Acute generalized exanthematous pustulosis L27.0

MacMillian, 1973; Tan, 1974; Beylot, 1980

Acute, generalized, mostly febrile, non-follicular, sterile, pustular (subcorneal pustule) exanthema, which occurs in connection with infections and/or medication, but also spontaneously, and which is always accompanied by marked systemic leukocytosis and neutrophilia and has a strong tendency to heal spontaneously.

The incidences are given as 0.1-0.5/100,000 inhabitants/year.

Women seem to be affected slightly more often than men.

Occurs in > 90% of cases after taking medication. Triggers include, among others:

Common medications  

Antibiotics:

• β-lactams and β-lactamase inhibitors: oxacillin, dicloxacillin, amoxicillin ± clavulanic acid, piperacillin-tazobactam, and faropenem.
• Cephalosporins: Cefixime, ceftriaxone, cefepime, and cefotaxime.
• Macrolides: Azithromycin
• Fluoroquinolones: Ciprofloxacin and Tosufloxacin
• Antibiotics of various classes: Clindamycin, tigecycline, telavancin, trimethoprim-sulfamethoxazole, vancomycin, daptomycin, metronidazole, and pristinamycin.

Antimalarials: Hydroxychloroquine is the second most frequently reported medication overall, after antibiotics (Catho G et al. 2013). Particularly during the 2019 (COVID-19) in 2020, there were increased reports of hydroxychloroquine-induced AGEP, which may be attributable to the increased use of the drug (see also Generalized Pustular Erythema). It is noteworthy that AGEP triggered by hydroxychloroquine typically has a delayed onset compared to other drugs due to its long half-life of 40–50 days. Other antimalarial drugs that can induce AGEP include: atovaquone/proguanil.

Antifungals:Terbinafine,fluconazole, miconazole gel, andnystatin

Antiviral agents:aciclovir, favipiravir, remdesivir, and ritonavir

Calcium channel blockers:Diltiazem

Less common trigger medications:

• Allopurinol
• Carbamazepine
• Glucocorticoids
• Ibuprofen
• Metamizole
• Oxicam
• Pseudoephedrine (in cold and flu medications)
• Acetaminophen
• Chemotherapy drugs: Bendamustine, docetaxel, doxorubicin, gemcitabine, mycophenolate mofetil, and paclitaxel
• Biological anticancer drugs: Cetuximab, Erlotinib, Rituximab,Sorafenib, and Vismodegib
• Immunotherapies: pembrolizumab, ipilimumab, nivolumab, atezolizumab, and IL-2.

Generalized subcorneal pustulosis may also be a symptom of certain genetic inflammatory systemic diseases (see below: DIRA—mutation inthe IL1RN gene). An association with HLA-B5, -DR11, and -DQ3 has been observed.

Infections: Several infectionshave been reported in association with the onset of AGEP. There are reports of AGEP following Chlamydia pneumoniae, Mycoplasma pneumoniae, coccidioidomycosis, COVID-19, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and parvovirus B19. It is conceivable that patients with an underlying infectious disease are more susceptible to developing AGEP. Furthermore, it is also conceivable that patients with an underlying infectious disease develop AGEP as a result of pharmacological treatment for the infection.

Vaccinations: There are reports of AGEP following influenza vaccination and Spikevax COVID-19 vaccinations/ Moderna (Hayashi E et al. 2021; Agaronov A et al. 2021; Mitri F et al. 2021). The pathogenesis could also be attributed to “cytokine storm-like” systemic immune activation, which can occur, for example, following a COVID-19 infection or vaccination. Given the high prevalence of influenza vaccinations and mRNA COVID-19 vaccinations on an international scale, it can be concluded that the epidemiological risk of developing AGEP is very low. 

Several immunological pathways are involved in the pathogenesis of AGEP. They all lead to increased secretion of interleukin (IL)-8 and the subsequent migration and survival of neutrophils.

It is generally assumed that AGEP is based on a T-cell-mediated delayed-type hypersensitivity reaction to a specific medication or another trigger. Following exposure to the triggering substance, antigen-presenting cells (APCs) present the antigen on their surface using molecules of the major histocompatibility complex. This leads to the activation of CD4+ and CD8+ T cells, which react in a drug-specific manner.

Furthermore, activated T-cells proliferate. They migrate into the dermis and epidermis. Viaperforin/granzyme B and Fas ligands, the drug-specific CD8+ T-cells induce apoptosis of keratinocytes. Histologically, this manifests as the formation of epidermal vesicles (Baker H et al. 1968). In addition, activated T cells secrete IL-8, which acts as a chemotactic factor for neutrophils. This results in pustules in the epithelial region, as well as associated systemic neutrophilia (Sidoroff A et al. 2007).

