Drug Hypersensitivity Flashcards
(78 cards)
1
Q
Types of drug reaction
A
- Type A: Expected based on known properties of drug. Most patients get these. Ex, overdose, side effects
- Type B: Rarer, harder to predict side effects. Usually idiosyncratic, genetic, or immunological in nature (drug hypersensitivity refers specifically to immunological)
2
Q
Most DHR involve. . .
A
the skin
3
Q
Certain small molecule drugs are just the right size and shape to . . .
A
. . . bind a specific HLA type of Class I MHC
4
Q
Sulfonamide hypersensitivity syndrome
A
Caused by a polymorphism resulting in slow catalysis by the N-acetyltransferase responsible for acetylating sulfonamide. Makes sulfonamides last longer.
5
Q
Why are β-lactams so immunogenic?
A
Because they are haptens!!!
6
Q
Manifestations of drug rashes
A
- urticaria
- exanthematous
- lichenoid (resembling a lichen)
- bullous
- pustular
7
Q
Common families of drug which cause DHR
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- β-lactams
- NSAIDs
- Anticonvulsants
- Antihypertensives
- Antiretrovirals
8
Q
Furosemide is associated with. . .
A
Type II hypersensitivity reaction against hemidesmosomes resulting in Bullous pemphigoid
9
Q
Cephalosporines and quinolones are associated with. . .
A
Type III hypersensitivity resulting in vasculitis
10
Q
Major mechanisms of Type IV Hypersensitivity
A
11
Q
A
Exanthematous drug reaction
12
Q
A
Steven-Johnson Syndrome aka Toxic Epidermal Necrolysis
13
Q
A
Acute generalized exanthematous pustulosis
14
Q
When making a drug chart, don’t forget to include. . .
A
- Non-perscription drugs
- Herbal medicines
- IV administered drugs
- Supplements
15
Q
Timeframe for EDE development
A
7-10 days, up to 14days; 1 day when it’s a rechallenge
16
Q
Timeframe for DRESS development
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2-6 weeks
17
Q
Timeframe for SJS/TEN development
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4-28 days, sometimes up to 8 weeks
18
Q
Most common drug eruption in hospitalized patients
A
Exanthematous drug reaction
19
Q
Synonyms for EDE
A
Morbilliform drug eruption
Maculopapular drug eruption
20
Q
Symptoms of exanthematous drug reaction
A
- Itchiness/Pruritis
- Generally well-feeling
- No fever or low-grade fever
- erythematous blanching macules and papules, which may coalesce to form larger macules and plaques
21
Q
Pattern of EDE skin lesions
A
- erythematous blanching macules and papules, which may coalesce to form larger macules and plaques
- Typically begins on the trunk and upper extremities and progresses downward
- symmetric
- Mucous membranes are spared
- As it resolves: begins to look dusky, targetoid appearance, post-inflammatory fine desquamation
22
Q
A
EDE
23
Q
Laboratory studies for EDE
A
- WBC may be slightly elevated
- Low-grade eosinophilia
- Liver function tests normal
24
Q
Targetoid appearance
A
two zones of color- a central darker zone and a surrounding lighter zone
25
Resolving EDE
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EDE on H and E
27
What causes EDE?
* NSAIDs
* allopurinol
* anticonvulsants
* antibiotics (β-lactams, sulfonamides, quinolones)
28
EDE differential
* **Viral exanthems:** **history of upper respiratory tract symptoms** and the presence of a **lymphocytosis or lymphopenia** on the white blood cell differential count (as opposed to an eosinophilia) point one towards a viral etiology
* **Measles:** **Pruritic,** starts on head/neck and spreads downwards, **c**ough, **c**oryza, **c**onjunctavitis (**three C's**), **Koplik spots**
* **DRESS**: edematous papules, vesicles, pustules, facial edema
* **SJS**: Initial lesions are painful, necrotic macules and targetoids
29
Treatment of EDE
* Discontinue offending drug (if feasible)
* Mid- to high-potency steroids for itch
* Creams/lotions on affected areas
* Antihistamines for severe itch
30
DRESS is characterized by. . .
