Acute generalized exanthematous pustulosis (AGEP) is a pustular reaction characterized by an abrupt onset of numerous nonfollicular sterile pustules, arising within an erythematous and edematous background. It is rare with the reported incidence of one to five cases per million people per year [
The medical records of 19 patients diagnosed with AGEP treated at Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, from August 2008 and November 2012 were retrospectively reviewed. Patients 18 years of age and above who had definite or probable diagnosis of AGEP (final score ≥ 5) according to the grading system proposed by the study group of the European study of Severe Cutaneous Adverse Reactions (EuroSCAR) (Table
Acute generalized exanthematous pustulosis validation score of the EuroSCAR study group [
Morphology | Score |
---|---|
Pustules | |
Typical | 2 |
Compatible | 1 |
Insufficient | 0 |
Erythema | |
Typical | 2 |
Compatible | 1 |
Insufficient | 0 |
Distribution/pattern | |
Typical | 2 |
Compatible | 1 |
Insufficient | 0 |
Pustular desquamation | |
Yes | 1 |
No/insufficient | 0 |
Course | |
Mucosal involvement | |
Yes | −2 |
No | 0 |
Acute onset (<10 d) | |
Yes | 0 |
No | −2 |
Resolution (<15 d) | |
Yes | 0 |
No | −4 |
Fever > 38°C | |
Yes | 1 |
No | 0 |
Neutrophils > 7,000/mm | |
Yes | 1 |
No | 0 |
Histology | |
Other diseases | −10 |
Not representative/no histopathology | 0 |
Exocytosis of neutrophils | 1 |
Subcorneal and/or intraepidermal nonspongiform or unspecified pustule(s) with papillary edema or subcorneal and/or intraepidermal spongiform or unspecified pustules(s) without papillary edema | 2 |
Spongiform subcorneal and/or intraepidermal pustule(s) with papillary edema | 3 |
Interpretation: <0: no AGEP, 1–4: possible, 5–7: probable, and 8–12: definite.
Statistical analyses were performed using computer software (SPSS version 18; SPSS Inc., Chicago, IL). Categorical variables (e.g., gender, prior drug allergy, distribution, culprit drug, clinical findings, and laboratory abnormalities) are expressed in percentage. Continuous variables (e.g., drug-AGEP latent period and resolution time) are reported as median. To compare various treatment regimens in correlation to the time of disease regression, ANOVA test was used. A
From August 2008 and November 2012, 25 patients of AGEP were identified. Nineteen patients had definite or probable diagnosis of AGEP according to the EuroSCAR AGEP validation score (final score ≥ 5). Fourteen patients had scores consistent with definite diagnosis and 5 patients were classified as probable cases of AGEP. Six cases classified as possible AGEP were excluded. The details of all patients and their reported comorbidities are summarized in Table
Patient data (demographics, underlying disease, drug exposure, onset of symptoms, EuroSCAR AGEP validation, and therapy).
Patient | Age (years)/sex | Drug allergy history | Comorbidities | Possible etiology and duration between drug initiation and AGEP | EuroSCAR score | Therapy |
---|---|---|---|---|---|---|
1 | 28/F | No | Cervical carcinoma stage IIIb | Omeprazole (15 days) | 8 | Topical steroid |
|
||||||
2 | 84/M | No | Pulmonary tuberculosis, diverticular bleeding | Isoniazid, rifampicin, pyrazinamide, and ethambutol (16 days) | 10 | Supportive |
|
||||||
3 | 73/M | No | COPD, pulmonary tuberculosis | Amoxicillin (3 days) | 8 | Topical steroid |
|
||||||
4 | 38/F | Yes | Submucous myoma, hyperthyroidism | Clindamycin (1 day) | 9 | Supportive |
|
||||||
5 | 74/F | No | Subarachnoid hemorrhage | Meropenem (4 days) | 8 | Oral prednisolone |
|
||||||
6 | 48/F | No | Cervical carcinoma stage IIIb | Celecoxib (11 days) | 7 | Topical steroid |
|
||||||
7 | 38/F | No | Ruptured appendicitis, Graves’ disease | Ceftriaxone (2 days) | 8 | Topical steroid |
|
||||||
8 | 65/M | No | Congestive heart failure | Piperacillin/tazobactam |
7 | Oral prednisolone |
|
||||||
9 | 45/M | No | Accidental fingers amputation | Cefazolin (2 days) | 8 | Oral prednisolone |
|
||||||
10 | 71/F | Yes | Rheumatoid arthritis, subacute lupus erythematosus, and lymph node tuberculosis | Clindamycin (2 days) | 9 | Topical steroid |
|
||||||
11 | 53/M | No | Atypical mycobacterial infection | Amikacin, clarithromycin, levofloxacin, and imipenem (25 days) | 9 | Oral prednisolone |
|
||||||
12 | 33/F | Yes | Morbid obesity post-Roux-en-Y gastrojejunostomy, carcinoma of the ovary | Omeprazole (3 days) | 9 | Topical steroid |
|
||||||
13 | 68/F | No | Renal failure, old stroke, and sepsis with pancytopenia | Meropenem (1 hour) | 8 | Topical steroid |
|
||||||
14 | 38/M | Yes | No | Amoxicillin (2 days) | 9 | Oral prednisolone |
|
||||||
15 | 31/M | No | Upper respiratory tract infection | Herbal medicine (1 day) | 6 | Topical steroid |
|
||||||
16 | 73/M | No | Chronic kidney disease with infected arteriovenous fistula | Vancomycin (21 days) | 7 | Topical steroid |
|
||||||
17 | 76/M | No | Double-vessel disease admitting for coronary artery bypass graft | Imipenem (4 days) | 6 | Topical steroid |
|
||||||
18 | 19/F | No | Donor for liver transplantation | Cefoxitin (3 days) | 8 | Topical steroid |
|
||||||
19 | 36/M | No | No | Viral infection | 9 | Oral prednisolone |
COPD, chronic obstructive pulmonary disease.
