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Acute generalized exanthematous pustulosis: an overview of the clinical, immunological and diagnostic concepts

European Journal of Dermatology. Volume 20, Number 4, 425-33, July-August 2010, Review article

DOI : 10.1684/ejd.2010.0932

Summary

Author(s) : Marijn M Speeckaert, Reinhart Speeckaert, Jo Lambert, Lieve Brochez , Department of Internal Medicine, Ghent University Hospital, De Pintelaan 185 9000 Gent, Belgium, Department of Dermatology, Ghent University Hospital, De Pintelaan 185 9000 Gent, Belgium.

Summary : Acute generalized exanthematous pustulosis (AGEP) is a significant adverse cutaneous reaction, most often provoked by drugs and acute infections. The recognition of AGEP is important, in order to avoid confusion with a systemic infection and consequently to avoid incorrect treatment. The clinical hallmark is the presence of multiple disseminated sterile pustules on an erythematous background, associated with fever and a massive neutrophilia and sometimes eosinophilia. The disease is characterised by an acute onset and a spontaneous resolution within 2 weeks. The involvement of drug-specific T cells in the pathomechanism can be confirmed by positive skin patch tests and lymphocyte transformation tests. In this review, we highlight the main clinical, pathophysiological and diagnostic aspects of this peculiar form of drug allergy.

Keywords : acute generalized exanthematous pustulosis, lymphocyte transformation test, neutrophilic inflammatory process, patch test, pathophysiology, T cells

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ARTICLE

Auteur(s) : Marijn M Speeckaert¹, Reinhart Speeckaert², Jo Lambert², Lieve Brochez²

¹Department of Internal Medicine, Ghent University Hospital, De Pintelaan 185 9000 Gent, Belgium
²Department of Dermatology, Ghent University Hospital, De Pintelaan 185 9000 Gent, Belgium

accepté le 15 Janvier 2010

Acute generalized exanthematous pustulosis (AGEP), a member of the “neutrophilic dermatoses” was first described by Baker and Ryan in 1968 as exanthematic pustular psoriasis [1]. The term of pustuloses exanthématiques aiguës généralisées (PEAG) was introduced by a French dermatologist (C. Beylot) in 1980 [2]. This pustular skin eruption, with an incidence of 1-5 per million/year, has an equal age and gender distribution. It is a self-limiting disease, with the following clinical features: (1) numerous, small non-follicular, intraepidermal or subcorneal pustules (< 5 mm) on an erythematous background, (2) typical histopathological changes, (3) fever (> 38 °C), (4) blood neutrophil counts > 7 × 10⁹/L and (5) an acute evolution with spontaneous resolution of pustules in less than 15 days [3]. In elderly patients with previous chronic diseases, a mortality rate of 1-2% has been reported [4].

General characteristics

Etiology

AGEP is an uncommon clinical and histopathological reaction pattern, most often described in association with drugs (90% of the cases), acute viral infections (entero-virus (coxsackievirus A9 and B4, echovirus 11 and 30), cytomegalovirus, Epstein-Barr virus, hepatitis B virus, parvovirus B19), Escheria Coli [5], Chlamydia pneumoniae [6], Mycoplasma pneumoniae, Echinococcus granulosus [7], spider bites [8], heavy metals (mercury) [9], dietary supplements, chemotherapy [10], radiation and PUVA [11, 12]. Tables 1 (most frequently mentioned drugs), 2A, 2B and 2C (less frequently mentioned drugs) give an overview of the broad range of drugs, with a predominance of antibacterials and a number of non-antibacterial drugs which may function as triggers.

Although symptoms of AGEP can present at any age, it is uncommon in children and may be atypical in its presentation [13]. Viral infections (Coxsackie B4 virus, Epstein-Barr virus) and vaccinations [14] are suggested as the most frequent triggers in the pediatric population [13]. Systemic medications (amoxicillin, vancomycin, ribavirin, labetolol) [15] and mercury exposure [16] have also been described as possible etiologies. Early diagnosis of AGEP and differentiation from other diseases (e.g. generalized pustular psoriasis) can prevent this subgroup from unnecessary treatment (including retinoids and immunosuppressive therapy) [15].
Table 1 Most frequently mentioned drugs causing acute generalized exanthematous pustulosis

