Acute Generalized Exanthematous Pustulosis (AGEP) 

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Acute Generalized Exanthematous Pustulosis

Description

  • Acute Generalized Exanthematous Pustulosis is a rare, severe, cutaneous reaction that is characterized by the acute onset of small, nonfollicular, sterile pustules on erythematous, intertriginous skin, accompanied by fever and leukocytosis(1,2,3)
  •  AGEP is caused by drugs in > 90% cases(1,2,3)
  •  most frequently caused by aminopenicillins, macrolides, pristinamycin, sulfonamides, quinolones, hydroxychloroquine, terbinafine, and diltiazem(1,2,3)
  •  symptoms usually resolve ≤ 2 weeks once culprit drug is withdrawn, however fatal systemic involvement reported in 5% of patients(1,2)

Also Called

  •  pustular drug eruption or rash
  •  toxic pustuloderma

Epidemiology

Who Is Most Affected

  •  any age may be affected with AGEP(1,2,3)
  • AGEP reported to be more common in women(3)

Incidence/Prevalence

  • AGEP is rare, with an incidence of 1-5 cases per million per year(1,2,3)
  •  adjusted annual incidence of 0.35 per million per year reported during 2002-2005 in Israel (Isr Med Assoc J 2008 Jun;10(6):410)

Risk Factors

  • risk of AGEP may be associated with prior history of drug reactions
    •  based on retrospective cohort study
    •  28 patients (mean age 56 years, 61% women) with AGEP at a single center (Mayo Clinic) in Minnesota, United States between January 1996 and December 2013 were assessed
    • in 22 patients for whom time elapsed between exposure and symptom could be confirmed
      •  mean time from drug administration to onset of symptoms was 8.3 days
      •  82% of patients had symptoms < 10 days after exposure, while remaining 4 patients had symptoms develop over a range of 14-28 days
    • etiologies described
      •  drugs in 25 patients (89%)
      •  intravenous contrast agent in 1 patient (4%)
      •  unknown causes in 2 patients (7%)
    •  86% of patients had a personal history of drug reactions before development of AGEP
    •  Reference – Int J Dermatol 2017 Apr;56(4):405
  • mutations in IL36RN gene
    • missense mutations of IL36RN may be associated with AGEP, and may be associated with oral involvement of lesions in patients with AGEP
      •  based on cohort study
      •  96 patients with AGEP from the International Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) were tested for missense mutations in IL36RN gene
      •  1 patient was homozygous for a loss-of-function mutation, and 3 patients had heterozygous mutations
      •  compared to the frequency in data sets of European ancestry, the frequency of heterozygous mutations was significantly associated with AGEP in this cohort (p < 0.012)
      •  compared to patients with wild-type IL36RN in this cohort, patients with mutations of IL36RN had significantly more intraoral involvement of AGEP (p < 0.014)
      •  Reference – J Invest Dermatol 2013 Jul;133(7):1904full-text
    •  homozygous mutation in exon 5 of IL36RN gene associated with recurrent episodes of AGEP and generalized pustular psoriasis with intraoral involvement in man aged in his 40s in case report (JAMA Dermatol 2015 Apr;151(4):452)
    •  heterozygous IL36RN mutation associated with dihydrocodeine phosphate-induced AGEP in woman in her 60s in case report (JAMA Dermatol 2015 Mar;151(3):311)

