**6. Acute generalized exanthematous pustulosis**

#### **6.1. Nosology**

In 1980, Beylot et al [222] introduced the term acute generalized exanthematous pustulosis (AGEP) to describe acute pustular reactions with distinct clinical and histological features thereby differentiating it from pustular psoriasis.

## **6.2. Epidemiology**

screening for *HLA-B\*5701* is not useful in predicting sensitivity in all patients. The racial variation may be partly explained by the differences in MHC haplotypes across different racial groups. The Caucasian 57.1 ancestral haplotype, which confers susceptibility to abacavir hypersensitivity possibly as a result of strong linkage disequilibrium with other candidate genetic factors such as cellular chaperones (e.g. heat shock proteins), inflammatory cytokines (e.g. TNF), and proteins involved in the stress response (e.g. MHC class I chain-related genes, MIC-A and MIC-B). African populations do not demonstrate this haplotype [216]. However, in a recent study by Saag et al, all 42 white patients with immunologically confirmed (i.e. positive patch tests) hypersensitivity reactions were *HLA-B\*5701* positive (sensitivity 100%, OR 1945 [110-34,352]) but in addition all 5 black patients with immunologically confirmed hypersensitivity reactions were *HLA-B\*5701* positive (sensitivity 100%, OR 900 [ 38-21,045]. Screening for the *HLA-B\*5701* has eliminated immunologically confirmed cases of abacavir

Early recognition of the syndrome with cessation of the causative drug is essential in improving patient outcomes. No randomized controlled trials have been conducted to determine the appropriate adjunctive therapy for DIHS/DRESS. Oral corticosteroids at 1 mg/kg/daily is commenced and tapered over at least 6-8 weeks to prevent relapse of various cutaneous and visceral manifestations of the syndrome. If symptoms deteriorate despite corticosteroid therapy then IVIg [218],[219], plasma exchange [220], rituximab, gangciclovir or a combination

Recently, the French Society of Dermatology formulated guidelines on the management of

**1.** Absence of signs of severity: topical corticosteroids, emollients and H1-antihistamines.

**2.** Presence of signs of severity (transaminases >5 times normal, renal impairment, pneu‐

**3.** Life-threatening signs: (hemophagocytosis with bone marrow failure, encephalitis, severe hepatitis, renal failure, respiratory failure): prednisone and IVIg 2 g/kg over 5 days.

**4.** Presence of signs of severity with confirmation of major viral reactivation: prednisone and

In 1980, Beylot et al [222] introduced the term acute generalized exanthematous pustulosis (AGEP) to describe acute pustular reactions with distinct clinical and histological features

monia, hemophagocytosis, cardiac involvement): prednisone 1 mg/kg/day.

hypersensitivity [217].

78 Skin Biopsy - Diagnosis and Treatment

of these modalities [221] can be considered.

gangciclovir and/or IVIg.

**6. Acute generalized exanthematous pustulosis**

thereby differentiating it from pustular psoriasis.

**5.8. Treatment**

DIHS/DRESS [133]:

**6.1. Nosology**

AGEP is rare with an incidence of 1-5 cases per million per year [223]. The EuroSCAR study comprising 97 validated cases of AGEP recruited from Austria, France, Israel, Italy and the Netherlands, revealed a mean age (±SD) of 56 (±21) years and a female preponderance with a male/female ratio of 0.8 [18]. The predominance in women was shown to be even greater in case series reports from Taiwan (68.7% of 16 cases) [224], and Israel (76.9% of 13 cases) [225]. AGEP has been reported in children, with the largest pediatric series of 20 cases from China [226].

### **6.3. Clinical features**

The clinical manifestations are characterized by fever and a pruritic or burning edematous erythema (Figs. 13 A&B) followed by the rapid appearance of dozens of small (< 5 mm) nonfollicular sterile pustules (Fig. 14). The skin lesions are often accentuated in the intertriginous areas (Fig. 13 C). There is usually an accompanying marked neutrophilia (7 x 109 /L) and in a third of cases, a mild eosinophilia. A mild non-erosive mucous membrane involvement occurs in 20% of cases. Internal organ involvement is uncommon and usually is confined to a slight reduction in creatinine clearance and mild elevation of aminotransferases.

