This blog post is based on a webinar hosted by Roxanna Daneshjou, MD, PhD, and is geared toward non-dermatologist clinicians, including NPs, and PAs. For upcoming webinars, click here.
Cutaneous drug eruptions may range from mild and self-limited to life-threatening. Approximately 5% of patients on antibiotics or aromatic anticonvulsants will develop a cutaneous eruption and 2% of them will be serious. Patients who are higher risk for drug eruption include those who are immunosuppressed, (eg, those with HIV, systemic lupus erythematosus, lymphoma), the elderly, and certain human leukocyte antigen (HLA) subtypes.
In this post, I introduce my 10-step framework for addressing cutaneous drug eruptions and what clinical findings indicate concern for a more severe reaction.
First, a review of different mechanisms of cutaneous drug-induced reactions:
Immunologic mechanism (unpredictable):
- Type I: IgE-dependent drug reaction (ie, response to COVID vaccine)
- Type II: Cytotoxic drug-induced reactions
- Type III: Immune complex-dependent reactions
- Type IV: Cell-mediated reactions
Non-immunologic mechanisms (sometimes predictable):
- Overdose
- Pharmacologic side effects
- Cumulative toxicity
- Delayed toxicity
- Drug-drug interaction
- Alterations in metabolism
- Exacerbation of disease
Idiosyncratic with a possible immunologic mechanism (we don’t understand why; unpredictable):
- DRESS
- SJS/TEN
- Drug reactions in the setting of HIV infection
- Drug-induced lupus erythematosus
10-step framework for thinking about drug reactions. We’ll dive deeper into each step with case studies below.
1. Sick or not sick?
What kind of emergency situation are we in? Should they be sent to the ED immediately or can we monitor?
Warning signs:
- Appear ill/high fever
- Systemic involvement
- Facial edema
- Blistering, erosions
- Mucosal involvement
- Lesions that are “dusky”
- Nikolsky sign – lateral pressure dislodges layers of skin
- New lab abnormalities – renal, hepatic, elevated eosinophils
2. What is the morphology?
As a dermatologist, I need to know the morphology. For nondermatologists, describe what you see or send a photo. David Harker’s recent blog, “Making Rash Decisions: How Dermatologists Think” or Twitter thread is a great place to start.
3. What is the distribution?
What part of body? It’s important to give a full body exam with any patient coming in with a new drug eruption just to make sure you’ve assessed all the areas. A patient may not realize the rash has spread.
4. Are the mucous membranes involved?
5. What are the associated symptoms?
6. Any extra-cutaneous exam findings?
7. Ask about DRUGS.
8. Ask about over-the-counter drugs and supplements, including drugs recently stopped.
9. What is the timing?
10. What do I need to do for management?
Case 1
A 55-year-old presenting with diffuse rash and fever. The rash is itchy. He also feels like his face is more swollen. Let’s go through our framework.
1. Sick or not sick?
Sick. Concerning features: fever, facial swelling.
2. What is the morphology?
Coalescing erythematous patches and plaques with fine scale.
3. What is the distribution?
Face, trunk, and extremities.
4. Are the mucous membranes involved?
No.
5. What are the associated symptoms?
Pruritus. Fever. Facial swelling.
6. Are there any extracutaneous exam findings?
Face and hands with mild edema. Cervical lymphadenopathy.
7. Ask about DRUGS.
8. Ask about over-the-counter drugs and supplements.
9. What is the timing?
- On simvastatin and lisinopril for 5 years.
- Occasionally takes vitamin D supplement.
- Started allopurinol 4 weeks ago for gout.
Diagnosis: Drug-induced hypersensitivity syndrome (DRESS)
- Milder presentation: rash, eosinophilia, lymphadenopathy. Be aware that the rash can be very subtle.
- Severe presentation: multi-organ dysfunction (mortality ~2%-10%).
- Latency period: 2-6 weeks from drug exposure (can be sooner if previous exposure). Note that symptoms can persist for weeks even after drug is discontinued.
Common offending agents:
- Antiepileptic drugs (carbamazepine, phenytoin, lamotrigine)
- Sulfa-based antimicrobials, (trimethoprim/sulfamethoxazole, sulfasalazine)
- NSAIDs
- Minocycline
- Allopurinol
- Abacavir
10. What do I need to do for management?
If you suspect DRESS:
- CBC with differential with or without peripheral smear (differential = looking for eosinophils; peripheral smear = looking for atypical lymphocytes)
- AST/ALT
- Creatinine, UA
- Low threshold for:
- cardiac evaluation (EKG, echocardiogram)
- pulmonary imaging
- Stop offending agent and put under patient’s allergies.
- Treatment depends on degree of systemic symptoms. Topical steroids for the rash. Organ dysfunction: systemic corticosteroids (eg, prednisone 1-2 mg/kg per day) with SLOW taper and close monitoring of labs during taper (median duration: 50 days).
- Note that some organ involvement is delayed: thyroid disease can be seen 3-6 months after initial presentation.
- Note that there can be cross-reacting medications (such as among anti-epileptic medications).
CASE 2
A 20-year-old woman comes in with this new rash of 2 days duration. It is slightly itchy. She looks well.
1. Sick or not sick?
Patient appears well.
2. What is the morphology?
- Subtle coalescing erythematous patches and papules.
- Coalescing erythematous papules and plaques; “morbilliform.”
3. What is the distribution?
Trunk and extremities. Face not involved.
4. Are mucous membranes involved?
No.
5. What are the associated symptoms?
Mild pruritus. No fever.
6. Any extra-cutaneous exam findings?
No facial or limb edema. No lymphadenopathy.