Antibiotics

Ampicillin [11, 12, 19, 34-36]

Amoxicillin [11, 12, 19, 34-36]

Amoxicillin/clavulanic acid [34]

Clindamycin [34, 35]

Cotrimoxazole [12, 34, 35]

Erythromycin [11, 12, 19, 34-36]

Metronidazole [3, 11, 34, 35, 37]

Penicillin [11, 12, 19, 34, 35, 37]

Pristinamycin [12, 19, 34, 35]

Spiramycin [12, 19, 34, 35]

Anticonvulsants

Carbamazepine [3, 12, 19, 34, 35, 38]

Antifungal agents

Nystatin [3, 11, 34, 36, 37]

Terbinafine [3, 11, 12, 19, 34, 36, 37]

Antihypertensives

Diltiazem hydrochloride [11, 12, 19, 34-36]

Antimalarial agents

Hydroxychloroquine [3, 12, 19, 34, 35, 39]

Table 2 A, B and C) Less frequently mentioned drugs causing acute generalized exanthematous pustulosis

A)
Antibiotics
Azithromycin [12, 36] Bacampicillin [12] Cefaclor [11, 12, 34-36] Cefalexin [12, 34, 35] Cefazolin [12, 19, 35] Cefotaxime [40] Cefoxitin [35] Cefradine [12, 35, 36] Ceftazidime [12, 35] Ceftriaxone [41] Cefuroxime [12, 35] Chloramphenicol [3, 11, 12, 34, 35, 38] Ciprofloxacin [12, 34] Cloxacillin [34] Doripenem [38] Doxycycline [11, 12, 19, 34, 35]	Enoxacin [12] Gentamicin [3, 19, 34, 35, 37] Imipenem [3, 12, 35, 37] Josamycin [12] Levofloxacin [42] Lincomycin [34] Minocycline [34, 36] Moxifloxacin [43] Nifuroxazide [3, 19, 34] Norfloxacin [12, 35] Oxytetracycline [12] Pipemidic acid [12, 19, 34, 35] Piperacillin [34] Propicillin [29, 34] Protease inhibitors [3] Resprim [11]	Rifabutin [44] Rovamycin [35] Roxithromycin [11, 12, 19, 34, 35] Streptomycin [12, 34, 35] Sulfasalazine [3, 12, 34, 37] Tazobactam [34] Teicoplanin [34] Tetracyclin [35] Trimethoprim [3, 12, 34, 35, 37] Vancomycin [3, 12, 19, 34, 35, 37]
B)
Anti-arrythmics Nadoxolol [3, 12, 19, 34, 35] Propafenon [34] Quinidine [3, 12, 34] Anticonvulsants Phenytoin [12, 35] Phenobarbital sodium [11] Antifungal agents Amphotericin B [35] Fluconazole [34, 37] Griseofulvin [3, 34, 35, 37] Itraconazole [3, 12, 19, 34-37] Antihypertensives Enalapril [3, 11, 12, 34, 35, 37] Fenoterol [3] Furosemide [3, 11, 12, 34, 37] Hydrochlorothiazid [34] Nifedipine [3, 12, 19, 34, 35]	Antimalarial agents Chloroquine [12, 37] Dapsone [45] Diaphenylsulfone [3] Mefloquine [12] Antipyretics/Analgetics Acetaminophen [11, 35] Acetylsalicylic acid [3, 12, 34] Celecoxib [34] Ibuprofen [34] Metamizol [34] Paracetamol [3, 12, 19, 34, 38] Valdecoxib [34] Anxiolytics/benzodiazepines Chlorpromazine [46] Clobazam [3, 12, 19, 34, 35] Clozapine [3, 38] Nitrazepan [47] Tetrazepam [48]	Chemotherapy Bleomycin [34] Cytarabin [34] Exemestane [49] Imatinib [34] Pemetrexed [10] Thalidomide [3, 38] Contrast Iodixanol [50] Iohexol [34] Iopamidol [34, 36] Ioversol [51] NSAIDS Bufexamac(topical) [3, 12, 34, 35] Diclofenac [12] Naproxen [35, 47] Phenylbutazone [35]
C)
Others
Acetazolamide [12, 19, 35] Allopurinol [3, 12, 34, 35, 37] Aminoglutethimide [12] Amoxapine [3, 12, 36, 37] Azathioprine [52] Bamifylline [34] Bromic acid vapour [17, 34] Buphenine [3, 12, 34] Calcium dobesilate [12] Carbutamide [3, 12, 19, 34, 35] Chromium picolinate [3] Cimetidine [3, 37] Clemastine [3] Dalteparin [53] Dexamethasone [3, 11, 34, 37] Disulfiram [3, 12, 34, 37] Dihydroquinidine [19] Eperisone hydrochloride [54] Eprazinone [4] Famotidin [34] Ferrous Fumarate [12] Icodextrin [34]	Isoniazid [3, 12, 34, 35, 37] Lamivudin [34] Lansoprazole [3, 37] Lopinavir [34] Mercury [3, 11, 12] Methoxalen [34, 35] Methylprednisolon [34] Pholcodine [19] Piperazine [3, 12, 35] Pneumococcal vaccine [3, 19] Progesteron [34] Prostaglandine E [18] Pseudoephedrine [34, 55] Pyrimethamine [3, 12, 34, 37] Ranitidine [19, 34] Ritonavir [34] Sertralin [34] Simvastatin [34] Sulbutiamine [3, 12, 19, 34] Sulfuric acid vapour [17] Thallium [47] Ticlopidine [11, 34] Zidovudin [34]