The clinical course is characterized by spontaneous resolution of skin and systemic manifes‐ tations over a period of up to 15 days once the offending agent is withdrawn [223]. AGEP has a favourable prognosis; the reported mortality rate is up to 5% and poor outcomes usually result from secondary infection in the elderly or those patients with significant comorbidities [227],[228].

#### **6.4. Etiology**

AGEP is caused by drugs in at least 90% of cases. According to the EuroSCAR study, the agents conferring the highest risk are pristinamycin, aminopenicillins, hydroxychloroquine, antibac‐ terial sulphonamides, terbinafine and diltiazem [18]. The latent period is short (usually 1-5 days) with the EuroScar study demonstrating that it may vary for different drugs. For antibiotics, including sulphonamides, the median latent period was 1 day, and for other drugs it was 11 days [18].

Contact sensitivity has been implicated in a few case reports. Causative agents include mercury[229], and bufexemac, a potent topical NSAID[230]. Neither of these agents was implicated in the 97 cases of AGEP in the EuroScar. The role of infectious agents in AGEP has been suggested in various case reports due to the absence of an inciting drug [231]. The organisms include coxsackie B4 [232], cytomegalovirus [233], parvovirus B19 [234], *Chlamydia pneumoniae* [235], and *Escherichia coli* [236]. No significant risk for infection was found in the EuroScar study although the study was not designed to identify potential causative organisms. Spider bites were suggested as a cause AGEP in a series of three cases from Israel, presumably as a result of the venom's ability to induce IL-8 and GM-CSF [237]. Finally, as illustrated in two recent cases, AGEP may develop without preceding medication or disease [238].

**6.5. Pathogenesis**

pustules.

**6.6. Diagnostic tests**

The pathogenesis of AGEP has been elucidated by patch [239],[240] and in vitro tests [241]- [243] and initially involves activation, expansion and subsequent migration of drug-specific CD4 and CD8 cells to the skin. The initial influx of CD8 cytotoxic T cells results in apoptosis of keratinocytes and the formation of subcorneal vesicles. The infiltrating CD4 cells release CXCL-8, which results in recruitment of neutrophils, and granulocyte macrophage-colony stimulating factor (GM-CSF), which prevents apoptosis of neutrophils. This results in the conversion of vesicles into pustules. CD4 cells also release IFN-γ, which stimulates keratino‐ cytes to secrete CXCL-8, as well as RANTES and IL-5, which contributes to the eosinophilia observed in some patients [244]. Resident Langerhans' cells may present drug antigens to CD4 cells and keratinocytes may act as antigen presenting cells to CD8 cells thereby augmenting the neutrophil-mediated inflammatory response. Genetic susceptibility to AGEP has not been

**Figure 14.** The lesions of AGEP occur rapidly and are characterized by dozens of small (< 5 mm) non-follicular sterile

Severe Cutaneous Adverse Reactions http://dx.doi.org/10.5772/54820 81

A pustular smear should be performed to exclude an infectious aetiology. A full blood count will reveal a neutrophilia. A skin biopsy may show (spongiform or non-spongiform) subcor‐ neal and/or intradermal pustules, edema of the papillary dermis, perivascular infiltrates with neutrophils and exocytosis of some eosinophils and focal necrotic keratinocytes (Fig. 15). The typical changes of psoriasis such as acanthosis and papillomatosis are usually absent. Patch testing may be useful in confirming the association between AGEP and the culprit drugs. In a

robustly examined and therefore remains largely unknown.

**Figure 13.** This patient with AGEP had an onset of erythema and edema of the face (A), erythema of the trunk (B) with a predilection for intertriginous areas (C).

**Figure 14.** The lesions of AGEP occur rapidly and are characterized by dozens of small (< 5 mm) non-follicular sterile pustules.

#### **6.5. Pathogenesis**

(a)

80 Skin Biopsy - Diagnosis and Treatment

(b)

)

(c)

with a predilection for intertriginous areas (C).