Etiology and Pathogenesis

Causes

Drugs
  •  > 90% of cases of AGEP are caused by drugs(1,2,3)
  • AGEP usually manifests 1-4 days after exposure to the culprit drug(1,2,3)
  • drugs most frequently associated with AGEP include(1,2,3)
    •  aminopenicillins (ampicillin/amoxicillin)
    •  pristinamycin and other macrolides
    •  sulphonamides
    •  quinolones
    •  hydroxychloroquine
    •  terbinafine
    •  diltiazem
  • other drugs reported associated with AGEP include
  • vancomycin associated with AGEP (J Intensive Care 2015;3:47) full-text
  •  ibuprofen determined by patch testing as culprit drug causing AGEP in 34-year-old male patient in case presentation (Contact Dermatitis 2018 Jul;79(1):40)
  •  systematic review of mostly case reports evaluating cephalosporin-induced AGEP in 43 patients can be found in J Clin Pharm Ther 2022 Dec;47(12):2008
  • terbinafine, clindamycin, acyclovir, amoxicillin, and ceftriaxone each associated with increased AGEP
    •  based on cohort study
    • 23,667,594 adverse drug reports submitted to the United States FDA Adverse Event Reporting System between 1969 and 2021 were assessed
    • 5,498 adverse drug reports were cases of AGEP (mean age of patients 57 years), of which 51% were due to antibiotics
    • reporting odds ratios (ROR) defined as odds of AGEP with specified medication compared to odds of AGEP with all other medications in database
    • medications associated with increased risk of AGEP include
      • terbinafine (ROR 65, 95% CI 56-75)
      • clindamycin (ROR 63.8, 95% CI 56.9-71.6)
      • acyclovir (ROR 61.7, 95% CI 54.3-70)
      • amoxicillin (ROR 54.6, 95% CI 49.1-60.6)
      • ceftriaxone (ROR 53.2, 95% CI 47.2-60)
      • valacyclovir (ROR: 39.06, 95% CI 33.1-46.1)
      • enoxaparin (ROR: 27.37, 95% CI 23.7-31.61)
    • Reference – J Cutan Med Surg 2024 Jan-Feb;28(1):51
  • radiocontrast media has been associated with AGEP in case reports:
Other Causes
  • bacterial, viral or parasitic infections reported to induce AGEP, although some evidence suggests AGEP is reaction to drug treatment of infection(1,2,3)
    •  parvovirus B19
    • Mycoplasma pneumoniae
    •  cytomegalovirus
    •  coxsackievirus B4
    • Chlamydia pneumoniae
    • Escherichia coli
    • Echinococcus granulosus
  • contact sensitivity to(1,2)
    •  mercury
    •  bufexamac
    •  lacquer
  •  herbal medications(1,3)
  •  psoralen combined with ultraviolet treatment(1,3)
  •  spider bites(1,2)
  •  AGEP presentation in 2 men with no preceding medication or infection in case report (Br J Dermatol 2008 Aug;159(2):492)

Pathogenesis

  • AGEP appears to be a T-cell-mediated, type IV, delayed hypersensitivity reaction(1,2)
    •  drug exposure leads to stimulation of drug-specific CD4 and CD8 cells which then migrate to the skin and proliferate
    •  T cells and cytotoxic proteins, such as granzyme and perforin, induce apoptosis of keratinocytes, resulting in formation of subcorneal vesicles
    •  infiltrating CD4 T cells and bystander inflammatory cells (such as keratinocytes, dendritic cells, macrophages, neutrophils) release various cytokines, interleukins, and chemokines
    •  chemokine (C-X-C motif) ligand 8 (CXCL8/IL-8), in particular, may lead to recruitment of neutrophils and granulocyte macrophage-colony stimulating factor (GM-CSF) and formation of pustules

