Drug Eruptions Medical Emergencies with Cutaneous Presentations

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					 Drug Eruptions & Medical
Emergencies with Cutaneous
      Presentations
 Undergraduate Dermatology Programme
            John R Sullivan
      Department of Dermatology
 Sydney South West Area Health Service
    Senior Lecturer (Conjoint UNSW)
    Adverse Drug Reactions
Common
A major reason for hospitalization (5%) and
prolongation of hospital stays
A major cause of patient morbidity &
mortality
A large proportion are cutaneous
Common nuisance eruptions to rare life-
threatening blistering disorders
          Drug Eruptions
Drug eruptions are a drug-induced disease.
They can mimic a range of diseases
– They should be approached as for any medical
  disease or disorder
– There is a differential diagnosis
Some drug eruptions are important because
they may be life threatening
Early recognition of severe reactions and
appropriate action can save lives
Assessing the Patient
                Diagnosis
Morphology
Fever
– Worrisome
– Think of systemic reactions
    Drug hypersensitivity syndrome
    Serum sickness-like reaction
    Stevens-Johnson syndrome
    Toxic Epidermal Necrolysis
              Approach
Diagnosis*
Differential*
Drug exposure
Diagnostic testing
Determine probabilities
*Dermatologist
             Diagnosis
Morphology
Fever
              Diagnosis
Morphology
– Exanthem-like
– Urticarial
– Pustular
– Blistering
– Other
Fever
                    Differential
Exanthem-like
– Drug vs Bug (vs CTD)
– Skin alone vs Systemic reaction e.g.
      Drug Hypersensitivity Syndrome (also known as DRESS: Drug
      rash, eosinophilia & systemic symptoms)
Urticarial
–   Drug vs Bug (vs other)
–   Urticaria vs Urticarial vasculitis
–   Skin alone vs Systemic Reaction e.g.
      Anaphylaxis
      Serum sickness-like reaction (SSLR)
             Male, 42 Years
12 days after starting
celecoxib
Mildly itchy, spotty, red,
slightly raised rash
Began on trunk, spread to
arms and legs, some spots
on hands, feet, palms, and
soles
Otherwise entirely well
(no fever, etc)
                  Male, 42 Years
Diagnosis -
Exanthematous eruption - Simple
Cause - Provisional
 – celecoxib
Differential diagnosis
 – Viral / bacterial infection
 – Drug Hypersensitivity
    Syndrome
 – Connective tissue disease
 – Timing makes these less likely
Causes of drug-exanthems
 – essentially all drugs
     Exanthematous: Simple
The common classic ‘maculopapular’ drug rash =
morbilliform, rubelliform, scarlatiniform
Red spotty changes, flat +/- raised +/- itch
Onset mostly within first 5-14 days of therapy
Otherwise systemically well
Resolution occurs with a change in color from
bright red to a brownish red, sometimes followed
by scaling or desquamation
Rx - antihistamine (cetirazine), cortisone cream
(0.5% betamethasone valerate)
            35 year old woman
Rash
– Exanthem / erythroderma
– Differential Diagnosis?
Associated Fever (39oC)
Internal organ
involvement? Ix’s
–   Liver (LFTs)
–   FBC & diff
–   EUC + Urine analysis
          35 year old woman
Rash
– Diagnosis?
– No good term
Fever
– Fever PLUS exanthem
  suggests
  Hypersensitivity Syndrome
  (DHS/DRESS)
Internal organ
involvement?
– Hepatitis
– Hemolytic anemia
Drug Hypersensitivity Syndrome
           (DHS)
     Triad of:
1.   High fever
2.   Skin eruption
3.   Internal organ involvement
•    Usually occurs during first prolonged
     course of an associated drug
   DHS: Prodrome (sentinel
         symptoms)
Fever
Malaise
Sore throat
Mimics viral URTI
  DHS: Associated eruptions
Exanthematic
Exfoliative or
erythrodermic (>50%)
– +/- nonfollicular
  pustules
Occasionally evolves
into SJS or TEN
– Itch changes to
  tenderness + pain +
  blisters
          Internal Toxicities
Lymphadenopathy
Hepatitis
Nephritis
Pneumonitis
(Pancreatitis - azathioprine)
Haematological (early: atypical lymphocytosis,
neutrophilia; later eosinophilia, cytopenias [red,
white, platelets)
Deaths: colitis, carditis, massive hepatic necrosiis
                                                  Frequency
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                                                    Literature
                                                    Case Series
                                              Frequency




