Severe cutaneous adverse drug reactions

1. Severe Cutaneous Adverse
Drug Reactions (SCAR)
Dr. S.A. Fareed
16th Aug 2017

2. Scope of The Presentation
• Overview of SCARs
• Definitions of
• Epidemiology
• Clinical Manifestations & Common Culprit Drugs
• Differential diagnosis
• Pathogenesis
• Management

3. • Adverse drug events (ADEs) are defined as any injuries resulting from
medication use, including physical harm, mental harm, or loss of
function
• Medication errors refer to any mistakes occurring in the medication
use process, regardless of whether an injury occurred or whether the
potential for injury was present (Approximately 1 in 100 medication
errors result in an ADE)
• Adverse drug reactions (ADRs) are ADEs that occur due to
pharmacologic properties of the drug. Undesirable clinical
manifestations of a particular drug ; this includes reactions due
to overdose ,predictable side effects and unanticipated adverse
manifestations. WHO definition is Any undesirable effect of a
drug beyond its anticipated therapeutic effects occurring during
clinical use

4. Prevalence 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 rash.
Around 2.5% of the children receiving medication experience drug
rash

5. Risk factors for ADRs
• Women
• Prior history of allergic drug reactions
• Recurrent drug exposure
• HLA type
• Certain disease states
• Drug metabolism
• Atopy
• Medication errors

6. Classifications of ADRs
• Type A reactions
• Type A reactions can affect any individual, given sufficient dose and
exposure, and are predictable from the known pharmacologic
properties of a drug. 85 to 90% of all adverse drug reactions.
• Type B reactions
• These are hypersensitivity reactions that occur in a susceptible
subgroup of patients, have signs and symptoms that are different
from the pharmacologic actions of the drug, and usually cannot be
predicted. 10 to 15% of adverse drug reactions

8. Classifications of ADRs based on immunologic
mechanism involved
• Type I: Immediate in onset and mediated by IgE and mast
cells and/or basophils
• Type II: Delayed in onset and caused by antibody (usually IgG)
mediated cell destruction
• Type III: Delayed in onset and caused by IgG:drug immune complex
deposition and complement activation.
• Type IV: Delayed in onset and T cell-mediated

9. Type I reactions
• reactions require the presence of drug-specific IgE.
• IgE-mediated reactions are dose-dependent.
• intravenously administered medications may cause symptoms in
seconds to minutes, orally administered drugs may cause symptoms
in 3 to 30 minutes if taken on an empty stomach, and in 10 to 60
minutes if taken with food.
• classical wheal and flare are hallmark signs of mast cell degranulation
• Clinical features are urticarial rash, pruritus, flushing, angioedema of
the face, extremities, or laryngeal tissues, wheezing, gastrointestinal
symptoms, and/or hypotension.
• Anaphylaxis is the most severe presentation of an IgE-mediated drug
reaction

10. Utricaria

11. Angioedema

12. Type II reactions
• are uncommon and involve antibody-mediated cell destruction when
drugs bind to surfaces of certain cell types and act as antigens.
• Clinical manifestations require the presence of high titers of
preformed drug-specific IgG (or rarely IgM) antibodies.
• Symptoms usually appear at least five to eight days after exposure,
but may begin after much longer periods of treatment
• usually present as hemolytic anemia, thrombocytopenia, or
neutropenia, since these are the cell types that are most often
affected.

13. Type III reactions
• are mediated by antigen-antibody complexes that precipitate in
various tissues, including blood vessels, joints, and renal glomeruli
• These reactions are uncommon and usually seen in the context of
high-dose, prolonged drug administration, similar to type II reactions.
• Signs and symptoms take one or more weeks to develop after drug
exposure, since significant quantities of antibody are needed to
generate symptoms related to antigen-antibody complexes.
• Re exposure to the same drug can cause a more rapid and severe
recurrence.
• Clinical presentation include serum sickness, Drug-induced
hypersensitivity vasculitis or drug fever.

14. • Type IV reactions
• Involve the activation and expansion of T cells, which requires time,
hence the name delayed type hypersensitivity.
• Reactions involving T cells have prominent skin findings, because the
skin is a repository for an enormous number of T cells.
• Recognized patterns of cutaneous involvement include Contact
dermatitis, Morbilliform eruptions, Severe exfoliative dermatitides,
such as Stevens-Johnson syndrome (SJS ) and toxic epidermal
necrolysis (TEN), drug rash with eosinophilia and systemic symptoms
(DRESS) and Acute generalized exanthematous pustulosis (AGEP).