History and Physical

Clinical Presentation

  • patients typically present with(1,2,3)
    •  acute rash with dozens of small, pinhead-sized (< 5 mm), sterile, nonfollicular pustules on an edematous erythematous base
    •  rash typically begins in intertriginous folds of axillary, inguinal, and submammary areas and spreads rapidly to trunk and limbs, although the rash may remain localized to the skin folds in some patients
    •  rash may be seen within a few hours to days from drug exposure
    •  sometimes rash is irregularly distributed in patches
    •  rash may be accompanied by itching or burning
    •  fever > 38 degrees C (> 100.4 degrees F)
    •  leukocytosis and neutrophilia
    •  elevated levels of C-reactive protein
  •  mild, nonerosive mucosal involvement (usually orally and on a single site like mouth or tongue) reported in 20%-25% of patients(1,2,3)
  • extent of internal organ involvement varies but may include(1,2,3)
    •  lymphadenopathy
    •  slightly reduced creatinine clearance
    •  mild elevation of liver enzymes
    •  usually associated with drug rechallenge
  • atypical symptoms and overlap syndromes may occur, including(1,3)
    •  facial edema
    •  blisters and vesicles
    •  purpura on lower extremities
    •  Stevens-Johnson syndrome-like atypical targets, and overlap of AGEP and Stevens-Johnson syndrome/toxic epidermal necrolysis
    •  overlap of AGEP and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome
    •  localized reactions, referred to as acute localized exanthematous pustulosis
  •  spontaneous resolution of skin lesions or resolution after withdrawal of drug results in a typical collarette-shaped desquamation(1,3)
  • cohort studies of systemic involvement
    • systemic involvement observed in patients with AGEP at a single center in Minnesota, United States
      •  based on retrospective cohort study
      •  28 patients (mean age 56 years, 61% women) with AGEP at a single center (Mayo Clinic) in Minnesota, United States between January 1996 and December 2013 were assessed
      • etiologies described
        •  drugs in 26 patients (89%)
        •  IV contrast agent in 1 patient (4%)
        •  unknown causes in 2 patients (7%)
      • in 22 patients for whom time elapsed between exposure and symptom could be confirmed
        •  mean time from drug administration to onset of cutaneous symptoms was 8.3 days
        •  82% of patients had symptoms < 10 days after exposure, while remaining 4 patients had symptoms develop over a range of 14-28 days
      •  24 patients (86%) had postpustular desquamation
      •  3 patients (11%) had mucous membrane involvement
      • systemic involvement including any or mixed type in 21 patients (75%)
        •  increased alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in 2 patients
        •  increased alkaline phosphatase in 2 patients
        •  increased creatinine > 1.5 times baseline in 9 patients
        •  pulmonary involvement in 7 patients
        •  hemodynamic instability in 2 patients
      •  86% of patients had a personal history of drug reactions before development of AGEP
      •  11% of patients had generalized skin eruptions or dermatitis that developed weeks to months after resolution of symptoms
      •  Reference – Int J Dermatol 2017 Apr;56(4):405
    • systemic involvement including liver, kidney, bone marrow, and lung observed in patients with acute generalized exanthematous pustulosis at a single dermatology center in France
      •  based on retrospective cohort study
      •  58 patients with a hospital discharge diagnosis of AGEP between January 2000 and December 2010 at a tertiary dermatology center in France were assessed
      •  patients were considered to have systemic involvement if they had ≥ 1 of the following
      • 10 patients (median age 56 years) had systemic involvement in locations including
        •  elevated liver function tests in 7 patients (70%)
        •  acute renal insufficiency in 6 patients (60%)
        •  dyspnea and/or hypoxemia in 2 patients (20%)
        •  bone marrow involvement with severe neutropenia in 1 patient (10%)
      • systemic involvement in AGEP associated with
        •  amoxicillin rechallenge (p = 0.03)
        •  duration of hospitalization (p = 0.03)
        •  high mean absolute neutrophil count (p = 0.04)
        •  high C-reactive protein level (p = 0.001)
      •  all patients with systemic involvement recovered after drug withdrawal, symptom management, and topical corticosteroids
      •  Reference – Br J Dermatol 2013 Dec;169(6):1223
  • case presentations of severe AGEP with systemic involvement
  • case presentations of atypical AGEP or overlap syndromes

History

Chief Concern (CC)

  • rapid onset of rash(1,2,3)
    •  multiple pinhead-sized pustules (< 5 mm) on an edematous diffuse erythema, typically beginning in intertriginous areas
    •  itching, burning sensation
  •  fever > 38 degrees C (> 100.4 degrees F)(1,2,3)

History of Present Illness (HPI)

  • usually presents 1-5 days after ingestion of culprit drug(1,2)
    •  time period from ingestion to reaction differs for different drugs
    •  median time for antibiotics reported to be 1 day
  •  ask about itching and burning sensations
  •  ask about underlying illness/disease for which drug was taken

Medication History

  • ask about recent use of all medications(1,2)
    •  ask about timing of symptoms in relation to drug administration
    •  include details of drug formulation and dose

Past Medical History (PMH)

  •  ask about past cutaneous reactions to any drugs(1)
  •  ask about any disease conditions or injuries(1)

Physical

General Physical

  •  assess for fever, typically > 38 degrees C (> 100.4 degrees F)(1)
  •  assess for lymphadenopathy(1)