* **Drug Reaction with Eosinophilia and Systemic Symptoms**
* Fever (sometimes accompanied by pharyngitis)
* Skin eruption (with facial edema! characteristic)
* Lymphadenopathy
* Hematologic abnormalities (leukocytosis, eosinophilia, atypical lymphocytes)
* Internal organ involvement (Liver, kidney, CNS, lungs, some others reported)
31
Mortality rate of DRESS
~10%
32
Onset and duration of DRESS
2 to 6 weeks after initial drug exposure, cutaneous and visceral involvement may persist for several weeks or months after drug withdrawal, and additional sites of involvement may develop weeks or months later
33
Laboratory workup for DRESS
* complete blood count with differential count, liver and renal panels
* urinalysis
* Further testing is based on the clinical picture for organ involvement
34
Differential for DRESS
* **EDE**: Patients generally well, no fever or organ involvement
* **Acute generalized exanthematous pustulosis (AGEP)**: Abrupt fever and rash, initially widespread erythmateous and edematous plaques, numerous tiny pustules, **no organ involvement**, begins **2-3 days** after drug interaction
* **SJS:** May be confused in cases with bullae. Major difference is the necrosis, look for this to differentiate
* **Viral exanthem**
35
AGEP
* acute generalized exanthematous pustulosis
* Fever
* Rash
* Initially widespread erythematous and edematous plaques
* After hrs to days evoles into widespread tiny pustules
* No internal organ involvement
* 2-3 days after drug encounter
36
Drugs that may trigger AGEP
* Antimicrobials
* Anticonvulsants
* Antimalarials
* Calcium channel blockers
* NSAIDs
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AGEP
38
Diagnosing DRESS
* **Histopathology** may be necessary: when there is prominent edema, bulla formation, skin peeling or tender duskiness to r/o SJS/TEN, or really any severe case. Findings of histopathology for DRESS may vary widely
*
39
Drugs that may cause DRESS
* Aromatic anticonvulsants
* **Sulfonamide** antibiotics
* **NSAIDs**
* **Allopurinol**
* Lamotrigine
* **Dapsone**
* Antiretrovirals
* minocycline
* azathioprine
40
Who is susceptible to DRESS?
* Certain HLA types for certain drugs
* Polymorphisms affecting drug metabolism
*
41
Anticonvulsant hypersensitivity syndrome
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Sulfonamide hypersensitivity syndrome
43
Complications of DRESS
* Reactivation of human herpesvirus 6 2-3 weeks after onset, flares with corticosteroid treatment
* Lasting eosinophilia
* Long term sequelae (may occur months to years later):
* Autoimmune Type 1 Diabetes
* Autoimmune thyroid disease
* Lupus
44
Treatment of DRESS
* Stop the offending drug (unlike EDE, continuing treatment with symptomatic palliation is really not an option, DRESS is much more serious)
* Mark on the patient's chart: Patient should NEVER receive this drug again, AND cross-reacting drugs should NEVER be used
* Oral steroids (course may be prolonged, weeks to months, as difficulty in tapering may be seen often)
* In case of HHV6 reactivation: ganciclovir and IVIG on top of corticosteroids
* Treatment of involved organ symptoms and IVIG to protect from infection during prolonged steroid use
45
Steven-Johnson Syndrome / Toxic Epidermal Necrolysis
* May be life threatening
* Sometimes characterized by extensive detachment of epidermis **and mucosal** epithelia (mucosal involvement an imporatant differential)
* onset of the eruption is reported to be **4 to 28 days** after initial drug ingestion, **rarely up to 8 weeks**
* **Mortality around 30%**
* Malaise and high fever
* prodrome that mimics a viral infection
* Skin pain, rash starting on upper chest and spreading outward, may involve face
* Painful erythematous macules, may appear targetoid, progress to necrotic macules, then detach, may form bullae, denudation
* Scalp is usually spared
46
Denudation
The process of removing the outer later. In skin, loss of epidermis
47
Confirmatory signs for SJS
* **Nikolsky sign**: extension of detachment of necrotic skin on lateral pressure applied to a necrotic free edge of skin
* **Asboe Hansen sign**: lateral extension of the edges of a bulla on downward pressure
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SJS
49
Up-close shot of necrotic SJS
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Early Bullous SJS
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Late bullous SJS
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SJS on hands
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54
In SJS, ___ involvement may preced ___ involvement.