Clinical aspects

Based on three aspects, (1) lesion morphology, (2) disease course and (3) histological features, the EuroSCAR study group developed an AGEP validation score system, differentiating possible/probable/definite cases [3].

Typical AGEP is characterised by an acute cutaneous eruption with non-follicular sterile pustules on an edematous erythema (figure 1), accompanied by fever above 38 °C. In most cases, the skin symptoms begin in the face or in the intertriginous areas, moving to the trunk and the lower limbs in a few hours. On a burning and/or pruritic erythematous background, hundreds of small (pinhead sized < 5 mm), whitish non-follicular sterile pustules arise, sometimes mimicking a positive Nikolsky's sign. The mean duration of the pustules is 9.7 days (4-10 days), followed by a characteristic postpustular pin-point desquamation for a few days [3, 4, 12].

About 50% of patients exhibit other skin symptoms like marked edema of the face, purpura lesions (especially on the legs), Stevens-Johnson-syndrome-like “atypical targets”, vesicles and blisters have been described but are not typical. However, clinical diagnosis remains difficult if a monomorphic eruption located on hands and feet is presented. Mild mucous membrane involvement on a single site (mostly a few erosions on the mouth and tongue) may occur in about 20% of cases [3, 4, 12, 17].

High fever usually begins abruptly on the same day (or within 2 to 3 days before or after the eruption) as the pustular eruption and lasts for about 1 week. Lymphadenopathy has been reported in some cases.

Sidoroff et al. identified two different temporal patterns of AGEP reaction from the beginning of administration to the onset of a reaction: a first group with a rapid onset (only a few hours to 2-3 days after drug intake, especially antibacterials) and a second group with an interval of 1 to 3 weeks (mean 11 days) for all other drugs. The pattern with a short interval is probably the result of a previous sensitization and/or an immunological recall phenomenon induced by T-cell reactivation. The reaction pattern that involves an extended interval from the start of drug intake until the development of skin symptoms may result from primary sensitization [3].

In 2005, Prange et al. introduced the definition of acute localised exanthematous pustulosis (ALEP) to describe a case which, according to the criteria of AGEP, was diagnosed with a localised pustular eruption on the face [18].

Differential diagnosis

A wide spectrum of cutaneous diseases or reactions is associated with pustular eruptions. In view of the self-limiting character of AGEP, it is essential to differentiate it from the wide spectrum of cutaneous diseases or reactions, which are associated with pustular eruptions (table 3) [3]. The principal differential diagnoses of AGEP consist of pustular psoriasis, Sweet's syndrome, pustular erythema multiforme, toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), subcorneal pustulosis (Sneddon-Wilkinson syndrome), pustular vasculitis, bullous impetigo [3, 19, 20].
Table 3A Differential diagnoses of acute generalized exanthematous pustulosis