**Figure 13.** This patient with AGEP had an onset of erythema and edema of the face (A), erythema of the trunk (B)

The pathogenesis of AGEP has been elucidated by patch [239],[240] and in vitro tests [241]- [243] and initially involves activation, expansion and subsequent migration of drug-specific CD4 and CD8 cells to the skin. The initial influx of CD8 cytotoxic T cells results in apoptosis of keratinocytes and the formation of subcorneal vesicles. The infiltrating CD4 cells release CXCL-8, which results in recruitment of neutrophils, and granulocyte macrophage-colony stimulating factor (GM-CSF), which prevents apoptosis of neutrophils. This results in the conversion of vesicles into pustules. CD4 cells also release IFN-γ, which stimulates keratino‐ cytes to secrete CXCL-8, as well as RANTES and IL-5, which contributes to the eosinophilia observed in some patients [244]. Resident Langerhans' cells may present drug antigens to CD4 cells and keratinocytes may act as antigen presenting cells to CD8 cells thereby augmenting the neutrophil-mediated inflammatory response. Genetic susceptibility to AGEP has not been robustly examined and therefore remains largely unknown.

#### **6.6. Diagnostic tests**

A pustular smear should be performed to exclude an infectious aetiology. A full blood count will reveal a neutrophilia. A skin biopsy may show (spongiform or non-spongiform) subcor‐ neal and/or intradermal pustules, edema of the papillary dermis, perivascular infiltrates with neutrophils and exocytosis of some eosinophils and focal necrotic keratinocytes (Fig. 15). The typical changes of psoriasis such as acanthosis and papillomatosis are usually absent. Patch testing may be useful in confirming the association between AGEP and the culprit drugs. In a controlled study, patch tests were positive in half of the 14 cases of AGEP [96]. Readings should not be restricted to 24 and 48 hours after the application of the drug but should also be determined at 96 and 120 hours to maximise sensitivity. Pustule formation is often observed in positive patch tests in cases of AGEP. The test can be conducted one month after resolution of the disease. The risk of AGEP with patch testing is considered to be low but not negligible [245]. A small number of studies have supported a role for LTT [246], IFN-γ release [247], lymphokine macrophage migration inhibition factor release assays [241] but these in vitro tests are not widely available and its value remains to be determined in large cohorts.

**Morphology Pustules**

Course

Acute onset

Resolution

Fever ≥ 38°C

**Histology**

papillary edema

papillary edema

**Table 6.** Diagnostic score for validation of AGEP

NOS, not otherwise specified.

Post pustular desquamation

Mucous membrane involvement

Polymorphonuclear cells ≥ 7/μl

*Typical* +2 *Compatible with disease* +1 *Insufficient* 0

*Yes* +1 *No* 0

*Yes* -2 *No* 0

*Yes* 0 *No* -2

*Yes* 0 *No* -4

*Yes* +1 *No* 0

*Yes* +1 *No* 0

Other disease -10 Not representative 0 Exocytosis of polymorphonuclear cells +1 Subcorneal and/or intraepidermal non-spongiform pustules or NOS pustules with papillary edema or subcorneal and/or intraepidermal spongiform pustulea or NOS pustules without

Spongiform subcorneal and/or intraepidermal pustules with

Score ≤ 0; excluded, 1-4: possible, 5-7: probable, 8-12: definite

+2

Severe Cutaneous Adverse Reactions http://dx.doi.org/10.5772/54820 83

+3

**Figure 15.** A moderate power view of a skin biopsy from a patient with AGEP shows spongiform subcorneal pustules, edema of the papillary dermis and perivascular infiltrates with neutrophils and exocytosis of some eosinophils.