Systemic drugs were the most common etiology. The criteria proposed by Naranjo et al. were used to identify the culprit drug [
The etiology of acute generalized exanthematous pustulosis (AGEP) in this study.
All patients presented with nonfollicular, pinpoint, and superficial pustules on erythematous background (Figure
Nonfollicular, pinpoint, and superficial pustules on an erythematous background.
(a) Numerous small superficial pustules on erythematous base in a patient with AGEP. (b) Erythema and desquamation 3 days after discontinuation of culprit drug, and administration of systemic corticosteroid.
A 31-year-old female presented with ALEP on the face 1 day after taking herbal medicine.
Thirteen patients (68.4%) had associated leukocytosis (normal 4,000–10,000/
Clinical characteristics and laboratory findings.
Pt. | Distribution | Fever | Facial edema | Oral involvement | Conjunctival involvement | Desquamation | Neutrophil count (/mL) | Eo | Hepatitis |
---|---|---|---|---|---|---|---|---|---|
1 | Abdomen, arms, and ankles | − | − | − | − | + | 4,602 | − | − |
|
|||||||||
2 | Face, back, and upper chest | + | − | − | − | + | 7,106 | − | − |
|
|||||||||
3 | Face, axillae, and trunk | − | + | − | − | + | 9,516 | − | − |
|
|||||||||
4 | Face, trunk, arms, and legs | + | + | − | − | + | 14,490 | − | − |
|
|||||||||
5 | Abdomen, back | − | − | − | − | + | 15,486 | − | + |
|
|||||||||
6 | Face, trunk, arms, and legs | − | + | − | − | + | 6,295 | − | − |
|
|||||||||
7 | Trunk, hands, and feet | − | − | − | − | + | 10,030 | − | − |
|
|||||||||
8 | Neck, upper chest, and back | − | − | − | − | + | 3,552 | − | − |
|
|||||||||
9 | Axillae, groins, lateral trunk, inner thighs, and volar surfaces of arms | + | − | − | − | + | 3,472 | 10% (WBC 5,260) | + |
|
|||||||||
10 | Proximal extremities | + | − | − | − | + | 18,620 | − | − |
|
|||||||||
11 | Chest, back, and intertriginous areas | + | − | − | − | + | 13,975 | − | + |
|
|||||||||
12 | Inframammary areas, lateral trunk, lower abdomen, and upper thighs | + | − | − | − | + | 9,672 | − | − |
|
|||||||||
13 | Inframammary areas, groins, and axillae | + | − | + | − | + | 814 | 33% (WBC 1,480) | − |
|
|||||||||
14 | Face, trunk, and extremities (about 90% BSA) | + | + | − | + | + | 11,025 | − | + |
|
|||||||||
15 | Face | − | − | − | − | − | 4,838 | − | − |
|
|||||||||
16 | Face, neck, trunk, and proximal extremities | + | + | − | − | + | 7,241 | − | − |
|
|||||||||
17 | Upper back | − | − | − | − | − | 9,316 | − | − |
|
|||||||||
18 | Back, groins | − | − | − | − | + | 11,398 | − | − |
|
|||||||||
19 | Trunk, extremities | + | + | + | + | + | 11,808 | − | + |
Remark: +, present; −, absent; Pt., patient; BSA, body surface area; WBC, white blood cells; Eo, eosinophils.
Four patients had history of cutaneous adverse drug reaction. Three patients had recurrent AGEP and one had prior exanthematous drug eruption. Two patients had past history of beta-lactam-induced AGEP. The first patient previously had AGEP from penicillin and developed AGEP the second time from clindamycin. The other had the first and second episodes of AGEP from ampicillin and amoxicillin, respectively. One patient had multiple recurrent AGEP from numerous medications (amoxicillin, dicloxacillin, piroxicam, diclofenac, and omeprazole) and this time developed AGEP from omeprazole. Given that the same medication (omeprazole) was commenced in several events, proton pump inhibitor is believed to be the culprit drug on these occasions. One patient had maculopapular rash due to cinnarizine, acetazolamide, isoniazid, and rifampicin and developed AGEP this time from clindamycin.