15. Severe Cutaneous Adverse Drug Reactions
• DRESS
• SJS
• TEN
• AGEP

16. DRESS
(Drug reaction with eosinophilia and systemic symptoms )
• is a rare, potentially life-threatening, drug-induced hypersensitivity
reaction that includes rash, hematologic abnormalities (eosinophilia),
lymphadenopathy, and internal organ involvement.
• Definition: 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) .

17. • Epidemiology
• annual incidence of 0.9/100,000.
• The frequency varies depending upon the type of drug and immune
status of the patient
• The mortality rate for DRESS is 5 to 10 percent
• may occur in children, but most cases occur in adults without sex
predilection
• It ranges from 1 to 5 per 10,000 patients exposed to the
anticonvulsants (CBZ, dNa) , even higher among patients
taking lamotrigine.

18. Etiology and risk factors
• Drug causality is determined as “highly probable” in approximately 80
percent of cases of DRESS and 10 to 20 percent of cases fulfilling the
diagnostic criteria for DRESS, but relationship with a drug cannot be
established.
• Antiepileptic agents ( carbamazepine, lamotrigine, phenytoin,
phenobarbital ) and allopurinol are the most frequent culprit of
DRESS . And sulfasalazine , dapsone , minocycline , and
vancomycin may also induce DRESS
• There is an association between HLA haplotypes and susceptibility to
DRESS.

19. Frequently reported Also reported
Allopurinol Betalactam antibiotics
carbamazepine oxcarbazepine
Lamotrigine telapevir
phenytoin
sulfasalazine
vancomycine
monocycline
Dapsone
sulfamethoxazole

21. Pathogenesis
• A drug-specific immune response and herpesvirus reactivation are key
factors in the pathogenesis of DRESS.
• Two main pathogenetic hypotheses
 DRESS is primarily a drug-specific immune reaction acting as a trigger
of viral reactivation by as yet unknown mechanisms.
(The amplification of regulatory T cells may contribute to virus
reactivation)
 The initial event in DRESS is a clinically inapparent viral reactivation
that induces the expansion of a T cell population cross-reacting with
the drug.

22. Clinical presentations
• Reaction begins two to six weeks after the initiation of the offending
medication.
• Systemic symptoms include fever (38 to 40°C ,malaise, lymphadenopathy,
and symptoms related to visceral involvement.

23. • Liver : 60 to 80% of patients. Hepatomegaly and jaundice, most often
hepatitis is asymptomatic and detected by routine liver function tests
• In the scoring system of the RegiSCAR, liver involvement is defined by
the finding of a serum ALT > 2 times of the upper limit of normal
values and/or ALP > 1.5 times the upper limit of normal values on at
least two different dates.
• LFT abnormalities are generally mild and transient, but severe
impairment of liver function may occur
• Severe hepatitis is responsible for the majority of deaths associated
with DRE

24. • Kidney involvement, manifesting as acute interstitial nephritis, occurs
in 10 to 30 percent of DRESS , most often in those induced
by allopurinol
• Older age and preexisting renal disease may be predisposing factors.
• Renal abnormalities include a moderate increase in creatinine level,
low grade proteinuria, and abnormal urinary sediment with
occasional eosinophils.
• Lungs involvement presents with cough, fever, and
tachypnea/dyspnea.

25. Many other organs can be involved in DRESS
• Heart (eosinophilic myocarditis, pericarditis)
• Gastrointestinal tract (diarrhea, mucosal erosions, bleeding)
• Pancreas (pancreatitis)
• Thyroid (autoimmune thyroiditis)
• Brain (encephalitis, meningitis)
• Muscle (myositis, increase in creatine kinase)
• Peripheral nerves (polyneuritis)
• Eye (uveitis)

26. Skin eruption starts as a morbilliform rash that progresses to a diffuse,
confluent, and infiltrated erythema with follicular accentuation. The
face and upper part of the trunk and extremities are involved initially.
• Facial edema (associated with erythema) develops in approximately
one-half of cases
• Inflammation and pain of mucous membranes is present and usually
involves a single site (most often the mouth or pharynx), and does
not progress to erosion
• The extent of the body surface area (BSA) involvement is an
important marker of disease severity
• In most cases, more than 50 percent of the BSA is erythematous and
In 20 to 30 percent of patients, erythema progresses to exfoliative
dermatitis (diffuse erythema and scaling involving >90 percent of
BSA)

27. • Diffuse erythematous
exanthematous
eruption
• Prominent facial
edematous erythema
• Purpuric eruption