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               An
                 ae
                                                                          Haematologic Changes




                   m
                     ia
                Onset
Typically 1-8 weeks, occasionally months
(esp anticonvulsants & allopurinol)
Recurrence in hours to days on rechallenge
            Implicated Drugs
Aromatic anticonvulsants (phenytoin, phenobarbitone,
carbamazepine), lamotrigine
Sulfonamide antibiotics, dapsone, trimethoprim,
minocycline, metronidazole,
Azathioprine
Abacavir & nevirapine
Allopruinol
  ‘Nonserious’ Simple
Exanthematous Eruption
            No systemic symptoms
            Normal labs
            If therapy important &
            limited therapeutic choice
             – Treating through with close
               vigilance is an option
               (consider specialist referral)
             – If treating through require,
               reliable patient, increase
               vigilance and close follow-up
      ‘Nonserious’ Simple
    Exanthematous Eruption
                        •Facial involvement minimal
                        •NO periorbital / facial edema
                        •NO lympadenopathy


•NO lip, mouth,
 or eye involvement
•Rash spotty,
 NOT confluent
•Peaks in days then
 settles (10-14 days)
              5 year old boy
Rash
– Started out with tender red
  skin
– Now blistering
– Mucous membranes
  involved
– Diagnosis?
Fever
Internal organ problems?
            EM, SJS, and TEN
Erythema multiforme minor
– Post viral, usually herpes simplex
– Distal, 3-ringed targets,
  absence of significant systemic symptoms & mucosal
  involvement
EM major, Stevens-Johnson Syndrome, Toxic
Epidermal Necrolysis
–   Post drug
–   A spectrum of disease
–   Each has mucous membranes involved
–   Main difference is the area of blistering
               5 year old boy
Rash
– 80% of body epidermis
  sloughed
– TEN
High Fever
Internal organ
problems?
– Neutropenia
– Respiratory Distress
  Syndrome requiring
  intubation & ventilation
TEN: Toxic Epidermal Necrolysis
 Rare (~1 per 106 per year)
 Lead to extensive painful full-thickness
 epidermal skin death with blistering and
 sheet-like shedding of >30% of epidermis
 Mortality 20-30%
 Death: sepsis, multi-organ failure, GI bleeds,
 pulmonary emboli
 SJS-TEN: Mucosal Changes
Unrelated to severity
or extent of skin
involvement
Ocular complications
can be devastating
Longterm
complications also
include: dry mouth,
phimosis and vaginal
adhesions
SJS-TEN: Early skin changes
Change from a
previously itchy
exanthematic eruption
to skin pain &
tenderness
Sudden appearance of
dusky ‘purpuric’ tender
skin changes
Early SJS-TEN
         Drug Associations
Delay 5-21/7, occ. up   Aminopenicillins
to 8/52                 Quinolones
(anticonvulsants)       Antiretrovirals
Sulfonamide             (Nevirapine)
antibiotics             Chinese Herbal
Anticonvulsants         Remedies
NSAID                   ‘Interacting’ drugs
Allopurinol             – Valproate
                        – Corticosteroids
     Sulfonamide Antibiotics
              Bioactivation
Sulfonamide                   Sulfonamide hydroxylamine


