## 6 Clinical Features and Variants  
Characteristically, patients with AGEP develop an acute rash with pinhead-sized pustules on an erythematous oedemaous base, starting in the main folds (axillary, inguinal and subammary areas) and spreading quickly (within a few hours) on the trunk and limbs (Figure 2). The time period from drug ingestion to reaction onset is usually within 48 h, with antibiotics having a median of 24 h [7]. There is an itching or sometimes burning sensation [3,32]. Mucosal involvement, especially orally, is reported in about 20%-25% of patients but mostly in a limited extension and only on one mucosal region [5].  
Systemic inflammation signs in the acute phase of the disease include fever (>38.0 \({}^{\circ}\)C), leucocytosis (>10,000/mL), elevated levels of C-reactive protein (CRP) and mostly increased levels of neutrophils (>7000/mL). As mentioned above, 30% of patients also present an eosinophil and in 75% of cases a hypocalcaemia, probably related to hypoolbuminemia, is found [5,33]. Multiorgan involvement has been reported in 17% of cases [33]. Skin eruptions are sometimes accompanied by lymphadenopathy and occasionally by hepatocellular dysfunction and cholestasis as well as nephritis. Lung and bone marrow might also be involved, leading to respiratory failure and neutropenia, respectively [33]. One case with phenytoin-induced AGEP and cerebellar symptoms has been reported, while it is unknown whether cerebellar symptoms were related to the drug reaction or to phenytoin toxicity [34]. AGEP usually shows a mild course but high fever or cutaneous superinfection can complicate the process and lead to severe illness and sometimes life-threatening situations, especially in patients of poor general condition. The reported mortality is under 5% [3,4]. Usually there is a spontaneous resolution of skin lesions within two weeks with a very typical colmarette-shaped desquamation in the region of previous pustulosis [3,4].  
Besides the normal presentation of AGEP, several atypical variants and overlap syndromes have been described. For example, an overlap of AGEP and drug reaction with eosinophil and systemic symptoms (DRESS) [35,36], or TEN [36,37,38,39,40,41,42,43,44], as well as an AGEP case with targetoid lesions [45,46] have been reported. A dozen of localized reactions have been reported, and referred to as acute localized exanthematous pustulosis (ALEP) [47,48,49,50]. In about 50% of patients, additional skin symptoms such as erythemat oedema of the hand and face, purpura, vesicles and blisters have been reported.  
Differential diagnosis of other pustular eruptions (such as bacterial or fungal infections, neutrophil dermatoses, etc.) can mostly be excluded easily by clinical picture, history and histopathological findings. Acute GPP can present with the same clinical picture and may be difficult to distinguish, as the histopathological findings can sometimes not clearly distinguish between these two diseases (Table 1). The most important factor for the diagnosis is the quicker resolution time seen in AGEP. Recent studies described similarities in the pathogenesis of AGEP and GPP, like mutations in  
Figure 2: (**A**) Widespread rash with numerous pinhead-sized pustules on an erythemat oedemaous base; (**B**) Flexural accentuation with characteristic colmarette-shaped desquamation is typically observed in AGEP.  
the IL-36 Ra and an elevated expression of IL-17 [51]. DRESS typically presents with a morphilliform rash spreading from the face to the rest of the body, but might present with pustules as well. DRESS develops with a longer latent period of two to six weeks and mucous membranes and systemic involvement are more common [52]. Stevens-Johnson syndrome (SJS) and TEN are characterized by epidermal detachment and histological full-thickness epidermal necrosis [53]. Severe cases of AGEP, especially those with mucosal involvement, might be difficult to distinguish from these entities, and overlap forms have been described.