By Lisa Scatena, MD, FAAD
Posted on June 13, 2008 – A 21-year-old woman is given amoxicillin for a sore throat. Four days later she returns with a diffuse, maculopapular eruption. Other than the sore throat, she feels well. Vital signs are stable. (Figure 1)
Your diagnosis:
A. Drug hypersensitivity eruption
B. Morbilliform drug eruption
C. Stevens-Johnson syndrome
D. Toxic Epidermal necrolysis
E. Viral exanthem
In two studies of over 39,000 medical inpatients performed by the Boston Collaborative Drug Surveillance Program, the overall cutaneous reaction rate to medications was 2.2%. In this study, penicillins, sulfonamides and blood products accounted for over 66% of all drug eruptions. Reaction rates for women were 35-50% higher than for men. Most reactions occurred within 1 week of starting the suspected drug.
Most drug eruptions are morbilliform (maculopapular) rashes and typically clear within 2 weeks of stopping the offending agent. In rare instances, a simple morbilliform eruption can progress into a life-threatening reaction such as a drug hypersensitivity syndrome or toxic epidermal necrolysis.
Several clinical features should alert the clinician to the presence of a more serious drug reaction including: confluent erythema, facial edema, skin pain, skin necrosis or blisters, mucous membrane erosions, fevers >40C, lymphadenopathy, hypereosinophilia >1000/L, lymphocytosis with atypical lymphocytes, and abnormal liver function tests. (Table 1)
Morbilliform Eruption
Maculopapular rashes, as presented in our case, typically begin on the trunk in the first 7-10 days of starting the medication. As it progresses, it can change from red to brown and eventuate into a scaling or desquamating eruption. Biopsies of morbilliform drug eruptions do not help distinguish drug rashes from viral exanthems as they are histopathologically similar. If the offending medication cannot be discontinued, it is usually okay to treat through an uncomplicated morbilliform rash, while watching the patient closely for signs and symptoms of progression to a more serious rash. Classic medications responsible are penicillin, allopurinol, sulfonamides, anticonvulsants, diuretics, gold, NSAIDS and ampicillin given to a patient with mononucleosis. (Figure 1)
Drug Related Eosinophilia and Systemic Symptoms (DRESS)
DRESS syndrome is estimated between 1 in 1,000 and 1 in 10,000 cases of patients treated with phenytoin, carbamazepine and phenobarbital and lamotrigine. These patients present with a severe exanthematous rash or exfoliative dermatitis 2-4 weeks after treatment begins with these medications. Multi-organ involvement distinguishes DRESS from more benign cutaneous drug eruptions. 30-50% of cases involve facial edema, fever, lymphadenopathy, hepatitis (51% of cases), interstitial nephritis, carditis, eosinophilia (>10%) and pleomorphic atypical lymphocytes. Prompt withdrawal of the offending agent and use of systemic corticosteroids are the mainstay of treatment. Because of the high rate of cross-reactivity between these aromatic anticonvulsants, the therapeutic benefit of this class of medications must be strongly reconsidered. (Figure 2)
Stevens-Johnson Syndrome (SJS)
SJS is seen most commonly in 20-40 year olds given sulfonamides, phenytoin, allopurinol and NSAIDs. It is twice as common in men as it is in women. SJS and TEN (see below) are seen more commonly in patients with HIV/AIDS, HLA-B12 phenotypes, bone marrow transplant recipients and patients with underlying lupus. Five percent of cases can be fatal. A prodrome of fever and flu-like symptoms often precedes the eruption by 1-3 days. Another early sign of involvement is extreme skin pain and burning. Small blisters atop dusky purpuric macules or atypical targetoid lesions occur within 1-3 weeks of initiation of drug treatment. Detachment of <10% of the skin’s body surface area is often seen. The hallmark of SJS is involvement of greater than 2 mucosal surfaces including the mouth, nares, eyes, anorectal and genital areas. (Figure 3)
Toxic Epidermal Necrolysis (TEN)
Unlike SJS, TEN presents with sloughing of large sheets of necrotic epidermis in >30% of the skin surface area. Most cases involve fever, leukopenia and some respiratory tract and gastrointestinal tract involvement. Scarring and strictures can result in significant morbidity following recovery. 30% of cases are fatal as a result of s. aureus and/or pseudomonas sepsis.
Nomenclature becomes messy as many physicians view SJS and TEN on a continuum with TEN being more severe. Prompt recognition of the condition is crucial to ensure early withdrawal of the culprit medication and transfer to a burn ICU where the patient can receive appropriate and meticulous care. Most literature is AGAINST systemic corticosteroids as studies thus far have failed to demonstrate a reduction in mortality. IV-Ig has been used in the setting of SJS and TEN, but not uniformly helpful. (Figure 4)
In our case, the amoxicillin was discontinued and the patient’s morbilliform rash faded. A positive monospot test confirmed the diagnosis of EBV and symptomatic care was instituted.
References
Bachot N, et al. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progressive study. ArchDermatol 2002; 138:1019.
Garcia-Doval I, et al. Toxic epidermal necrolysis and Stevens-Johnson syndrome: Does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol 2000;136:323.
Kaur S, et al. Anticonvulsant hypersensitivity syndrome. Pediatr Dermatol 2002; 19:142.
Renn, CN, et al. Amoxicillin-induced exanthema in young adults with infectious mononucleosis: demonstration of drug-specific lymphocyte reactivity. Br J Dermatol 2002; 147:1166.
Stern RS, Wintroub BU. Cutaneous reactions to drugs. Dermatology in General Medicine (Fitzpatrick ed. 5) 1999; Ch 140; 1633-42.
Dr. Scatena, MD, FAAD, is a Clinical Instructor of Internal Medicine, University of Colorado Health Science Center and practices clinical dermatology in Boulder, Colorado.
