis is due increased release of bradykinin. H1 antihistaminics are the drugs of choice. However when severe, Oral
or IV corticosteroids along with IM Adrenaline may have to be
administered.

Drug induced vasculitis

Approximately 10% cases of cutaneous vasculitis are drug
induced. It is probably a type III hypersensitivity reaction
(immune complex deposition) of post capillary blood vessels.
In this condition antibodies which are formed against the

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m e d i c a l j o u r n a l a r m e d f o r c e s i n d i a 6 9 ( 2 0 1 3 ) 3 7 5 e3 8 3

drugs (hapten), act on the vascular endothelium and vascular

wall leading to vasculitis. Palpable purpura in lower extremities, hemorrhagic blisters, ulcers, Raynauds and digital necrosis may all occur. Drug induced cutaneous necrotising
vasculitis may also involve internal organs, including the
heart, liver, joints and kidneys with fatal results. It usually
occurs 1e3 weeks after drug intake. The main drugs implicated are NSAIDs, thiazides, aspirin, allopurinol, penicillin,
cephalosporins, propylthiouracil, quinolones and sulphonamides. Most of the cutaneous vasculitis induced by drugs are
leukocytoclastic in morphology. Other forms of vasculitis
which can also be caused by drugs are HenocheSchonlein
purpura, polyarteritis nodosa, Wegeners granulomatosis and
ChurgeStrauss vasculitis. There exists no significant difference in either the clinical presentation or serologic abnormalities or pathologic findings between drug induced and
idiopathic forms of these vasculitides. Drug induced vasculitis
patients show a higher rate of ANCA, ACLA, ANA and antihistone antibodies with low C4 values as compared to idiopathic. Histologically endothelial cell swelling, fibrinoid
necrosis, a neutrophilic infiltrate in and around blood vessels
along with nuclear dust is found [Fig. 6]. Direct immunofluorescence reveals deposits of IgM, C3 and fibrin within and
around capillaries.
Withdrawal of drug is therapeutic in most cases. Antihistamines along with non-steroidal anti-inflammatory drugs
generally reduce the arthralgias and myalgias. Only severe
disease warrant oral corticosteroids.

Table 7 e Assessment of drug causality.

Sr no
1
2

3
4
5

Factors
Duration between beginning of drug usage and onset
of the adverse reaction
Was drug present in the body before the onset of adverse
reaction? Factors considered:
a. Drugs half-life
b. Patients liver and kidney function
Results of prechallenge/rechallenge and dechallenge
Relative risk of drug in causing reactions (updated
literature review of drug reactions to specific drugs)
Other causes for the reaction ruled out

instituting any specific therapy. Other similar looking skin

conditions have to be ruled out. Stop the offending drug and
institute other measures as explained. Patient and first degree
relatives should be counselled to avoid causative and related
drugs. Patients should be advised to carry a card hung around
their necks or in their wallets identifying their drug allergies
and reactions. The causality of adverse drug reaction to a
particular drug can be assessed by mainly two scales: World
Health Organizations ADR probability scale,37 and Naranjos
scale.38 An algorithm to assess drug causality has been
devised which helps in identifying the responsible drug
[Table 7].39

Conclusion
Approach to a patient with SCAR
The first aspect is to have suspicion of possibility of drug
reaction. Any new skin rash in patients with no history of skin
disorders should raise a suspicion. The offending drug has to
be identified quickly. When a patient is on multiple drugs,
careful history taking can usually identify the drug causing
reaction. Prior similar reactions give definitive clues. The
incriminating drug should ideally be identified before

In conclusion, prompt diagnosis, immediate withdrawal of

incriminated drug, early referral to a specialised centre,
aggressive management, good supportive care with fluid and
nutritional support, multidisciplinary team work, and control
of infection are crucial in minimising the morbidity and rate of
mortality.

Conflicts of interest
All authors have none to declare.

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Fig. 6 e Histopathology of drug induced vasculitis revealing

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