Acute generalized exanthematous pustulosis




Acute generalized exanthematous pustulosis (AGEP) (also known as pustular drug eruption and toxic pustuloderma) is a rare skin reaction that in 90% of cases is related to medication.

AGEP is characterized by sudden skin eruptions that appear on average five days after a medication is started. These eruptions are pustules, i.e. small red white or red elevations of the skin that contain cloudy or purulent material (pus). The skin lesions usually resolve within 1–3 days of stopping the offending medication. However, more severe cases are associated with a more persistent disorder that may be complicated by secondary skin infections and/or involvement of the liver, lung, and/or kidney.

Severe cutaneous adverse reaction (SCAR) disorders are regarded as the drug-induced activation of T cells which then initiate innate immune responses that are inappropriately directed against self tissues. Studies on the DRESS syndrome, Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and SJS/TEN overlap indicate that many individuals are predisposed to develop these reactions to a particular medication based on their genetically determined expression of particular human leukocyte antigen (i.e. HLA) alleles or T-cell receptors and/or their efficiencies in adsorbing, distributing to tissues, metabolizing, and/or eliminating) a particular SCARS-inducing medication. Evidence for these predispositions in AGEP has not been as well-established


AGEP is characterised by the rapid appearance of sterile, non-follicular, pin-head sized pustules on an erythematous base, typically starting on the face and skin flexures before becoming more widespread. Over 90 percent of cases of AGEP are provoked by medicines. The rash usually develops rapidly, within two days of exposure to the offending medicine, but onset may occur up to two weeks after initial exposure to some medicines.

In the acute phase, patients may have a fever above 38°C and an elevated neutrophil count, but internal organ involvement is uncommon.

Most patients recover from AGEP within 10–14 days of withdrawal of the causative medicine. The pustular eruptions desquamate during the recovery phase. The mortality rate from AGEP is approximately 2–4 percent.

Figure 1: Patient with acute generalised exanthematous pustulosis (AGEP), showing pinpoint pustules on an erythematous base


About 90% of AGEP reactions are associated with medications. The remaining cases of AGEP have been associated with infective and other agents.


The diagnosis of AGEP may be forthright in typical cases in which an individual: has taken a drug known to cause the disorder; develops multiple sterile pustules overlying large areas of red swollen skin starting a few days after initial drug intake; and has a histology of biopsied lesions that shows pustules just below the skin’s Stratum corneum (outermost layer), apoptotic (i.e. necrotic) keratinocytes, spongiosis of the stratum spinosum, and infiltration of these tissues by neutrophils plus, in many but not all cases, eosinophils. Many cases of AGEP, however, present less clear cut clinical features of the disorder. AGEP must be differentiated from generalized pustular psoriasis (GPP) with which it shares many clinical and histological features. A history of psoriasis, the presence of typical psoriatic skin lesions at the time of diagnosis, and histological evidence in skin lesions of necrotic keratinocytes, neutrophil-rich infiltrates, eosinophil infiltrates, and/or lack of tortuous or dilated blood vessels favors a diagnosis of to AGEP. Other conditions sometimes confused with AGEP include pustular eruptions caused by bacteria, funguses, herpesviridae, and the varicella zoster virus (i.e. causative agent of chicken pox).

Several tests have been proposed to be useful for supporting the diagnosis of and/or implicating a particular drug as the cause of AGEP particularly in individuals who develop skin lesions while taking multiple drugs. These include patch tests in which small amounts of suspect drugs absorbed on patches are applied to the skin; skin allergy tests in which drugs are applied by skin prick or intradermal injection; and oral provocation in which drugs are taken in a single small dose orally. These tests have not been widely adopted because of their insensitivity and, most particular with oral provocation tests, the possibility of causing a relapse or worsening or the disorder. In vitro tests, including mixed lymphocyte reaction tests in which the response of individuals’ blood mononuclear cells to suspect drugs and ELISPOT tests in which specific drug-reactive lymphocytes or their drug-induced release of AGEP mediators (e.g. interferon-γ interleukin 4, or granulysin) are measured have likewise not been broadly adopted because of their lack of specificity


The treatment of AGEP begins with the immediate cessation of the offending drug. For individuals developing AGEP while taking multiple drugs, non-essential drugs should be discontinued and essential drugs should be replaced by chemically unrelated drugs that are used as alternatives to the discontinued drug(s). In cases of multiple drug intake, skin and/or in vitro testing may be of some use in identifying the offending drug. Beyond identifying and discontinuing the offending drug, individuals with mild symptoms may require no further treatment. Those troubled by more significant symptoms such as itching or fever may require antihistamines, topical corticosteroids, systemic corticosteroids, and/or antipyretics. Individuals with liver, lung, kidney, and/or severe skin complications may require high dosage systemic corticosteroids and organ-specific interventions. Skin infections, which may lead to sepsis, are potentially lethal complications of AGEP; preventative methods and rapid treatment of such infections with appropriate antibiotics and, where needed, further supportive measures are critical in the treatment of this complication. Overall, however, AGEP has a lethality of less than 5% with recent reports showing no fatalities. Typically, individuals with AGEP have rapid rates of recovery even in when experiencing the cited complications