                                  Aromatic Nitroso Sulfonamide
Non-toxic
Acetylated
Metabolites
       Other detoxification
       mechanisms
                          Drug Hypersensitivity
                           Syndrome, toxicity,
                              teratogenesis
  How Reactive Metabolites
cause immune hypersensitivity
                 Reactive Drug Metabolites
                                               Redox cycling


Binding to                                 Cellular injury
Tissue haptens                  The Danger Signs of cell stress
                   The          Hypothesis
                   Hapten
    Signal 1       Hypothesis                   Signal 2

                 Hypersensitivity Reaction
      Cell damage in SJS/TEN
                    TNF
 Cytotoxic T FasL
Lymphocytes
                                   (Death receptors)


       Other        Mito                  Reactive Drug
    Other                                 Species / ROS
                    (Epithelial cell)
                    Epithelial cell




                                        Apoptosis
 Disease Modifying Interventions
1. Stop associated drug(s) ASAP
   + other drug related issues
2. Management of the dying epidermis
   (toxic)/Wound care/Toxic neutropenia
3. Can we turn off the tissue destruction?
  –   Intravenous gamma-globulin (IVIG)
  –   Cyclosporin
  –   Avoid traditional immunosuppressives
          Associated drugs
Very early cessation improves outcome
– Morbidity & mortality
Drugs with a longer half-life are associated
with a worse outcome
? Role for drug-drug interactions
– e.g. lamotrigine and valproate; phenytoin and
  H2 blockers