Skin

  • assess rash for type of eruption, distribution, color, and any secondary changes(1,2,3)
    •  typical findings are multiple (dozens to hundreds) pinhead-sized, nonfollicular pustules on erythematous base
    •  usually starts in large body flexures of inguinal, axillary, and submammary areas and spreads rapidly
    •  irregularly distributed patches may also be seen
    •  confluence of pustules may mimic positive Nikolsky sign (rubbing of the skin with lateral traction which induces a blister), which is typically seen with toxic epidermal necrolysis (TEN))
    • atypical features that can also be seen include
      •  facial edema
      •  blisters and vesicles
      •  purpura on lower extremities
  •  assess lips, mouth, and tongue for mild erosions indicating mucosal involvement(1,2,3)

Diagnosis

Making the Diagnosis

  • suspect AGEP in patient with typical clinical presentation, including(1,2,3)
    •  acute rash with dozens of small, pinhead-sized (< 5 mm), sterile, nonfollicular pustules on edematous erythematous skin, typically beginning in main folds of axillary, inguinal, and submammary areas and spreading rapidly on trunks and limbs
    •  itching and burning sensation accompanying rash
    •  fever > 38 degrees C (100.4 degrees F)
    •  symptom onset 1-5 days after initiation of culprit drug
  • diagnosis of AGEP is based on typical clinical presentation and typical laboratory findings, such as(1,2,3)
    •  neutrophilia (> 7 x 109/L)
    •  leukocytosis (> 10,000/mL)
    •  elevated C-reactive protein (CRP)
    •  mild eosinophilia
    •  exclusion of infection by negative smear or culture of pustular lesion
    • skin biopsy showing spongiform subcorneal and/or intraepidermal pustules with papillary edema
  • European Registry of Severe Cutaneous Adverse Reactions (EuroSCAR) diagnostic validation score may be used for confirming diagnosis (1,2)
    •  scoring based on typical presentation of morphology of lesions, course of disease, and histology of lesions
    •  total scoring determines definite AGEP, probable AGEP, possible AGEP, or no AGEP diagnosis

Differential Diagnosis

  • generalized pustular psoriasis (von Zumbusch type)(1,2,3)
    •  presents with similar clinical manifestations and histopathological findings

Table

Table 1: Comparison of AGEP and Pustular Psoriasis

AGEPGeneralized Pustular Psoriasis
Onset of pustulesRapid (hours or days after drug exposure)Slower
Size of pustulesTiny (pinhead)Larger
Distribution patternInitial predominance in intertriginous areasMore generalized
Duration of pustulesRapid resolution after culprit drug withdrawal (in a few days, 15 days at most)Longer
Duration of eruption/feverShorter (resolution in a few days after drug suspension)Longer
Recent drug exposure> 90%Less frequent
History of prior drug reactionUsualUncommon
History of psoriasis (family/personal)Usually lackingOften present
ArthritisRareAbout 30%
HistologySingle-cell necrosis of keratinocytes, edema of papillary dermis, vasculitis, exocytosis of eosinophilsPapillomatosis, acanthosis, tortuous or dilated vessels

Table

Table 1: Comparison of AGEP and Pustular Psoriasis

AGEPGeneralized Pustular Psoriasis
Onset of pustulesRapid (hours or days after drug exposure)Slower
Size of pustulesTiny (pinhead)Larger
Distribution patternInitial predominance in intertriginous areasMore generalized
Duration of pustulesRapid resolution after culprit drug withdrawal (in a few days, 15 days at most)Longer
Duration of eruption/feverShorter (resolution in a few days after drug suspension)Longer
Recent drug exposure> 90%Less frequent
History of prior drug reactionUsualUncommon
History of psoriasis (family/personal)Usually lackingOften present
ArthritisRareAbout 30%
HistologySingle-cell necrosis of keratinocytes, edema of papillary dermis, vasculitis, exocytosis of eosinophilsPapillomatosis, acanthosis, tortuous or dilated vessels

