1. Acute generalized exanthematous pustulosis
Overview
Acute generalized exanthematous pustulosis (AGEP) is a rare, acute eruption characterized by the development of numerous nonfollicular sterile pin head sized pustules on a background of edematous erythema. AGEP is caused by drugs in approximately 90 percent of cases, and starts within few hours to days.
Presentation
During the acute phase, fever above 38°C (100.4°F), leukocytosis with a neutrophil count >7000/microL, and mild eosinophilia are often present. Severe cases of AGEP may be similar to Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).
Assessment
The diagnosis of AGEP is based upon the clinical presentation and histologic examination of a skin biopsy
Plan
AGEP is a self-limiting disease with a favorable prognosis. Management includes withdrawal of the offending drug, supportive care, and symptomatic treatment.
Prognosis
Skin symptoms usually resolve without treatment in one to two weeks after the discontinuation of the offending drug.
MedDRA PTs
Acute generalized exanthematous pustulosis
Strengtheners
Leukocytosis, neutrophilia, onset within hours or days of exposure to the offending drug, resolution in 1 to 2 weeks after discontinuation of the offending drug, skin biopsy.
Most frequently reported offending drugs include: (Hydroxy-)chloroquine, Aminopenicillins, AmphotericinB, Cephalosporins, Chloramphenicol, Clindamycin, Diaphenylsulfone, Diltiazem, Fluconazole, Gentamicin, Griseofulvin, Isoniazid, Itraconazole, Ketoconazole, Lincomycin, Macrolides, Metronidazole, Nifuroxazide, Nystatin,Protease inhibitors, Pyrimethamine, Quinolones, Telavancin, Terbinafine, Tetracyclines, Trimethoprim/sulfamethoxazole, Vancomycin
Disqualifiers
Generalized acute pustular psoriasis (von Zumbusch type), SJS, TEN, Subcorneal pustular dermatosis (Sneddon-Wilkinson disease), DRESS, Bullous impetigo (all on day of index date)
2. Stevens-Johnson Syndrome-Toxic Epidermo necrolysis composite
Overview
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe mucocutaneous reactions, most triggered by medications. They are characterized by extensive necrosis and detachment of the epidermis. Mucous membranes are affected in over 90 percent of patients. SJS and TEN are considered a disease continuum and are distinguished by severity. SJS is the less severe condition, in which skin detachment is <10 percent of the body surface. TEN involves detachment of >30 percent of the body surface area. Incidence is higher in patients with HIV infection or active cancer than in the general population.
Presentation
Acute phase is 8-12 days, with persistent fever, severe mucous membrane involvement, and epidermal sloughing.
Assessment
Anemia and lymphopenia are common, while eosinophilia is unusual. Skin biopsy, positive Nikolsky sign, SCORTE score, bacterial and fungal cultures from blood, wounds, and mucosal lesions. Chest Xray. PCR or serologies for M. pneumoniae in children.
Plan
Patients suspected of having SJS/TEN require immediate in-hospital evaluation. Prompt identification and withdrawal of the offending agent. Acute management includes wound care and supportive care (fluid/electrolyte), pain control, nutrition,
Prognosis
Re-epithelialization may begin after several days and typically requires two to four weeks. Skin that remained attached during the acute process may peel gradually, and nails may be shed. In severe cases with extensive skin detachment, acute complications may include massive loss of fluids through the denuded skin, electrolyte imbalance, hypovolemic shock with renal failure, bacteremia, insulin resistance, hypercatabolic state, and multiple organ dysfunction syndrome.
MedDRA PTs
Stevens-Johnson syndrome
Disqualifiers
Mycoplasma pneumoniae infection (children) short term before index date
Strengtheners
Most frequently offending drugs initiated short term (1-4 weeks) before index date - Allopurinol, aromatic antiseizure medications, lamotrigine, antibacterial sulfonamides (including sulfasalazine), nevirapine, oxicam nonsteroidal anti-inflammatory drugs (NSAIDs); in children: Sulfonamide antimicrobials, phenobarbital, carbamazepine, and lamotrigine
Offending drug initiated short term (1-4 weeks) before index date, transfer to specialized centers (dermatology units, burn centers), concurrent HIV infection, active malignancy (in particular hematologic malignancies), systemic lupus erythematosus (all on day of index date)
3. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
Overview
Severe drug adverse reaction that occurs usually after a latent period (T cell-mediated hypersensitivity reaction) of 2 to 8 weeks with skin and visceral organ involvement (at least one organ is involved in 90% of cases). Also known as drug-induced hypersensitivity syndrome (DIHS), anticonvulsant hypersensitivity syndrome, allopurinol hypersensitivity syndrome, dapsone syndrome etc. based on causative agent.
Presentation
Varied presentation, not all symptoms present simultaneously, with prolonged disease duration despite cessation of offending drugs. Extensive skin rash with visceral organ involvement, lymphadenopathy, eosinophilia, and atypical lymphocytosis. Acute phase may resolve and be followed by flare ups.
Acute phase - skin lesions may last more than 15 days. Average recovery time is 8 weeks. resolution < 15 days is against the diagnosis.
Flare up: about 5 months after resolution, mostly cutaneous with rare organ involvement.
Latency phase - two to 8 weeks - minimal or no symptoms, nonspecific symptoms (fever, malaise, lymphadenopathy)
-
Cutaneous and mucosal: maculopapular eruption, pustules, exfoliative dermatitis, target like lesions
-
Organ involvement - Liver: most common – hepatitis (cholestatic, hepatocellular, mixed), rarely acute liver failure, Kidney: proteinuria to renal failure from acute intestinal nephritis. may need kidney biopsy, Lung: shortness of breath, cough, intestinal infiltrates on CT chest/CXR (intestinal pneumonitis, intestinal pneumonia), Cardiac: hypotension, tachycardia, dyspnea, left ventricular dysfunction (cardiac failure) - may need endomyocardial biopsy.