7. Ask about drugs.
8. Ask about over-the-counter drugs and supplements.
9. What is the timing?
- She has been on birth control for 1 year.
- She started cephaxelin 7 days ago for a UTI.
- She started vitamin C 3 months ago.
Diagnosis: Exanthematous or morbilliform drug eruption
- Most common cutaneous drug eruption (75%-90% of cases).
- Usually 7-14 days after drug exposure (unless previously exposed to the medication).
- Common culprits: antibiotics (penicillins, sulfonamides, cephalosporins), anticonvulsants, NSAIDs, and calcium channel blockers.
- Symptoms include itchiness and occasionally low-grade fever.
- Differential diagnosis: viral exanthem, DRESS syndrome, early Stevens-Johnson syndrome, acute graft-versus-host disease.
10. What do I need to do for management?
- If at all concerned for DRESS syndrome: watch for facial swelling, fevers, lymphadenopathy, get labs – CBC with differential (to assess eosinophils), AST/ALT, Cr, UA.
- Hold unnecessary medications and suspected trigger (note: if suspected medication is absolutely required, can treat through with monitoring).
- Treat symptoms: Antihistamines and topical steroids. Make sure you’re using an appropriate strength: lower potency in face, groin, arm pits; at least medium strength on the rest of the body. Order enough.
Case 3
You admit a 60 year old man to the hospital. He comes in with fever, rhinorrhea, and malaise and a rash. He states his skin “burns.” It also burns upon urination.
1. Sick or not sick?
SICK!
What is the morphology?
- Targetoid macules and patches with central “duskiness” followed by the development of blisters and erosions/ulcerations.
- Dusky coalescing macules with erosions.
- Significant erosions and ulcerations on the lip with crusting.
What is the distribution?
Trunk and extremities. Lips. Penis.
Are mucous membranes involved?
Yes.
What are the associated symptoms?
Fever, rhinorrhea, burning on urination.
Any extracutaneous exam findings?
Involvement of mucous membranes. Rhinorrhea.
Ask about DRUGS.
Ask about over-the-counter drugs and supplements.
What is the timing?
- He has been on simvastatin and amlodipine for years.
- He occasionally takes ibuprofen for headaches.
- He started on phenytoin about 3 weeks ago after new-onset seizures.
Diagnosis: STEVENS-JOHNSON SYNDROME (SJS) / TOXIC EPIDERMAL NECROSIS (TEN)
- Life-threatening condition: Cutaneous and mucous membranes with massive keratinocyte death leading to loss of epidermal barrier.
- Can start with “URI-like” prodrome.
- High risk of secondary infection, fluid/electrolyte shifts, scarring.
- Exists on a spectrum:
- SJS < 10% body surface area (BSA)
- SJS/TEN overlap 10%-30% BSA
- TEN > 30% BSA
- 95% of the time medication associated.
- Timing: 7-21 days (earlier if previously exposed to medication).
- More than 100 drugs have been found to cause it.
- Offenders include: lamotrigine, carbamazepine, phenytoin, phenobarbital, allopurinol, trimethoprim-sulfamethoxazole, cephalosporins, aminopenicillins, quinolones, oxicam non-steroidal anti-inflammatory drugs, nevirapine.
- Mortality: ~5% for SJS, 25-50% for TEN
10. What do I need to do for management?
- Find the medication culprit and stop it.
- Add medication to allergy list.
- Hospital admission (ICU, and in some cases, burn unit if they’ve lost their epidermal barrier).
- Depending on mucous membranes involved; ophthalmology, urology, gynecology, and otolaryngology may all need to be involved.
- Ophthalmology consult FOR SURE due to high rate of ocular scarring.
CASE 4
A 48-year-old with a history of high blood pressure and angina presents complaining of a red rash that started on her face and body folds then spread throughout the body over the past day. She felt that she had a fever as well. Now has noticed “pus bumps” everywhere.
1. Sick or not sick?
Sick, not super sick but borderline.
2. What is the morphology?
Erythematous patches with overlying pustules.
3. What is the distribution?
Particularly on the face and intertriginous areas, but also generalized.
4. Are mucous membranes involved?
No.
5. What are the associated symptoms?
Fever. Some itchiness.
6. Any extra-cutaneous exam findings?
No lymphadenopathy.
7. Ask about DRUGS.
8. Ask about over-the-counter drugs and supplements.
9. What is the timing?
- On simvastatin since 2 years ago.
- Occasional ibuprofen for arthritis.
- Lisinopril for the past 3 years.
- Simvastatin for the past 3 years.
- Started diltiazem 2 days prior to first symptoms.
Diagnosis: Acute generalized exanthematous pustulosis (AGEP)
- Within 1-2 days of drug exposure, skin lesions on the face and intertriginous areas appear that can then generalize to erythroderma and the appearance of non-follicular sterile pustules.
- Need to differentiate from pustular psoriasis (ask psoriasis history).
- Causes include antibiotics, calcium channel blockers (diltiazem in particular), antimalarials, radiocontrast dye, dialysate, and others.
- AGEP/DRESS overlap does exist.
- Patients can also have fever, lymphadenopathy, edema, and rarely mucosal involvement.
10. What do I need to do for management?
- Identify culprit drug and stop it.
- Check labs: CBC with differential (can see leukocytosis, neutrophilia, and eosinophilia, CMP (can see changes in renal function/liver function), calcium (rare cases of hypocalcemia).
- Remember to watch for features of DRESS/AGEP overlap.
- Topical steroids.
About Dr. Daneshjou
Roxana Daneshjou, MD, Ph.D. is a clinical scholar in dermatology at Stanford. She completed her medical school and residency at Stanford. Her interests include equity in dermatology and bias in artificial intelligence.
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