         Garcia-Doval I et al, Arch Dermatol, 2000;136:323-7
          15 year old boy
Rash
– Itchy
– Diagnosis?
Fever
Sore joints
          15 year old boy
Rash
Morphology =
Urticarial
– Raised red wheals
– Dermographism
  Pressure sites
– Bizzare shapes
– Lesions NOT fixed
          15 year old boy
Rash
Fever
Sore joints
Drug history
– Cefaclor X 8 days
Diagnosis?
 Serum sickness-like reaction
Rash - Urticarial       Seen with many drugs
                        –   Cefaclor
Fever
                        –   Cefazolin
Arthralgia, arthritis   –   Zyban
NOT same as Serum       –   Griseofulvin
Sickness                –   (Infliximab, Ritixumab)
– Does NOT have renal   Rx symptomatic:
  disease               Antihistamines,
– Is NOT due to serum   paracetamol, topical
                        cortisone
– Is NOT a vasculitis
            Conclusions
Remember to always consider, could this be
a drug reaction
The D’s for approaching a possible drug
reaction
Is this a potentially serious reaction?
              Approach
Diagnosis*
Differential*
Drug exposure
Diagnostic testing
Determine probabilities
*Dermatologist
          Serious Drug Eruptions
When Associated with:
 Systemic Symptoms and/or High Fever?
  – Precede / Co-incide / Follow eruption onset
 Eruption:
  –   Confluent
  –   Associated, periorbital puffiness and/or facial swelling
  –   Tender or Painful Eruption
  –   Mucous membrane Symptoms or Signs e.g. crusting
      and erosion of lips, gritty eyes..
               Erythroderma
Intense widespread
inflammatory skin
involvement associated
with increased turnover
and shedding of epidermal
cells
Red, inflamed, prominently
scaling, +/- fissured skin
+/- serous exudate +/-
oedema
Lymphadenopathy &
hepatosplenomegaly can
be associated
               Erythroderma
In more severe cases the increased nutritional
requirements, electrolyte and fluid shifts,
compromised skin barrier function and impaired
temperature regulation can lead to:
– Hypothermia
– Sepsis
– High output cardiac failure
Can be extremely itchy
– Can have hair fall out
– Ectropion
– Nails thickened and/or shed
Describe Morphology….
  PLUS Complication
     Causes of Erythroderma
Drugs (many fulfill criteria for DHS)
Internal malignancy (especially lymphoma & other
haematologic malignancies)
Cutaneous T-cell Lymphoma
Immunodeficiency (HIV)
Hyperinfested scabies
Dermatitis including, Contact allergy, disseminated stasis
dermatitis and atopic dermatitis
Psoriasis
Pityriasis rubra pilaris
Idiopathic (unknown) ~30%
            Management
Discontinue all unnecessarily and potentially
causal medications
Monitor fluid balance, body temperature,
cardiac function
Maintain skin moisture
Treat secondary infection
Look for other potential causes
Hospital admission and specialist care
       Cutaneous Vasculitis
Inflammation of skin blood vessels
(capillaries, venules, arterioles, lymphatics)
May occur with skin involvement alone or in
conjunction with systemic organ involvement
(systemic vasculitis)
– Kidneys, liver and gastrointestinal tract most
  commonly involved
             Clinical Features
Dependent areas
– Lower limbs
– Buttocks
Erythematous macules
which become tender and
evolve to purpuric papules
+/- haemorrhagic blisters
+/- ulcerate
Some may have urticarial
lesions that burn and sting
instead of itch & resolve
with bruising
                     Causes
Associations Include:
–   Infections / sepsis (bacteria, viruses)
–   Malignancy
–   Connective tissue disease, Henoch-Schonlein purpura,
    polyarteritis nodosa
–   Drugs, Foods
–   Reduced blood flow
–   May be multifactorial e.g. malignancy, neutropenia &
    infection following chemotherapy, treated with CSF’s
    and antibiotics
–   No cause is found in many cases only involving
    dependent areas of the skin
               Management
Investigate causes of vasculitis e.g.
–   Hepatitis and strep serology
–   EPG, IEPG, Cryoglobulins
–   Autoimmune disorders: RF, ANA, ENA,
Assess for systemic involvement especially if
symptoms of fever, malaise, arthralgia, GI upset
– FBC, EUC, LFT, Urine
– ESR, CRP, C’
Skin biopsy with immunofluorescence (fresh lesion
<48hrs old)
Drug Induced PAN
Meningococcal Sepsis
    Embolic versus Vasculitic
With vasculitic lesions /
infarct involving distal
extremities always
consider emboli
including septic
emboli, cholesterol
emboli (AAA) +
cryoglobulinaemia
        Bullous Pemphigoid
Autoimmune blistering disorder
Usually affects elderly
Presents with very itchy tense blisters and/or
urticarial plaques, uncommon to involve mucosa
May be widespread or limited e.g. skin below the
knees
Due to antibodies (IgG) to basement membrane
zone
Skin Biopsy needed for diagnosis:
Immunofluroescence and H & E
Bullous Pemphigoid
Bullous Pemphigoid Histology
               Subepidermal blister
               Lots of eosinophils
Bullous Pemphigoid Direct
  Immunofluorescence
              IgG and C3 along
              Basement Membrane
              Zone
              (Bullous pemphigoid
              antigen I and II)
              Collagen XVII
Bullous Pemphigoid
              Management
Potent topical corticosteroids (e.g. Diprosone,
Elocon) in localised or limited forms or in
conjunction with
Prednisolone 0.5mg/kg until new blisters cease,
then reduce weekly
Tetracyclines - can be used in less severe cases
instead of prednisolone
Steroid sparing immunosuppressives
– Dapsone
– Azathioprine, Methotrexate
Staph Scalded Skin Syndrome
Febrile, irritable infant who
develops a very tender Red skin
that rapidly Blisters & Erodes
producing a burn or scald-like
appearance
Due to epidermolytic toxins A & B
from toxigenic strains of S aureus
(toxins bind to desmosomes
which are responsible for helping
adjacent skin cells adhere to each
other)
Toxin is usually rapidly removed
by renal excretion
  Staph Scalded Skin Syndrome
Thus should normally only
  consider in:
  Young children OR
  Adults with renal failure +/-
  immuno-suppression
  Look for a localized staph
  infection
  Often affects
  institutionalized individuals