Sixteen cases were hospitalized and 3 patients were seen at an outpatient department. Most cases (11 patients) were treated with topical corticosteroid. Six patients were given oral prednisolone, which were patients with extensive cutaneous diseases and/or systemic involvement such as hepatitis. The remaining 2 patients received supportive care. The median duration of drug cessation to resolution of pustules was 3 days (2–12 days). There was one patient who had vancomycin-induced AGEP with exceptionally long resolution time of 12 days. This patient has chronic kidney disease stage 4 which leads to longer drug clearance time.
There were no differences between various treatment regimens regarding the median duration of medication cessation to resolution of pustules which were 2 days for topical corticosteroid, 3 days for oral prednisolone, and 2.5 days for supportive care (
We present here the first case series of AGEP in Thailand. The most common etiology for AGEP was beta-lactams antibiotics. Among these, carbapenems has emerged as one of the leading causes of AGEP, reflecting the increasing use of broad-spectrum antibiotics. We also present the first report of a herbal drug, namely,
Our study revealed no sexual predominance, in agreement with the previous two large series [
Antibiotics were the leading cause of AGEP (73.7%), followed by omeprazole (10.5%), celecoxib (5.3%), and herbal drug (5.3%). Interestingly, a more recent antibiotic implicated for drug resistant nosocomial infection in the carbapenem group, such as imipenem and meropenem, was found to be the cause of AGEP in 3 patients (15.8%). This may reflect drugs commonly given in a tertiary care setting.
Herbal drug was the cause of AGEP in one patient.
Viral infection was the suspected cause of AGEP in one patient based on the clinical presentation and peripheral blood picture profile; however, viral serology was not performed. Reports have shown that enterovirus, adenovirus, parvovirus B19, Epstein-Barr virus, cytomegalovirus, and hepatitis B virus were related to AGEP [
The pathophysiology of AGEP appears to be delayed type hypersensitivity to a specific drug. After exposure to the causative agent, activation of specific CD4 and CD8 occurs. These T cells then migrate to the skin and the drug-specific CD8 T cells use perforin/granzyme B and Fas ligand to cause keratinocytes apoptosis resulting in epidermal vesicle formation. Drug-specific T cells (mainly) and keratinocytes (to a lesser extent) produce CXCL8 (IL-8), a potent neutrophil-attracting chemokine, which leads to neutrophil accumulation within the vesicles. Moreover, interferon gamma and granulocyte/macrophage colony-stimulating factor are enhanced which help increase the survival of neutrophils and augment the formation of neutrophil accumulation [
In this study, the median latent period between drug initiation and skin eruption was 3 days (1 hour–25 days). However, the interval of more than 10 days was found in 5 patients. Two of these patients received omeprazole and celecoxib, which were nonantibiotics. This supports data from a previous study that drugs other than antibiotics had longer time between the administration of suspected drug and the onset of skin eruption [
Localized lesions of AGEP were found in two patients, one on the face and one on the upper back. Prange and colleagues first defined acute localized exanthematous pustulosis (ALEP) in 2005 [
Other less common features such as facial edema, mucosal involvement, blister, and erosion, which were found in our series, have been described previously [
Fever (52.6%) and neutrophilia (68.4%) were detected lower than previous studies [
History of prior cutaneous adverse drug reaction was detected in 4 patients (21.1%), comprising AGEP in 3 and maculopapular rash in 1. Recurrent AGEP is rarely reported in the literature. The major culprit drugs to cause recurrence are beta-lactam antibiotics, which is in consistence with an early report [
The diagnosis of AGEP is determined on morphology, clinical presentation, laboratory data, and histopathology. Several diagnostic criteria have been proposed and a well-recognized scoring system elaborated by EuroSCAR project has been used in this study [
The differential diagnoses include generalized pustular psoriasis of Von Zumbusch, pustular vasculitis, pustular Sweet’s syndrome, autoimmune blistering disease, and pustular eruption from infections such as bacterial folliculitis, dermatophyte, candida infection, herpes, and varicella infection. Although most can be excluded without difficulty, some may be a diagnostic challenge especially differentiating between AGEP and generalized pustular psoriasis [
Due to the self-limited and benign nature of this disease, treatment is usually not necessary except for symptomatic therapy and discontinuation of the offending drugs. However, in certain patients, the clinical course may be extensive and protracted necessitating systemic corticosteroids [
The limitations of this study are its retrospective nature and small number of subjects. Nevertheless, given the rarity of AGEP, large-scale studies are limited. Patch testing was not done as a part of the workup of AGEP.
This study received approval from the Mahidol University Institution Review Board (IRB) for human subject research (Protocol number 035645).
Informed consent was exempted by the Mahidol University Institution Review Board (IRB).
The authors declare that there is no conflict of interests regarding the publication of this paper.