Typical pustular	Pustular psoriasis (von Zumbusch type) [3, 20, 56-58]	Subcorneal pustulosis (Sneddon-Wilkinson) [59, 60]	Bullous impetigo [61]
General chatacteristics	♀> ♂, middle-aged	No marked age- or gender-related trend	Children and young adults, no gender-related trend
Cutaneous findings	Confluent annular or polycyclic erythematous patches with pinhead-sized pustules at the periphery and a central area of desquamation, mucous membrane lesions on the oral mucosa	Skin lesions represent classical secondary (symptomatic) livedo reticularis, a relapsing symmetrical pustular eruption, pustules arising on normal skin or slightly erythematous base coalescing in annular or serpiginous patterns	Small vesicles and pustules developing into bullae, containing clear yellow or slightly turbid fluid without surrounding erythema, arising on a normal appearing skin; with rupture, bullous lesions decompress and shallow moist erosions are formed
Location	Starting in intertriginous areas and spreading to extremities and trunk	Trunk, intertriginous areas, flexor aspects of the limbs, palms and soles	More common in intertriginous sites
Associated findings	Fever with chills, burning sensation, arthralgia, polyarthritis, muscle weakness, diarrhea, nausea, malaise, associated respiratory or other infection	Oral lesions (rare), neurological symptoms	Sometimes lymphangitis and/or regional lymphadenopathy
Laboratory findings	Leukocytosis, elevated erythrocyte sedimentation rate (ESR), positive C-reactive protein (CRP), high anti-streptolysin O antibody levels, increases in IgG or IgA, hypoproteinemia, hypocalcemia	Association with various forms of immune dysfunction	Culture and Gram's stain: Gram-positive cocci
Histology	Psoriasiform acanthosis, parakeratosis, spongiform, subcorneal and/or intraepidermal pustules, perivascular infiltrate, papillary dermal edema, Munro's microabscesses, papillomatosis	A perivascular inflammatory infiltrate with neutrophils and occasional eosinophils; neutrophils migrate through the epidermis to aggregate beneath the stratum corneum, leading to sterile subcorneal pustules	Vesicle formation (very early lesion) in the subcorneal or granular region, acantholytic cells, spongiosis, dermal perivascular infiltrate of lymphocytes and neutrophils; Gram-positive cocci in blister fluid and within neutrophils
Immunofluorescence	Deposits of complement C3 in the vessel walls and/or in the dermal-epidermal junction	Classically negative	Negative

