CASE #1
A 40-year-old man presented with a recent history of a putative upper respiratory infection for which his internist had prescribed ampicillin. Four days after starting treatment, the man developed a rash, first on his back and then on his upper arms. The eruption did not itch, burn, or hurt. The patient did not have a fever. On basic laboratory testing, WBCs, liver function, and antinuclear antibodies were within normal limits.
CASE #2
The patient was a 50-year-old man who noted fine blood vessels spreading over his chest but nowhere else on his body. The eruption was asymptomatic; scratching did not cause urtication. The patient had a history of hepatitis, but current liver function tests and a hepatitis screen were normal. He did not report GI upset. A colonoscopy was unremarkable. The patient had never had any abnormal reactions to sun exposure. Tests for carcinoid were negative.
What is the diagnosis?
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CASE #1: Exanthematous drug eruption
Most drug eruptions manifest with erythematous macules and papules, giving them an appearance that may be referred to as exanthematous, mobilliform, or scarlatiniform. The basis for this is not clear. We will refer to them as exanthematous drug eruptions (EDEs)
EDEs can emerge as soon as 48 hours after a medication is administered. Onset is often within the first two weeks of administration, although some EDEs manifest as much as 10 days after a medication has been stopped. EDEs usually are not associated with fever or systemic changes, such as lymphadenopathy. Drug reactions associated with lymphadenopathy are referred to as drug eruption with eosinophils and systemic symptoms (DRESS) or pseudolymphoma. A genetic basis for such severe drug reactions as DRESS and pseudolymphoma continues to be defined.
EDEs typically do not manifest on the face. Instead they tend to start on the central body and spread centrifugally. In my experience, the rash often starts on the back of hospitalized patients and in the axilla or groin of others, progressing next to the front of the body and then to the arms and legs. The eruption can be confluent. Some EDEs occur only in sun-exposed areas, the so-called UV recall reaction. A sunburn as many as two weeks to 10 months prior to development of the reaction may have provided a fecund setting for such a reaction.
The chief differential diagnoses of EDE include viral eruptions and insect bites. Most viral eruptions do not itch, while bites and some EDEs are associated with pruritus. Generally the rash of insect bites is not so generalized or confluent as that of an EDE. Histology can distinguish the three diagnoses and help explain the absence or presence of pruritus. The typical EDE involves an interstitial and perivascular infiltrate of lymphocytes and often eosinophils. The infiltrate is usually superficial but can be both superficial and deep. Histologically, viral eruptions manifest only with lymphocytes. Because eosinophils and mast cells are key to the development of pruritus, eruptions that have only lymphocytes do not itch. Clinically, bites have a less uniform appearance, and histologically, they have a deeper and more wedge-shaped array of superficial and deep eosinophils.
EDEs are a type IV hypersensitivity reaction. Hypersensitivity reactions are divided into four categories: Type I hypersensitivity reactions are allergic and immediate and involve immunoglobulin E (IgE)-dependent reactions that can result in hives and breathing problems, while type II hypersensitivity reactions involve cytotoxic T-cells that lyse other cells and can result in hemolysis and purpura. Like type III hypersensitivity reactions, type IV hypersensitivity is a delayed-type reaction requiring the formation of haptens, which are immune complexes composed of immunoglobulin and molecules of the allergen. In type IV hypersensitivity, lymphocytes carry the haptens back to the lymph nodes and return to the site of the reaction sensitized to the allergen. Drug-induced hypersensitivity syndrome and allergic contact dermatitis are other examples of type IV hypersensitivity reactions.
Some medications are more likely to cause EDEs than others. The medications most commonly involved are sulfa antibiotics and amoxicillin/ampicillin. Aromatic anticonvulsants, such as phenytoin (Dilantin), also cause allergic reactions. Other possibilities include allopurinol (Zyloprim) and abacavir (Ziagen). Bear in mind that any medication can cause a reaction at anytime. Moreover, patients can react to a combination of medications even if they haven't previously reacted to an individual medication. Use of ampicillin/amoxicillin in certain disorders seems to carry a higher risk of EDE. For example, 95% of patients who are infected with Epstein-Barr virus and 30% of patients with chronic lymphocytic leukemia may experience EDE when treated with ampicillin/amoxicillin. Pregnancy that leads to a recrudescence of EBV infection can cause patients to have develop an EDE following use of ampicillin, a popular antibiotic among obstetricians.
When an EDE is suspected, make a list of all the patient's medications and when they were started (and stopped, if appropriate). Discontinue all unnecessary medications, using particular care when stopping psychiatric agents.
Treatment of EDE is primarily symptomatic and supportive. Begin by trying to identify the offending medication and stopping it. Apply triamcinolone 0.1% ointment (available in a 1-lb size) to all affected areas. Side effects, such as adrenalsuppression, are much less likely with a class IV corticosteroid than with a class I corticosteroid, such as clobestasol (Temovate), and patients will have sufficient steroid to cover their entire body.
An antihistamine such as hydroxyzine 25 mg used at night can aid with sleeping; fexofenadine (Allegra) 180 mg can sometimes be used in the daytime. Eruptions tend to clear within two weeks of discontinuing the offending agent and starting therapy. The patient knows that the eruption is resolving when areas of erythema evolve into areas of desquamation.