28. Confluent morbilliform
rash with follicular
accentuation

29. Diffuse and confluent
rash in a patient with
DRESS

30. Diffuse , confluent and
infiltrated erythematous
rash in a patient with
DRESS

31. • The skin eruption and visceral involvement generally resolve gradually
after drug withdrawal. The average time to recovery is six to nine
weeks.
• Relapses have been reported concurrently with human herpesvirus 6
reactivation.
• The diagnosis of DRESS is suspected in a patient receiving a drug
treatment who presents with the following signs and symptoms:
1. Skin eruption (morbilliform or diffuse, confluent, and infiltrated)
2. Fever (38 to 40°C [100.4 to 104°F])
3. Facial edema
4. lymph nodes

32. Diagnosis
• the diagnosis is based on the following findings
 History of exposure to a high risk medication in the two to six weeks
before the onset of symptoms
Morbilliform rash progressing to confluent and infiltrated erythema or
exfoliative dermatitis involving >90 percent of the total body surface area
Hematologic abnormalities (eosinophilia >700/microL and/or atypical
lymphocytosis)
Systemic symptoms and organ involvement which may include:
Fever , Facial edema
Enlarged lymph nodes
Abnormal liver , and or renal function tests
Interstitial pneumonia and/or pleural effusion
Myocarditis

33. • European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR)
devised a scoring system based upon clinical features
item present Absent
Fever > 38.5 0 -1
Enlarged LN ( > 1CM at least two side) 1 0
Eosino > 700 or > 10% > 1500 or > 20% 1 2 0
Atypical lymphocyte 1 0
Rash > 50% of BSA 1 0
Rash suggestive (facial oedema, inflitration) 1 0
Skin biopsy suggesting alternating diagnosis -1 0
Organ involvement one two 1 2 0
Disease duration 0 -2
Investigation for alternative cause > done and negative 1 0

34. • If total score
< 2 - DRESS excluded
2-3 - Possible
4-5 – Probable
≥ 6 – Definite DRESS.

35. Investigations
• FBC : eosinophil . 700 microL , lymphocytosis (> 4500), atypical lymphocytes on
peripheral smear also support the diagnosis of DRESS.
• LFT: ALT > twice the upper limit, ALP > 1.5 times upper limit of normal
• Serology for viral studies : Serology for viral hepatitis may be useful in excluding
acute viral hepatitis in patients with abnormal liver function test results.
• RFT : moderate rise in serum creatinine , low grade proteinuria and abnormal
urinary sediment with occasional eosinophils in the UFR
• Skin biopsy: mild spongiosis and a lymphocytic infiltrate in the superficial dermis,
predominantly perivascular, with eosinophils and dermal edema, although not
specific, supports the diagnosis of a drug hypersensitivity reaction
• Testing for herpesvirus infection: The search for active infection with human
herpesvirus ( [EBV], [HHV-6], [HHV-7]) has no or minor impact on treatment of
DRESS. However, testing for EBV, HHV-6, or HHV-7 is performed, since viral
reactivation may be a marker of prolonged course and increased risk of
complications

36. Investigations
• To confirm the diagnosis : FBC, Blood picture, Inflammatory markers,
viral serology ( PCR for HHV6, HHV7 EBV )
• To exclude alternate diagnosis : Blood culture, ANA, serology for
hepatitis, lymph node biopsy.
• To assess the organ involvement
LFT, RFT,UFR, CPK, Troponin, ECG
PT/INR, CT scans, USS of abdomen, biopsies

37. Histology of DRESS
1. Dyskeratosis
2. Basal vacuolation
3. Lymphocyte exocytosis
4. Dermal oedema
5. Superficial perivascular
inflammation

38. Differential diagnosis for DRESS
• SJS/TEN
• AGEP
• HES
• Sezary syndrome
• Acute cutaneous lupus erythromatosus
• Angioimmunoblastic T cell lymphoma

39. Management
• Drug withdrawal and supportive measures .
Identification and prompt withdrawal of the offending drug is the
mainstay of treatment.
Avoidance of introducing new medications
Those with exfoliative dermatitis require fluid, electrolyte, and nutritional
support. Additional measures include a warm and humid environment and
gentle skin care with warm baths/wet dressings and emollient.
• Patients without severe organ involvement
For symptomatic relief of pruritus and skin inflammation - High potency
topical corticosteroids

40. • Patients with severe organ involvement
Liver - withdrawal of the offending drug.
Systemic corticosteroids are of unproven benefit
If Severe hepatocellular injury may evolve to acute liver failure
and the only effective therapy may be liver transplantation
Lung and Kidney - systemic corticosteroids for patients with severe
involvement of the lungs or kidney. Moderate to high dose of systemic
corticosteroids are given until clinical improvement and normalization of
laboratory parameters are obtained and then tapered over the ensuing
8 to 12 weeks. A more rapid tapering may increase the risk of relapse.
The optimal dose and duration of corticosteroid therapy are not known.