Assessment
Look for recent (past 2 to 8 weeks) exposure to new drug treatment. Exposure to certain anticonvulsants (carbamezapine, phenytoin, lamotrigine), allopurinol, sulfonamide-containing antibacterial, mexiletine, minocylcine, vancomycin, iodine contrast media (recent CT scan) with known DRESS syndrome association, Biopsy may be needed. Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) scoring system for confirmation.
Plan
- Identification and withdrawal of the causative medication, switch epileptic patients to nonaromatic drugs (e.g., to valproic acid, topiramate, gabapentin), supportive care. Mild disease (no organ involvement or mild liver involvement): High-potency topical corticosteroids. Severe disease with single or multiple organ involvement: First line - systemic glucocorticoids (oral prednisone or IV methylprednisolone), refer to liver transplant specialist if signs of acute liver failure. Second line – cyclosporine, antiviral therapy (ganciclovir, valganciclovir)
Prognosis
- Most patients recover completely in weeks to months after drug withdrawal
MedDRA PTs
Drug reaction with eosinophilia and systemic symptoms
Disqualifiers
Exanthematous drug eruptions - acute generalized exanthematous pustulosis (AGEP), and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). (on day of index date)
- Sézary syndrome (on day of index date)
Acute cutaneous lupus erythematosus (on day of index date)
Viral infection (IMV, CMV, Measles, Viral hepatitis, Dengue) – short term before index date
Strengtheners
Start of drug 2 to 8 weeks before index date. Allopurinol, Carbamazepine, Dapsone, Ethambutol, Isoniazid, Lamotrigine, Mexiletine, Minocycline, Nevirapine, Oxcarbazepine, Phenobarbital, Phenytoin, Pyrazinamide, Rifampicin, Sulfadiazine, Sulfasalazine, Trimethoprim-sulfamethoxazole, Vancomycin
4. Severe cutaneous adverse reaction (composite SJS, AGEP, TEN, DRESS, Generalized Bullous Fixed Drug Eruption, Erythema Multiformae)
Source for generalized bullous fixed drug eruption (GBFDE):
- Cho Y, Chu C. Treatments for Severe Cutaneous Adverse Reactions. J Immunol Res 2017;2017:1503709.
- Anderson HJ, Lee JB. A review of fixed drug eruption with a special focus on generalized bullous fixed drug eruption. Medicina (Kaunas) 2021:57(9): 925
- Up to Date: Subsection in: Shiohara T. Fixed drug eruption. Topic 15760 Version 9.0. Updated 23 May 2022.
Overview
SCAR = SJS, AGEP, TEN, DRESS, Generalised bullous fixed drug eruption, Erythema Multiformae (EM)
This would be a composite outcome. We have SJS, TEN, AGEP, DRESS and separate phenotype description above.
Presentation
AGEP: see above
SJS/TEN: see above
DRESS: see above
Generalized bullous fixed drug eruption (GBFDE): GBFDE is a rare and severe form of fixed drug eruption (FDE). It is characterized by large areas of well-demarcated erythematous or hyperpigmented patches with blisters or erosions developed soon after administrating the culprit drugs. GBFDE has been defined as typical fixed drug eruption lesions as well as blisters and erosions involving at least ten percent of the body surface area and at least three of six different anatomic sites (specifically, the head and neck, anterior trunk, back, upper extremities, lower extremities, and genitalia). Systemic symptoms, such as fever, malaise, or arthralgias may be present. It exhibits typical features of FDE but may resemble the presentations of SJS/TEN. GBFDE has a shorter latency (1 to 2 weeks, most frequently within 48 hours, mean 3.2 days) and less mucosal involvement than SJS. Histopathology is different from SJS with more eosinophil infiltration and more dermal melanophages in skin specimens, and lower serum granulysin levels.
Common culprit drugs in GBFDE were shown to be antibiotics, including cephalosporins, penicillins, and anti-infective sulfonamides, followed by nonsteroid anti-inflammatory drugs
Assessment
AGEP: see above
SJS/TEN: see above
DRESS: see above
GBFDE: Histopathological examination of skin, serum granulysin levels
Erythema Multiformae
Plan
AGEP: see above
SJS/TEN: see above
DRESS: see above
GBFDE: Identify and remove offending drug. Patients with extensive skin detachment may require intensive supportive care. Topical or systemic corticosteroids.
Prognosis
AGEP: see above
SJS/TEN: see above
DRESS: see above
GBFDE: Patients recover in general within 7 to 14 days after drug discontinuation. Prognosis of GBFDE may be unfavorable in older patients, particularly in those with comorbidities.
MedDRA PTs
Severe cutaneous adverse reactions (SMQ) narrow
Disqualifiers
AGEP: see above
SJS/TEN: see above
DRESS: see above
GFBDE: Initiation of offending drug 48 hours to 2 weeks before event onset
Strengtheners
AGEP: see above
SJS/TEN: see above
DRESS: see above
GFBDE:
- Average age 69.1, median age 74 years
- Onset within 48 hours to 2 weeks of Company drug
- Resolution within 7 to 14 days after drug discontinuation
Shiny app with Cohort diagnostics: https://data.ohdsi.org/Phenotype_0006_SCAR/
Pending:
Literature review
Evaluation report