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
|
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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