41. • Role of antiviral treatments are usually not recommended but they
may be warranted for patients with DRESS in whom virus reactivation
is demonstrated and suspected of contributing to severe
complications ( encephalitis, hemophagocytosis)
• Monitoring of progression of the skin eruption and development of
symptoms related to organ involvement. Laboratory monitoring with
FBC, LFT, RFT
• PROGNOSIS - Most patients with DRESS recover completely in weeks
to months after drug withdrawal. Autoimmune diseases might
develop months or years after the resolution of the drug reaction.
The mortality rate is 5 to 10 percent . The main causes of death are
acute liver failure, multiorgan failure, fulminant myocarditis, or
hemophagocytosis

42. Severe Cutaneous Adverse Drug Reactions
• DRESS
• SJS
• TEN
• AGEP

43. Acute generalized exanthematous pustulosis
(AGEP)
• Its characterized by acute eruption characterized by the development of
numerous nonfollicular sterile pustules on a background of edematous
erythema and The eruption develops within hours or days of drug exposure
and resolves spontaneously in one to two weeks after drug discontinuation.
• Epidemiology
• Incidence is one to five per million per year
• most often affects adults.

44. • Etiology and pathogenesis
• caused by drugs in 90 percent of cases.
• 10 % cases are associated with infections ( parvo B19, CMV, Cosackie B4,
mycoplasma) or cause remains undetermined.
• AGEP is a T cell mediated neutrophilic inflammation involving drug-specific
CD4 + T cells, cytotoxic CD8 + T cells, and inflammatory cytokines and
chemokines.

46. Histopathology
• The histologic hallmark of AGEP is a spongiform subcorneal
and/or intraepidermal pustule and Other features include a marked
edema of the papillary dermis, necrosis of single keratinocytes, and a
superficial, interstitial, and mid-dermal inflammatory infiltrate of
neutrophils with perivascular accentuation

47. Two subcorneal,
intraepidermal pustules with
papillary edema
and a mixed inflammatory
infiltrate of mainly
neutrophils and some
eosinophils.

49. • Clinical features AGEP typically manifests with the rapid development of
dozens to hundreds non-follicular, sterile, pinhead-sized pustules on a
background of edematous erythema with flexural accentuation .
• The eruption usually occurs a few hours to a few days after the
administration of the offending drug
• The eruption generally begins on the face or intertriginous areas and
rapidly extends to the trunk and limbs with a diffuse or patchy distribution
• Involvement of mucous membranes is unusual and, when present, is
limited to erosions of the lips
• During the acute phase, fever above 38°C (100.4°F) and leukocytosis with a
neutrophil count >7000/microL are usually present.
• Eosinophilia, a mild increase in serum transaminases, or a reversible
reduction in the creatinine clearance can be found in some patients

50. • Skin symptoms usually resolve without treatment in one to two
weeks after the discontinuation of the offending drug. The pustular
eruption is followed by desquamation with characteristic collarettes
of scale
• secondary skin infection, hypocalcemia may occur in older or
compromised patients.

51. Diagnosis
• The diagnosis of AGEP is suspected in a patient presenting with an acute,
febrile pustular eruption a few hours or days after starting a drug treatment
• Histologic examination of a skin biopsy is necessary to confirm the diagnosis
and rule out other pustular eruptions
• Clinical and laboratory criteria for the diagnosis of AGEP are as follows:
• Rapid development of a febrile pustular eruption a few hours or days after
beginning a drug treatment
• dozens to hundreds of pinhead-sized, nonfollicular pustules on a background
of edematous erythema
• Leukocytosis with marked neutrophilia (>7000/microL)
• Pustular smear and culture negative for bacteria
• Rapid resolution of the rash after drug discontinuation

52. AGEP

53. AGEP

54. Differential diagnosis

55. Pustular psoriasis

56. Subcorneal pustular dermatosis

57. Pustular vasculitis

58. Investigation
• Patch testing with one or multiple suspected drugs may be useful in
identifying the cause of AGEP
• Patch testing is generally performed four to six weeks after the
disease resolution.
• A positive test can confirm a suspected drug as the cause of AGEP
• However, a negative result does not exclude that a certain drug is the
causative agent

59. Management
• Drug withdrawal and supportive measures
• Symptomatic treatment
 moist dressings and antiseptic solutions may be used for relief of
pruritus and prevention of bacterial superinfection
 In the desquamation phase, emollients may be helpful
 symptomatic relief of pruritus and skin inflammation topical
corticosteroids