Table 3B Differential diagnoses of acute generalized exanthematous pustulosis

Not typical pustular	DRESS [4, 20, 62-64]	Stevens-Johnson syndrome and Toxic epidermal necrolysis (TEN) [61, 65]	Erythema multiforme [20, 66, 67]	Acute febrile neutrophilic dermatosis (Sweet's syndrome) [20, 68-70]	Pemphigus [61, 71]
General characteristics	No gender- or age-related trend	no gender-related trend, middle-aged	♂ > ♀, especially young adults (20-40 years)	♀ > ♂, most 30 to 60 years	Middle-aged and older patients, no gender-related trend
Cutaneous findings	Generalized maculopapular eruption with oedema of the face; plaques and nodules are also possible	Flat, irregular, atypical target lesions or diffuse purpuric macules that frequently have necrotic centers (particularly in TEN) and tend to coalesce over the course of time; flaccid blisters; positive Nikolsky sign; permanent alopecia; anonychia	Hundreds (a)symptomatic target- or iris-like lesions, circular erythematous plaques in a concentric array, central blister or area of necrosis may be present, transient hypo- or hyper- pigmentation	Abrupt onset of tender erythematous lesions (plaques, papules, nodules), oral or vaginal ulcers	Pemphigus vulgaris (PV): mucosal-dominant (MD): mucosal lesions but minimal skin involvement mucocutaneous (MC): extensive skin blisters and erosions with mucosal involvement		Pemphigus foliaceus (PF): scaly and crusted superficial erosions of the skin but not of the mucous membranes; positive Nikolsky's sign
Location	Face, upper trunk, and upper extremities followed by the lower extremities	Mostly on the trunk and face, but can also occur on the neck and proximal extremities	Acral regions (< 10% of the body surface area, usually dorsal surfaces of hands, feet, elbows, knees + face) in a fixed position with a symmetric distribution	Face, neck and extremities	PV: scalp, face, chest, axillae, groin, umbilicus, erosions on mucous membranes PF: most commonly on face, scalp, upper chest, abdomen, may also involve the entire skin
Associated findings	Fever, lympadenopathy, hepatitis,hepatosplenomegaly, interstitial nephritis, interstitial pneumonia, carditis, arthralgias	Influenza-like symptoms, mucosal lesions, keratitis, acute conjunctivitis, symblepharon, stomatitis, dyspnea, diarrhea, abdominal pain, dehydration, hemodynamic shock	Low-grade fever, erosive oral mucosal lesions, cough, rhinitis, malaise, diarrhea, myalgia, arthritis	Fever, upper respiratory tract infection, malaise, pathergy, conjunctivitis, episcleritis, arthralgias, polyarthitis, fasciitis, myalgias, myositis, hematological malignancy	PV: no pruritus, but burning and pain, epistaxis, hoarseness, dysphagia, weakness, malaise, weight loss
Laboratory findings	Atypical lymphocytosis or eosinophilia, increased liver transaminases and total bilirubin, HHV-6, HHV-7, CMV and/or EBV reactivation	Anemia, lymphopenia, eosinophilia (uncommon), neutropenia	No abnormalities of significance	Elevated ESR and CRP, leukocytosis (> 70% neutrophils), p-ANCA sometimes positive	IgG antibodies that bind to the surface of normal keratinocytes
Histology	Dense, pleiomorphic, lymphocytic infiltrate in the superficial dermis and/or perivascular region; dermal edema; interstitial deposition of an amorphous acidophilic material	Early phase: vacuolization/ necrosis of basal keratinocytes and individual cell necrosis throughout the epidermis Late phase: full-thickness epidermal necrosis and subepidermal split above the basement membrane, little or no inflammatory infiltrate in the dermis	Necrotic keratinocytes, intraepidermal blisters	Dense neutrophilic infiltrate in the dermis without leukocytoclastic vasculitis	PV: loss of cell adhesion in the deep epidermis, just above the basal layer, leading to acantholysis and bulla PF: loss of cell adhesion in the more superficial epidermis, just below the stratum corneum
Immuno-fluorescence	Unremarkable, ruling out other blistering disorders	Unremarkable, ruling out other blistering disorders	Usually not useful, but deposits of IgM and C3 in the walls of superficial blood vessels can usually be identified; granular deposits of IgM, C3 and fibrinogen along the basement membrane	Negative direct IF in fresh lesions	Direct IF: IgG and often C3 on the surface of the keratinocytes Indirect IF: circulating IgG antibodies against desmoglein-1 (DSG1) and/or desmoglein-3 (DSG3)
						Anti-DSG1	Anti-DSG3
					PF	Yes	No
					PV
					MD	No	Yes
					MC	Yes	NO

Histopathology (figure 2)

The typical histopathology and immunochemistry of AGEP is characterised by spongiform subcorneal and/or intraepidermal pustules, marked papillary edema (occasionally with the formation of a subepidermal blister) and polymorphous perivascular infiltrates with neutrophils and exocytosis of some eosinophils. In a minority of cases, leukocytoclastic vasculitis with fibrinoid deposition and/or focal necrosis of keratinocytes is observed. The presence of extravasated red blood cells, without chemo-attractant or cell adhesion molecule receptors within the intraepidermal pustules, probably indicates a passive process related to transepidermal elimination of a papillary edema, rather than a specific chemotaxis or cell migration as in psoriasis. Psoriatic changes like acanthosis and papillomatosis (as seen in pustular psoriasis) are usually absent [4, 12].

Laboratory findings

In 90% of cases, the blood neutrophil counts are elevated (> 7.10⁹/L). A mild eosinophilia is present in about 30%. Renal function is slightly reduced (creatinine clearance < 60 mL/min) in 30% of the cases, with urinary features of “pre-renal” azotemia. Liver tests are usually normal. Hypocalcemia and a mild elevation of aminotransferases (< twice the upper limit of the normal range) can be observed. No involvement of other internal organs has to be expected. In a small study of AGEP patients, HLA B51 (human leukocyte antigen), DRB1*07, DR11, and DQ3 were found more frequently than in the average population. Although Staphylococcus aureus may be present in a few cases, the pustules are most often amicrobial [1, 3, 4, 21-23].