This patient's ampicillin was stopped, and he was treated with triamcinolone 0.1% ointment and hydroxyzine 25 mg at night. Within a week, the erythema evolved into desquamation. At no time did the patient have a fever or abnormal laboratory values.
CASE #2: Telangiectasia macularis eruptiva perstans
Also referred to as paucicellular mastocytosis, telangiectasia macularis eruptive perstans (TMEP) is just one of several forms of cutaneous mastocytosis. The other variants include urticaria pigmentosa, maculopapular cutaneous mastocytosis, diffuse cutaneous mastocytosis, mastocytoma of the skin, and erythrodermic mastocytosis. Cutaneous mastocytosis is an uncommon cause of skin disease.
The epidemiology of TMEP has yet to be fully defined. While urticaria pigmentosa, the most common of the cutaneous mastocytoses, is common in children, TMEP is very rare in children. Familial TMEP has been reported and can occur in children. In the United States, 0.1%-0.8% of new patients seeking care in dermatology clinics have some form of mastocytosis. Less than 1% of patients visiting dermatology clinics with mastocytosis have TMEP.
The physical manifestations of TMEP include telangiectases measuring 2-6 mm, sometimes on a background of erythema or tan discoloration. TMEP represents permanent vasodilation of the skin, secondary to mast-cell release of chemical mediators and angiogenic factors. TMEP most commonly involves the trunk but has been reported in rare instances to occur unilaterally. Heat and pressure may produce localized urticaria.
TMEP rarely has systemic complications. Most patients complain only of variable degrees of pruritus. Darier's sign, a wheal surrounded by erythema in an area of skin with mast cells, is almost always present in urticaria pigmentosa but may not be present in TMEP. Rare cases of TMEP are associated with episodic headaches, flushing, GI upset, palpitations, syncope, hepatosplenomegaly, increased numbers of mast cells in the bone marrow, and abnormal findings on skeletal radiographs.
The differential diagnosis of TMEP includes essential generalized telangiectases (those simply present since birth), nevoid telangiectases, telangiectases due to liver disease, carcinoid syndrome rosacea, carcinoid syndrome, hepatopathy or collagenosis, and hereditary hemorrhagic telangiectasia. TMEP manifesting as a pseudoallergic food reaction has been reported.1 One woman presented late in the second trimester with an anaphylactoid reaction, rash of blood vessels, uterine contractions, and vaginal bleeding.2 The patient had a markedly elevated urinary histamine level, and skin biopsy revealed perivascular mast-cell infiltration, establishing the diagnosis of TMEP. She was treated successfully with tocolytics and antihistamines.
The histologic findings of TMEP involve mast cells surrounding capillary venules and the superficial venular plexus. Mast cells have a “fried egg” appearance and can be definitively detected with Giemsa, toluidine blue, chloroacetate esterase, and aminocaproate esterase stains, which are picked up by metachromatic cytoplasmic granules. On occasion, the mast cells are somewhat sparse, complicating the pure histologic establishment of a diagnosis and necessitating clinicopathologic correlation.
TMEP associated with malignant melanoma was reported in 2009, but no role for TMEP as a marker of malignancy has yet been established. Mutations in the c-kit (mast cell growth factor) proto-oncogene are not found in all patients with cutaneous mastocystosis. Alterations in this proto-oncogene may indicate more aggressive mastocytosis and have been observed in melanoma but not TMEP.
Although TMEP is a cutaneous manifestation of mastocytosis, systemic involvement may occur. Elevated serum tryptase levels may serve as a guide for systemic involvement. In a study of 52 patients, the prevalence of bone-marrow biopsy specimens indicating systemic mastocytosis rose as the level of total tryptase increased. The biopsy specimens were 100% positive when total tryptase was >75 ng/mL and 50% positive when total tryptase levels were 20-75 ng/mL.3
Treatment of TMEP, if it is symptomatic, involves H1- receptor antagonists, such as hydroxyzine, to help reduce pruritus or flushing. The 585-nm flashlamp-pumped dye laser, which targets blood vessels, has yielded some success. Pre-laser treatment with appropriate H1- and H2-receptor blockers is important to avoid potential complications from laser-induced mediator release. Total electron beam radiation has been successfully used in one patient.4 Psoralen with UVA and UVB, which inhibits the release of histamine by mast cells, has been used for the treatment of mastocytosis. This approach might also work for TMEP, but no studies have been reported.
Workup of this patient, who had few symptoms, revealed laboratory results that were within normal limits. He was reassured that his skin eruption, while noticeable, did not pose a threat to his overall health.
Dr. Scheinfeld is assistant clinical professor of dermatology at Columbia University in New York City, where he has a private practice.
References
1. Vidal C, del Rio E, Suárez-Peñaranda J, Armisén M. Telangiectasia macularis eruptiva perstans presented as a pseudoallergic food reaction. J Investig Allergol Clin Immunol. 2000;10:248-250.
2. Donahue JG, Lupton JB, Golichowski AM. Cutaneous mastocytosis complicating pregnancy. Obstet Gynecol. 1995;85(5 Pt 2):813-815.
3. Kanthawatana S, Carias K, Arnaout R, et al. The potential clinical utility of serum alpha-protryptase levels. J Allergy Clin Immunol. 1999;103:1092-1099.
4. Monahan TP, Petropolis AA. Treatment of telangiectasia macularis eruptiva perstans with total skin electron beam radiation. Cutis. 2003;71:357-359.