Cutaneous manifestations may occur 6–12 h after drug intake, but typically begin within 1–2 weeks. The maculopapular exanthem is pruritic and morbilliform in nature, with symmetric macules and papules, starting on the trunk and spreading to the face and extremities. No pustules or blisters are present. Erythroderma, palmoplantar involvement, and fever may occur. Mucous membranes are typically spared. Before resolving, the rash becomes hyperpigmented and red-brown, and then ultimately desquamates after approximately 2 weeks.

The findings are relatively non-specific, with a superficial perivascular lymphocytic.

Viral exanthems can be practically identical in presentation and histopathologically and viral titers can be helpful. Clinical features can aid in the exclusion of acute graft-versus-host disease, toxic shock syndrome, scarlet fever, Kawasaki disease, and juvenile arthritis.

Symptomatic treatment is indicated, as the reaction is typically self-limited. The risks and benefits of continuing or discontinuing the medication(s) should be weighed carefully. If the drug cannot be stopped, close monitoring is best. Reactions can dissipate even when the causative drug is continued. For the pruritus, antihistamines, emollients, and topical corticosteroids can help. These reactions do not progress to more severe, life-threatening reactions, but it is best to assess the likelihood of an early evolving severe reaction. Worrisome signs include bullae, facial edema, fever, mucosal involvement, and positive Nikolsky sign. With re-challenge of the offending medication(s), a reaction may appear quickly, often within 72 h.

High fever is the first manifestation of disease (>38 °C), quickly followed by a violaceous rash, cervical lymphadenopathy and pharyngitis. The rash is present in 95 % of patients with DRESS and may last several weeks. It begins on the face, often peri-orbitally, and upper trunk, and subsequently spreads caudally. The rash can have varied presentations including a morbilliform exanthem (80 % of cases), erythroderma (10 % of cases), exfoliative dermatitis, vesicobullous eruption, pustular eruption, or targetoid lesions. Mucosal sites are involved in approximately 25 % of cases, including the mouth, lips, throat, and genitalia. Facial edema is present in 25 % of cases. Systemic involvement includes lymphadenopathy, hepatomegaly (50 % of cases), myocarditis, lung disease, gastrointestinal symptoms, and endocrine abnormalities. Thyroiditis is a delayed manifestation, often presenting several months after disease onset.

DRESS is thought to be due to a delayed T-cell mediated hypersensitivity reaction, but the exact cause remains unknown. Re-challenge with the offending medication causes return of fever and erythroderma within hours. Of note, the antiepileptics can have significant cross-reactivity; therefore, if there is a reaction to carbamazepine, phenobarbital, or phenytoin, the patient should avoid all three.

A complete blood count often shows an atypical lymphocytosis and eosinophilia. Other recommended tests include coagulation panel, viral serologies (hepatitis B, C, EBV, HHV-6), liver and renal function tests, muscle enzymes, thyroid function tests, and/or glucose levels.

A sparse perivascular inflammatory infiltrate with lymphocytes and eosinophils typifies the morbilliform rash. Eosinophils may be absent. Vacuolization of the basal layer and rare apoptotic keratinocytes may be seen. These features are all relatively non-specific, as the histology of DRESS syndrome is not pathognomonic.

Viral exanthem, erythema multiforme, fixed drug eruption, TEN.

Timely withdrawal of the medication(s) is crucial. In patients with systemic involvement, prednisone (1–2 mg/kg/day) is usually indicated. For symptomatic relief, antihistamines and topical corticosteroids are beneficial.

Benzoyl peroxide, in addition to topical or oral antibiotics, as well as topical tretinoin cream, can be helpful as well as discontinuation of the offending medication(s).

Clinically, AGEP presents with diffuse mildly pruritic and edematous erythema of the intertriginous areas. Subsequently, numerous sterile non-follicular pustules develop. This reaction occurs within hours of drug intake. Fever is usually present but afebrile cases have been reported. Mucous membranes are involved in 20 % of cases and extracutaneous involvement is rare.

Studies have demonstrated AGEP is a drug-specific process mediated by CD4 T-cells, which release GM-CSF and IL-8/CXCL8 cytokines, the latter of which is a potent neutrophil chemoattractant.

Peripheral leukocytosis is common, with a neutrophil count over 7000/μL.

Subcorneal or intraepidermal pustules, superficial papillary edema, and a lymphohistiocytic perivascular inflammatory infiltrate are present. Scattered eosinophils and neutrophils can be seen. Single-cell keratinocyte necrosis or vasculitis may be seen.

DRESS syndrome, pustular psoriasis, leukocytoclastic vasculitis, and subcorneal pustular dermatosis. Differentiation histopathologically may be impossible.

After the offending agent(s) are removed, the reaction should resolve within a couple of weeks. Fine desquamation without scarring may occur. Anti-histamines and a short course of oral corticosteroids (1–2 mg/kg/day) can be used for symptomatic relief of pruritus.

Clinically, there is a mucocutaneous distribution of pruritic or painful, well-circumscribed and edematous, round red-to-purple patches. They can be solitary or multiple. Vesicles and blisters are variably present. Lesions heal with pigmentary alteration, often darkly hyperpigmented. The most common sites of involvement include lips, trunk, legs, arms, and genitals. Lesions occur within 14 days of original medication assault, and the latency period decreases with subsequent administrations.

The pathogenesis is unclear, but intraepidermal cytotoxic CD8+ T cells most likely release pro-inflammatory cytokines with drug administration. Expression of intercellular adhesion molecules (ICAM) is seen specifically in lesional epidermis, which may explain the sharp localization and circumscription of the lesions. With drug re-challenge, a flare is usually noticed within 1–8 h.

Hydropic degeneration of basal layer keratinocytes, lymphocytic lichenoid infiltrate, and superficial dermal melanophages are present. Scattered necrotic keratinocytes are also seen. Bullae can be seen, as well as extensive confluent epidermal necrosis. Detachment of the epidermis does not have to occur for necrosis to be present. Histologic distinction from erythema multiforme and TEN is not always achievable.

Mostly supportive, but topical corticosteroids may be helpful.

Cell-poor blisters with festooning are present and resemble PCT histologically.

In drug-induced pseudoporphyria, discontinuation of the suspected drug is recommended and necessary. It can take months after discontinuation of the offending drug for resolution of blister formation. Sun protection is advised for all patients.