Score ≤ 0; excluded, 1-4: possible, 5-7: probable, 8-12: definite

**Table 6.** Diagnostic score for validation of AGEP

controlled study, patch tests were positive in half of the 14 cases of AGEP [96]. Readings should not be restricted to 24 and 48 hours after the application of the drug but should also be determined at 96 and 120 hours to maximise sensitivity. Pustule formation is often observed in positive patch tests in cases of AGEP. The test can be conducted one month after resolution of the disease. The risk of AGEP with patch testing is considered to be low but not negligible [245]. A small number of studies have supported a role for LTT [246], IFN-γ release [247], lymphokine macrophage migration inhibition factor release assays [241] but these in vitro tests

**Figure 15.** A moderate power view of a skin biopsy from a patient with AGEP shows spongiform subcorneal pustules, edema of the papillary dermis and perivascular infiltrates with neutrophils and exocytosis of some eosinophils.

> *Typical* +2 *Compatible with disease* +1 *Insufficient* 0

> *Typical* +2 *Compatible with disease* +1 *Insufficient* 0

**Morphology Pustules**

82 Skin Biopsy - Diagnosis and Treatment

Erythema

Distribution

are not widely available and its value remains to be determined in large cohorts.

#### **6.7. Differential diagnosis**

AGEP, which is characterized by non-follicular pustules can be readily distinguished from diseases with follicular pustulosis such as bacterial folliculitis, furunculosis, acneiform eruptions, pustular contact dermatitis, dermatophyte infection, viral exanthema with primary vesiculation and secondary postulation, impetigo, Sweet syndrome and SSSS. Other diseases are not as easily differentiated from AGEP. Generalized pustular psoriasis (Zumbusch psoriasis) is characterized by pustules that slowly develop on areas of psoriasis accompanied by the histological changes of psoriasis on skin biopsy. There is also usually a family history of psoriasis. Sneddon-Wilkinson disease (subcorneal pustulosis) and subcorneal IgA derma‐ tosis are characterized by the subacute development of larger pustules than those that erupt in AGEP and maybe associated with hyopyon formation.

**Author details**

Suran L. Fernando1,2

Australia

**References**

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1 Department of Clinical Immunology and Allergy, Royal North Shore Hospital, Sydney,

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[1] von Hebra F. Acute exantheme und hautkrankheiten. *Handbuch der Speciellen Patholo‐*

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[3] Thomas BA. The so-called Stevens-Johnson syndrome. *Br Med J* 1950;1(4667):1393-7.

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[7] Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC. Clinical classifica‐ tion of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema

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[9] Villiger RM, von Vigier RO, Ramelli GP, Hassink RI, Bianchetti MG. Precipitants in

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2 Sydney Medical School – Northern, Sydney University, Sydney, Australia

A diagnostic score was devised to validate the diagnosis of AGEP based on the morphology, course of disease, and histology and assist in the differentiation from similar diseases [223].

#### **6.8. Treatment**

As AGEP is a self-limiting disease with a favourable prognosis. Cessation of the causative agent and supportive treatment is usually all that his required. In the pustular phase, supportive measures consist of moist dressings with drying and disinfecting solutions to avoid superin‐ fection. In the postpustular desquamation phase, emollients are used to optimise preservation of skin barrier function. In a study of nine cases from Israel, all of who made a full recovery, seven received supportive care alone and the other two received corticosteroids [248]. It remains to be established whether oral or parenteral corticosteroids hasten the resolution of disease. A brief course of systemic corticosteroids may be considered in patients with severe and widespread inflammation of the skin.

## **7. Conclusion**

SCARs such as SJS/TEN, DIHS/DRESS, and AGEP are idiosyncratic and specific types of reactions that have distinct clinical, laboratory and histological features. The definition of DIHS/DRESS has not been universally adopted and will need to be clarified once the role of herpetic viruses and characteristic histological features are known. The early identification of these reactions and the subsequent prompt withdrawal of therapy and the implementation of supportive and adjunctive therapies are crucial in minimising morbidity and rates of mortality. Multicentre randomized studies are required to adopt the most suitable therapies for these potentially life-threatening conditions. The emergence in the understanding of HLA suscept‐ ibility genes will enable patients to be screened for the risk of developing a SCAR and will hopefully be more widely performed once cost effective and rapid methods of detection are widely available to the prescribing doctor.