Table

Table 2: Differential Diagnosis of Similar Severe Cutaneous Conditions

DRESSSJS/TENAGEPErythroderma
Cause(s)Drugs (most commonly antiepileptics, allopurinol, sulfa drugs, antibiotics)Drugs (> 100 implicated, most commonly antibiotics, sulfa drugs, allopurinol, antiepileptics)Drugs (most commonly antibiotics) Flare of preexisting chronic skin condition (for example, psoriasis, seborrheic dermatitis, atopic dermatitis) Drug reactions Lymphoma/leukemia (for example mycosis fungoides) Idiopathic
Onset of eruption after drug initiation2-6 weeks1-3 weeks48 hours1-3 weeks
FeverPresentPresentPresentPresent
Mucocutaneous findings Morbilliform eruption Facial edema Pustules Exfoliative dermatitis Tense bullae Possible target lesions Bullae/sloughing Atypical target lesions Mucocutaneous erosions Skin tenderness/pain Pinpoint pustules that start in intertriginous regions Possible target lesions Possible mucosal involvement Erythematous plaques Edema affecting > 90% of total skin surface with or without diffuse exfoliation
LymphadenopathyProminentNegativePossiblePossible
HepatitisMarkedMinimal to moderateMinimal to moderateNot associated
Other organ involvement Interstitial nephritis Pneumonitis Myocarditis Thyroiditis Tubular nephritis Tracheobronchial necrosisPossiblePossible
NeutrophilsIncreasedDecreasedSubstantially increasedIncreased
EosinophilsSubstantially increased–IncreasedIncreased
Atypical lymphocytes+––+ (if associated with mycosis fungoides)
Mortality10%5%-35%5%5%-15%

Citation: Abbreviations: AGEP, acute generalized exanthematous pustulosis; DRESS, drug reaction with eosinophilia and systemic symptoms; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.

Testing Overview

  • obtain blood tests to evaluate for typical abnormalities, including
    •  leukocytosis
    •  neutrophilia
  •  consider skin biopsy to assess pustules and to distinguish from other pustular cutaneous conditions
  • consider evaluation of other abnormalities based on clinical signs and symptoms, such as
    •  blood tests for liver function, renal function
    •  other tests as required based on extent of systemic manifestations
  • culprit drug usually determined based on clinical judgement from history of drug exposure
    •  if the exact culprit drug is unclear, consider further testing after symptoms have resolved, such as skin patch testing to determine causality

Blood Tests

  • findings on complete blood count with differential(1,3)
    •  leukocytosis (> 10,000/mL)
    •  neutrophilia (> 7 x 109/L)
    •  mild eosinophilia may be seen in 30% of cases
  •  elevated levels of C-reactive protein(1,3)
  •  hypocalcemia, likely related to hypoalbuminemia, is seen in 75% of cases(1)
  • less common lab findings include(2)
    •  reduced creatinine clearance
    •  mild elevation of liver enzymes
  •  consider pustular smear or culture to rule out infectious etiology(2)

Biopsy and Pathology

  •  skin biopsy should include a pustule to allow for differentiation of AGEP from other pustular conditions(1,2)
  • biopsy findings typically show(1,2,3)
    •  spongiform subcorneal and/or intraepithelial pustules with edematous papillary dermis
    •  inflammatory infiltrate in dermis may have perivascular accentuation and mainly consists of neutrophils and some eosinophils
    •  necrotic keratinocytes and leukocytoclastic vasculitis can be seen in some cases
    •  erythrocyte extravasation may be seen in some cases
    •  characteristic features of psoriasis such as acanthosis and papillomatosis are absent

Scoring System

  • diagnostic validation score for validation of AGEP may be useful to distinguish AGEP from other similar appearing presentations (level 2 [mid-level] evidence)
    •  based on descriptive cohort study of 63 patients with AGEP from European registry of severe cutaneous adverse reactions (EuroSCAR)
    •  components include assessment of morphology of lesions, course of disease, and histology of lesions

Table

EuroSCAR Diagnostic Score for Validation of AGEP

ComponentCharacteristicsFindingsScoring
MorphologyPustulesTypical+2
Compatible with disease+1
Insufficient0
ErythemaTypical+2
Compatible with disease+1
Insufficient0
DistributionTypical+2
Compatible with disease+1
Insufficient0
Postpustular desquamationYes+1
No0
CourseMucous membrane involvementYes-2
No0
Acute onsetYes0
No-2
ResolutionYes0
No-4
Fever ≥ 38 degrees C (100.4 degrees F)Yes+1
No0
Polymorphonuclear cells ≥ 7/mcLYes+1
No0
HistologyOther diseaseN/A-10
Not representativeN/A0
Exocytosis of polymorphonuclear cellsN/A+1
Subcorneal and/or intraepidermal non-spongiform pustules orNOS pustules with papillary edema or subcorneal and/orintraepidermal spongiform pustules or NOS pustules without papillary edemaN/A+2
Spongiform subcorneal and/or intraepidermal pustules with papillary edemaN/A+3

Citation: Abbreviations: AGEP, acute generalized exanthematous pustulosis; EuroSCAR, European Registry of Severe Cutaneous Adverse Reactions; N/A, not applicable; NOS, not otherwise specified. Note: ≤ 0: excluded, 1-4: possible, 5-7: probable, 8-12: definite.