Pathophysiology

Although the pathophysiological mechanism is not yet understood, a genetic hypersensitivity or a type IV allergic reaction is suggested. The pathophysiology of AGEP can be divided into three phases (figure 3).

After drug intake, antigen-presenting cells activate drug-specific T cells by presentation of the drug to MHC class I (for CD8⁺ T cells) and class II (for CD4⁺ T cells) in the lymph nodes. Drugs can be presented covalently bound to the peptide/MHC complex or in a labile, non-covalent way [24]. This is followed by expansion and migration of T cells into the dermis and epidermis (Phase I) [25]. In Phase II, drug-presenting keratinocytes (on MHC class I) and Langerhans’ cells (on MHC classes I and II) stimulate the infiltrating T cells to produce high levels of the potent neutrophil-attracting chemokine CXCL8 (Interleukin 8, IL8) and an additional chemotactic factor acting via CXCR2 (not yet identified). CXCL8⁺ T cells bear a specific chemokine receptor profile (CCR5, CXCR3 and CXCR6) on their cell surface and express mainly a Th1-type cytokine profile [Granulocyte/Macrophage-Colony-Stimulating Factor (GM-CSF), Interferon-gamma (IFNγ), Tumor Necrosis Factor-alfa (TNF-α)] and occasionally IL-4 and IL-5 (Th2-type cytokine profile). GM-CSF and IFN-γ enhance the neutrophil survival. In combination with eotaxin/CCL11 and RANTES (Regulated on Activation, Normal T cell Expressed and Secreted)/CCL5 released occasionally by perivascular cells, such T-cell clones may contribute to the eosinophilia observed in ~ 30% of AGEP cases, due to the high IL-5 expression. Besides IFNγ production, CD8⁺ cytotoxic T lymphocytes are key players in tissue destruction. The combined release of inflammatory cytokines (e.g. IFNγ, GM-CSF, TNF-α) may stimulate the keratinocytes to secrete CXCL8 and express ICAM-1 [Inter-Cellular Adhesion Molecule 1 or CD54 (Cluster of Differentiation 54)] on their surface, facilitating the recruitment of T cells and neutrophils to the inflamed skin [25, 26] Based on a perforin/granzyme and a Fas/FasL-mediated mechanism, CD8⁺ cytotoxic drug-specific T cells are responsible for keratinocyte killing, which leads to tissue destruction and formation of subcorneal vesicles [26]. In comparison with the scattered distribution of CD4+ and CD8+ cells in the epidermis, the subcorneal vesicles are mainly filled by CD4+ cells [25, 26]. Phase III is characterised by the attachment of an increasing number of neutrophils at the site of inflammation to adhesion molecules (e.g. ICAM-1), expressed on activated endothelial cells. Migration of these polymorphonuclear leukocytes along the increasing CXCL8 gradient through the dermis and the epidermis into the vesicles results in the formation of pustules. The T cells accumulate in the dermis (CD4⁺ > CD8⁺) and around blood vessels (CD4+ = CD8+) [25].

Human IL-17 is a 16-kDa protein, secreted by CD4+ as well as CD8+ activated memory (CD45RO+) T cells which may constitute a link between activation of certain T cells and mobilization of neutrophils. During tissue inflammation, IL-17 mobilizes neutrophils by granulopoiesis, CXC chemokine induction and by increasing their local survival. Multiple studies reported the enhanced production of potent neutrophil attracting factors (IL-6 and IL-8) in keratinocytes and a weak induced expression of ICAM-1 and HLA-DR. In contrast, IFN-γ and TNF-α-induced production of RANTES was markedly inhibited by IL-17. Finally, IL-17 modulates the fibroblast function by inducing their IL-6, IL-8, IL-11, GROα (growth-related protein alfa) and G-CSF production. This indirect CXCL8 induction ensures an additional regulatory stage in the T-cell orchestration of PMN (polymorphonuclear leukocyte)-rich inflammation [27].

AGEP is a very interesting topic of immunological research. Drug hypersensitivity reactions have been classified as type I to IV reactions. A new subclassification of delayed-type IV hypersensitivity reaction (a-d) has been proposed according to the cytokine production, the cytotoxic activity of the T cells and the participation of different effector cells. AGEP may represent a peculiar type of delayed hypersensitivity reaction, where cytotoxic T cells (type IV c) emigrate and kill tissue cells (keratinocytes). In addition, T cells produce large amounts of certain cytokines and chemokines (IL-8/CXCR8), which preferentially activate and recruit neutrophils (type IV d) [28].

