Answer: C

Acute generalized exanthematous pustulosis (AGEP) is a rare adverse skin reaction usually caused by medication or acute infection. As numerous diseases may present with pustular eruptions, it is imperative that the diagnosis of AGEP is determined by a thorough history and recognition of its unique clinical and histologic features. In the past, widespread pustular eruptions were often classified as GPP, but further research has shown that AGEP has its own set of histopathologic and clinical features and should be classified as a separate entity.9

The incidence of AGEP has been estimated to range from 1 to 5 cases per million persons per year, with no difference based on sex.9 A personal or family history of psoriasis is not usually associated with AGEP. Removal of the offending drug often protects against recurrence, as 87% to more than 90% of cases have been associated with medications.9,10 Some of the frequent offending agents include aminopenicillins, macrolides, and clindamycin antibiotics; antimalarial agents; and calcium channel blockers. Infectious causes of AGEP are more rare and include parvovirus B19, mycoplasma, cytomegalovirus, Coxsackie B4, Chlamydia pneumoniae, Escherichia coli, echinococcus, and spider bites.11

The clinical hallmark of AGEP is the sudden onset of dozens of sterile, nonfollicular pustules with an edematous, erythematous background within hours to days of taking an inciting medication. This acute rash initially develops in skin folds (axillary, inguinal, and submammary areas) or on the face and spreads quickly to the trunk and limbs within a few hours.11 The skin lesions will often be pruritic, and patients may experience fever, headache, neutrophilia, and possibly eosinophilia. The lesions tend to resolve within 1 to 3 days of stopping the offending medication. However, a postpustular desquamation period usually follows and fully resolves within 15 days. Although systemic complications are rare, severe cases have been reported involving the liver, lung, kidney, and/or bone marrow.9

Biopsy of a pustule and histopathologic examination are crucial for distinguishing AGEP from other pustular eruptions. Typically, examination will reveal subcorneal and/or intraepidermal pustules, spongiosis of the stratum spinosum, edema of the papillary dermis, necrotic keratinocytes, and infiltration of neutrophils and possible eosinophils.11

Although pustular eruptions can be found in a wide spectrum of cutaneous diseases, most can be easily differentiated from AGEP with a thorough physical examination, history, and histopathologic findings. Differential diagnosis of AGEP includes bacterial folliculitis, localized pustular contact dermatitis, GPP, drug hypersensitivity syndrome (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).

The presentation of DRESS includes a morbilliform rash, with possible pustules, that spreads from the face to the rest of the body. DRESS, however, has a 2- to 6-week latent period, a less-pronounced pustular component, and more commonly has systemic and mucous membrane involvement  compared with AGEP.11 Furthermore, SJS and TEN characteristically have full-thickness epidermal necrosis and detachment with sparse inflammatory infiltrate, while epidermal detachment is much more superficial in AGEP.11 Severe cases of AGEP may be difficult to differentiate from these entities, but one of the most important clinical factors for the diagnosis of AGEP is the shorter resolution time.12

Acute GPP can often present with a clinical picture and histopathologic findings similar to those seen with AGEP, making differentiation especially difficult. While AGEP tends to distribute to the face and/or skin folds, GPP has a more generalized distribution pattern.10 Key histologic features distinguishing AGEP from GPP is the presence of eosinophils in the pustules or dermis, necrotic keratinocytes, and the absence of dilated, tortuous blood vessels. Additionally, psoriatic characteristics like papillomatosis and acanthosis are usually present in GPP but absent in AGEP.13 Although distinguishing AGEP from GPP may be difficult, it is important to do so in order to identify the offending agent and provide the correct treatment.

In 2001, a multinational epidemiologic case-control study on severe cutaneous adverse reactions (EuroSCAR study group) presented the AGEP validation score. This scoring system helps standardize the process of diagnosing AGEP. It takes into account the morphology of skin lesions, clinical course, presence of fever, and laboratory and histopathologic findings.9 In cases of polymedication, a patch test, skin allergy test, and/or in vitro testing may be performed in order to identify the offending agent. The patch test must be performed after complete resolution of the lesion. Positive results show small pustules at the location of testing.14 However, due to their lack of specificity and sensitivity, these tests have not been widely adopted for the diagnosis of AGEP.  

AGEP often has a benign, self-limited course after cessation of the offending agent. If a patient requires treatment for an underlying condition, an alternative medication should be prescribed. Systemic corticosteroids are usually not necessary; however, antipyretics, antihistamines, and local corticosteroids may be given for symptomatic relief. Additionally, superinfection of skin lesions, high fever, and organ involvement can sometimes lead to life-threatening situations in elderly or immunocompromised patients. Rapid administration of systemic corticosteroids, antibiotics, supportive care, and/or organ-specific interventions are critical in the treatment of these complications.15 For the patient in the case described, a biopsy of the lesions was performed and results of histopathologic examination were consistent with AGEP. Amoxicillin was determined to be the likely culprit, and the patient was advised to discontinue that medication. After discontinuing amoxicillin, the lesions resolved with no recurrence.

Table. Generalized Pustular Psoriasis vs Acute Generalized Exanthematous Pustulosis

Alexandria Brown, BSA, Shravya Pothula, BS, and Emily Burns, BA, are medical students at Baylor College of Medicine, and Christopher Rizk, MD, is a certi­fied dermatologist at Elite Dermatology in Houston, Texas.

References

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10. Roujeau JC, Bioulac-Sage P, Bourseau C, et al. Acute generalized exanthematous pustulosis. Analysis of 63 cases. Arch Dermatol. 1991;127(9):1333-1338.

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12. Kardaun SH, Kuiper H, Fidler V, Jonkman MF. The histopathological spectrum of acute generalized exanthematous pustulosis (AGEP) and its differentiation from generalized pustular psoriasis. J Cutan Pathol. 2010;37(12):1220-1229.

13. Orime M. Immunohistopathological findings of severe cutaneous adverse drug reactions.  J Immunol Res. 2017;2017:1-5.

14. Wolkenstein P, Chosidow O, Fléchet ML, et al. Patch testing in severe cutaneous adverse drug reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Contact Dermatitis. 1996;35(4):234-236.

15. Thienvibul C, Vachiramon V, Chanprapaph K. Five-year retrospective review of acute generalized exanthematous pustulosis. Dermatol Res Pract. 2015;2015:1-8.