  • interpretation
    •  0 points – no AGEP
    •  1-4 points – possible AGEP
    •  5-7 points – probable AGEP
    •  8-12 points – definite AGEP
  •  Reference – J Cutan Pathol 2001 Mar;28(3):113

Other Diagnostic Testing for Culprit Drug

  • causality assessment to identify culprit drug(1,2,3)
    •  drug responsible for the cutaneous reaction usually determined based on clinical judgement from the history and physical workup
    •  confirmatory testing may prevent future episodes
    • consider skin patch testing 1 month after complete resolution of symptoms
      •  readings usually performed between 24 and 120 hours to maximize sensitivity
      •  positive result often characterized by small pustules at location of testing
      •  negative patch test does not exclude drug from being the culprit drug
      •  exercise caution as systemic adverse reactions, although rare, may occur
    •  other exploratory in vitro tests include lymphocyte transformation tests, interferon gamma release assay, lymphokine macrophage migration inhibition factor release assays

Management

Management Overview

  • withdrawal of culprit drug generally leads to resolution of AGEP
  •  limited evidence to guide drug treatment of AGEP
  • treatment is usually supportive
    •  in acute pustular phase of disease, consider dressings and/or drying and disinfecting solutions to reduce risk of superinfection
    •  consider topical steroids for symptomatic relief
    •  consider antipyretics and antihistamines for symptomatic relief only if they are not suspected to be culprit drugs
    • systemic steroids can be considered in patients with severe and widespread inflammation and systemic involvement
    • cyclosporine can be considered for AGEP that is refractory to systemic steroids
    •  emollients to preserve skin barrier function are usually used in the postpustular desquamation phase

Treatment Setting

  •  patients with extensive systemic involvement may require treatment in intensive care settings