Another possible pathophysiological mechanism is the production of antigen-antibody complexes induced by an infection or drug that activates the complement system and causes neutrophil chemotaxis [11].

Diagnosis

Although the diagnosis of AGEP is based on the five main criteria mentioned in the introduction, additional tests may be used to identify the causative substance. Multiple in vivo (patch test) and in vitro (lymphocyte transformation test (LTT), histological and immunohistological studies and generation of T-cell lines and clones) tests have been developed to confirm a drug specific T-cell reaction [29].

The gold standard for the sensitivity (and specificity) of a test for drug reaction is normally a positive drug provocation test, carried out by physicians experienced in this particular field. However, in the case of severe reactions, such as DRESS, Stevens-Johnson syndrome, TEN and AGEP, the drug provocation test is avoided [30].

For want of an animal disease model, cutaneous drug patch tests are important tools to analyze the pathogenesis of and to determine the etiology of AGEP [6]. T-cell involvement and a delayed-type hypersensitivity reaction mimic the original skin eruption at the patch test site. Due to a particular priming of drug-specific T cells in AGEP, the immune response to a drug is persistent once generated and does not change on subsequent exposures, which can occur via the skin or by the oral route [3, 12, 29]. In most cases, the test reaction is limited to the test site; however, a few reports of reactions spreading beyond this site are known [12]. In comparison with cases of Stevens-Johnson syndrome and TEN, patch testing seems more appropriate for AGEP, as the proportion of positive tests is significantly higher. The sensitivity of patch testing to drugs in AGEP is approximately 50% (up to 80% for certain antibiotics) [31]. In clinical practice, patch testing has been reported to be a safe and irrefutable method in determining the culprit drug of AGEP [32]. Although patch testing may not be required in patients with a classic presentation (primary diagnosis is always based on a detailed history and a thorough clinical examination), it can help to narrow the differential diagnosis in ambiguous cases.

Different in vitro tests like the macrophage migration inhibition factor (MIF) test, the mast cell degranulation (MCD) and the LTT have been used to elucidate the cause of AGEP [3]. The LTT is the most widely used test to detect a T-cell sensitization to drugs. It is based on a drug-specific memory T-cell response, measuring ³H-thymidine uptake of dividing cells, after encountering an antigen. Those T cells need to be present in sufficient amounts in the circulation to lead to a detectable response by the in vitro stimulation. During the acute phase, the immune system (in particular T cells) is strongly activated. For that reason, it is better to perform the test after remission (4-8 weeks after the reaction) [29, 33]. Treatment with immunosuppressive drugs may suppress the proliferation in vitro. A particular advantage of an in vitro system measuring T-cell reactions to drugs is its potential to detect both the conductor as well as the key players of the immune system [29]. The LTT was observed to have a higher sensitivity (78%) than the patch test and a comparable specificity (85%). Despite this, its application in routine diagnosis is still controversial, due to the great heterogeneity of drug hypersensitivity reactions. The LTT requires experience with cellular techniques, certain expensive equipment and in-depth background information on the pharmacology and immunology on the part of the interpreter [29, 33].

Therapy

Due to the self-limiting course of AGEP, specific treatment is generally unnecessary. No therapy is available to prevent lesion extension and a further decline of the patient's general condition. The causative drug has to be discontinued and antibiotics are not to be given unless there is superinfection of the skin lesions. Systemic antipyretics can be given symptomatically if not suspected as a causative drug. Corticosteroid treatment, which is often taken into consideration, is usually not necessary [3].

Conclusion

AGEP is an adverse skin reaction in which the T cell/PMN interplay plays an important pathogenic role in the pathogenesis. The etiological relationship between drugs and this pustular eruption pattern is well described. Early diagnosis of AGEP is important to avoid unnecessary investigations and/or the administration of expensive and sometimes risky antibiotics. Combination of in vivo and in vitro test systems might be required to pinpoint the causative drug for a hypersensitivity reaction. More systematic research should be directed towards simplification and an improved sensitivity for the diagnostic tests.

Acknowledgements

Financial support: none. Conflict of interest: none.

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