In SJS, **skin** involvement may preced **mucosal** involvement.
55
SJS with orolabial mucosa involvement
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Differential for SJS
* **EDE in resolution phase** (here the macules may look dusky, but they are not actually necrotic). Also no accompanying fever, patient feels generally well
* **Erythema multiforme**: usually associated with infections (herpes simplex virus, most commonly), patients generally feel well and are afebrile, hands, feet, extensor aspects are most involved
* **Staphylococcal scalded skin syndrome**: Many similar features including true necrosis and epidermal detachment, difficult distinction to make clinically. SSSS is usually in younger children or infnants though
57
Diagnosis of SJS
* Histopathology:
* "Jelly roll": Roll necrotic skin around a q-tip, call dermatopathologist to do a frozen section to confirm full thickness necrosis
* Conventional confirmatory biopsy
*
58
SJS on histopathology
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SJS necrosis on histopathology
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The SCORTEN
Prognostic indicator
61
Risk factors for SJS
* Women at higher risk
* Certain HLA types with certain drugs and certain genetic backgrounds
* Often history of other drug eruption makes more likely
* Certain metabolic genotypes/phenotypes (ex, slow acetylators)
62
Drugs which may result in SJS
* Sulfonamides
* aromatic anticonvulsants
* allopurinol
* NSAIDs
* nevirapine
* lamotrigine
63
What causes necrosis in SJS?
1. CTL-mediated killing of keratinocytes
2. NK cell-mediated killing of keratinocytes
3. Fas-FasL-mediated killing of keratinocytes
64
Treatment of SJS
* Identify target drug and cease now and forever
* Transfer to burn unit ICU
* Supportive care (temperature control, protect airway, replace fluids, support nutrition, manage pain, etc)
* IVIG (no proven benefit, but may protect from infection)
* Systemic corticosteroids for at least 3 days
* Cyclosporine
* Etanercept (anti-TNF)
* Treatment of skin lesions (drain bullae, petrolatum application to necrotic skin lesions, absorbent nonadhesive dressings, etc)
* Ophthalmology and Gynecology consults for eye and vaginal/uterine mucosa involvement, even if unsuspected
65
Type II hypersensitivity skin disorders manifest earliest in . . .
. . . **the oral mucosa!!!!**
66
Melanocytes on H and E
Little haloed nuclei in the epidermis. The melanin diffuses into solution during the staining process, hence the white halo.
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68
Acantholysis
When the whole skin "unzips" due to loss of interkeratinocyte connectivity
69
Rituximab
Anti-CD20
Used for basically any B cell disease or malignancy, including type II hypersensitivity disorders like pemphigus or pemphigoid
70
Bullous pemphigoid prodrome
Starts out with hive-like wheel and flare, develops into full bullae
71
Straight lines of small vesicular blisters are pathopneumonic for \_\_\_\_.
Straight lines of small vesicular blisters are pathopneumonic for **poison ivy**.
72
True urticaria lesions last for no more than \_\_\_.
True urticaria lesions last for no more than **24 hours**.
If it lasts for more than a day, it's not a hive! It's not allergic! Could be a precursor to bullous pemphigoid
73
Wheel
A well demarkated, circinate edematous plaque
74
DRESS and TEN are type ___ hypersensitivity
DRESS and TEN are type **IVc (CD8-mediated)** hypersensitivity
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EDE is type ___ hypersensitivity
EDE is type **IVb (Th2-mediated)** hypersensitivity
77
AGEP is type ___ hypersensitivity.
AGEP is type **IVd (Th1-mediated)** hypersensitivity.
78
Pathologic mechanism of TEN
Rampant IFN-g and TNF-a production leads to Fas/FasL expression on keratinocytes and ligand-dependent apoptosis of epidermis