Medications

  • discontinue suspected culprit drug(1,2,3)
    •  withdrawal of drug considered mainstay of management
    •  active lesions resolve within few days of culprit drug discontinuation
  • limited evidence to guide management(3)
    •  no randomized control trials of treatment of AGEP
    •  medication used mostly as supportive therapy, and mostly based on case series, reports, or expert opinion
  • oral antihistamines and oral antipyretics
    •  consider antipyretics for relief of fever (3)
    •  antihistamines, such as diphenhydramine, hydroxyzine, fexofenadine, cetirizine, levocetirizine or loratadine have been used for symptom relief (Int J Dermatol 2017 Apr;56(4):405)
    •  ensure antihistamine and antipyretic used is not suspected to have caused AGEP
  • topical corticosteroids
    •  medium potency topical steroids commonly advised for a few days to reduce pruritus and erythema
    •  options include betamethasone, triamcinolone, hydrocortisone, fluocinolone, fluocinonide, or a combination (Ann Allergy Asthma Immunol 2018 Jan;120(1):92, J Cutan Med Surg 2017 Jul/Aug;21(4):351)
    •  topical steroids may be associated with shorter duration of hospitalization in patients with AGEP (level 2 [mid-level] evidence)
      •  based on retrospective cohort study
      • 59 patients who were hospitalized with a diagnosis of AGEP at different time periods at a single center in France were assessed
        •  20 patients in period 1, 1994-1996
        •  20 patients in period 2, 1999-2001
        •  19 patients in period 3, 2009-2011
      •  median age ranged from 50 to 63 years and the male to female ratio ranged from 0.33 to 0.46
      •  no significant differences in age or comorbidities among patients in the 3 time periods
      • comparing patients in period 1 vs. period 2 vs. period 3
        •  topical steroids use in 25% vs. 40% vs. 89% (p < 0.001)
        •  median days of hospitalization of 7 vs. 6.5 vs. 5 (p = 0.045)
      •  no significant difference in mean hospitalization duration among all dermatology patients in the 3 time periods
      •  Reference – Br J Dermatol 2015;172(5):1455
  • systemic steroids
  • topical corticosteroids, systemic steroids, or supportive care each associated with similar time to symptom resolution in patients with AGEP (level 2 [mid-level] evidence)
    •  based on retrospective cohort study
    •  19 patients (mean age 52 years) with definite diagnosis of AGEP according to European Registry of Severe Cutaneous Adverse Reactions (EuroSCAR) AGEP validation score from August 2008 to November 2012 at a single hospital in Bangkok, Thailand were assessed
    • possible etiologies
      •  antibiotics in 14
      •  omeprazole in 2
      •  celecoxib in 1
      •  herbal medication (Andrographis paniculata) in 1
      •  viral infection in 1
    •  latent period from drug administration to onset of symptoms ranged from 1 hour to 25 days with a median of 3 days
    • treatment regimens
      •  topical corticosteroid in 11 patients (68.8%)
      •  oral prednisolone in 6 patients (37.8%)
      •  supportive care in 2 patients (1.3%)
    •  overall, median duration to resolution of pustules from withdrawal of drug was 3 days (2-12 days)
    •  no significant differences in days to resolution of pustules between various treatment regimens (p = 0.171)
    •  Reference – Dermatol Res Pract 2015;2015:260928full-text
  • cyclosporine
    •  cyclosporine 4 mg/kg/day (gradually tapered to 1.5 mg/kg/day) for 2 months and prednisolone 1 mg/kg/day reported to improve skin lesions and improve symptoms in 67-year-old woman with severe hydroxychloroquine-induced AGEP that was recalcitrant to supportive treatment and systemic corticosteroids in case report (Ann Dermatol 2015 Aug;27(4):431full-text)
    •  cyclosporine 5 mg/kg/day gradually tapered to 1.5 mg/kg/day for a total of 4 months reported to resolve pustular skin lesions in 63-year-old woman with severe hydroxychloroquine-induced AGEP that was recalcitrant to supportive treatment and IV systemic corticosteroids in case report (Clin Exp Dermatol 2009 Dec;34(8):e757)

Other Management

  •  consider moist dressings with disinfectants and drying solutions in the acute pustular phase to prevent infections(2)
  •  consider emollients and rehydrating lotions during the postpustular desquamative phase to protect epidermal barrier(2)

Follow-Up

Complications and Prognosis

Complications

  • complications may include(1)
    •  high fever
    •  superinfection of lesions
    •  severe systemic involvement
  • factors that may increase risk of complications include(2,3)
    •  advanced age
    •  immunocompromised status
    •  comorbid medical conditions
    •  general poor health

Prognosis

  •  AGEP is self-limiting and generally benign(1,2,3)
  •  skin lesions resolve rapidly ≤ 2 weeks after the culprit drug is withdrawn with a very typical collarette-shaped desquamation in region of pustulosis, that heals eventually within days to weeks(1)
  •  reported mortality < 5%, but associated with elderly patients and medical comorbidities(1,2)

Prevention and Screening

Prevention

  •  not applicable

Guidelines and Resources

Guidelines

United States Guidelines

United Kingdom Guidelines

European Guidelines

  • European Academy of Allergy and Clinical Immunology (EAACI) position paper on how to classify cutaneous manifestations of drug hypersensitivity can be found in Allergy 2019 Jan;74(1):14.

Review Articles

  •  to search MEDLINE for (Acute generalized exanthematous pustulosis [AGEP]) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis

Patient Information

References

General References Used

The references listed below are used in this DynaMed topic primarily to support background information and for guidance where evidence summaries are not felt to be necessary. Most references are incorporated within the text along with the evidence summaries.

  1. Feldmeyer L, Heidemeyer K, Yawalkar N. Acute Generalized Exanthematous Pustulosis: Pathogenesis, Genetic Background, Clinical Variants and Therapy. Int J Mol Sci. 2016 Jul 27;17(8):doi: 10.3390/ijms17081214full-text.
  2. Fernando SL. Acute generalised exanthematous pustulosis. Australas J Dermatol. 2012 May;53(2):87-92.
  3. Sidoroff A. Acute generalized exanthematous pustulosis. Chem Immunol Allergy. 2012;97:139-48.

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