• Note: There is no AGEP without neutrophilic leukocytosis!  

In AGEP, T-helper (Th) 1 cells predominate. This leads to increased secretion of interferon (IFN)-γ and granulocyte/macrophage colony-stimulating factor, which in turn promotes the survival of neutrophils. Th2 cells, which produce IL-5, may also play a role. This is particularly true in patients with associated eosinophilia . IL-5 is a potent eosinophil stimulator. Th17 lymphocytes also appear to play a role in the pathogenesis of AGEP, as the cytokines IL-17 and IL-22 produced by these cells synergistically promote downstream IL-8 secretion(Sidoroff A et al. (2007).

Genetic basis of AGEP: Mutations in the IL36RN gene, which encodes the IL-36 receptor antagonist, are more common in patients diagnosed with both AGEP and pustular psoriasis than in unaffected individuals. Interleukin-36 is a proinflammatory cytokine secreted by macrophages and keratinocytes. In AGEP, IL-36 receptors are detected in high concentrations on the surface of antigen-presenting cells (APCs) in the skin. See also Interleukin-36 Receptor Antagonist Deficiency Syndrome(DITRA). Typically, the IL-36 receptor antagonist blocks the signaling of inflammatory cytokines such as IL-36α, IL-36β, and IL-36γ (Song HS et al. 2016). The gene encoding this receptor antagonist (the IL36RN gene) is a small gene with six exons located on chromosome 2 at position q14. Dysregulation of this signaling pathway (e.g., due to the identified mutations in this gene) leads to enhanced IL-36 signaling and, consequently, to increased production of the downstream cytokines IL-6, IL-8, IL-1α, and IL-1β. It is reasonable to assume that the increase in these signaling pathways predisposes individuals to pustular eruptions (Baker H et al. 1968). It has been demonstrated that amoxicillin and letrozole can specifically trigger the production of IL-36γ cytokines by sensitized CD14+ macrophages from peripheral blood via Toll-like receptor 4 and by keratinocytes in patients, respectively.

Noteworthy are reports of overlap between AGEP and generalized pustular psoriasis(GPP). For example, such a scenario was reported in response to ceftriaxone, in which a patient with psoriasis vulgaris developed a pustular rash after taking the antibiotic. However, it was unclear whether this was a case of AGEP in a patient with a history of psoriasis or an acute exacerbation of pustular psoriasis (Isom J et al. 2020; Vyas NS et al. 2019).

AGEP isa polygenic disease: In a larger study (n=67 patients), the coding exons of IL36RN, CARD14, and AP1S3 —61 with GPP, two with acute generalized exanthematous pustulosis (AGEP), and four with acrodermatitis continua suppurativa (Hallopeau). The majority of patients (GPP/64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were detected in 15 (24%) and 5 (8%) patients with GPP, respectively. The only significant genotype-phenotype correlation observed in IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers (Mössner R et al. 2018).

A special age disposition does not exist. Children are less frequently affected than adults.

Typical is the infestation of the large flexures (axillary, submammary, inguinal region); but generalized infestation is also possible. AGEP can be accompanied by oedema of the facial skin.

Onset of the disease with significant impairment of the general condition; often febrile course with temperatures > 38°C.

Typical onset is on the face and the large bends of the joints with disseminated, synchronized, relapsing, extensive erythema or red swellings on which multiple, constricted, non-follicular pustules about 0.1 cm in size form. These merge to form large lakes of pus, whereby the delicate pustule cover can be pushed away from its lower surface (Nikolski phenomenon) and lies on top like a crumpled damp cloth. The pustular exanthema is accompanied by itching or stinging or burning pain (needle-like).

In some cases, erythema exudativum multiforme-like cockade patterns may develop, in which the pustules are usually arranged towards the edges, either disseminated or in groups. The pustules persist for a few days; they heal with a shaggy, raised, keratolytic scaling (thin -carlatiniforme horn lamellae - see Fig.).

Involvement of mucous membranes close to the skin (oral mucosa, genitalia) can occur but is rather rare. If present, clinically mild exfoliating enanthema is more common.

Systemic involvement: Systemic involvement is any organ dysfunction that occurs together with the cutaneous symptoms and cannot be attributed to another cause or disease. Studies have shown that 17-20% of AGEP cases have internal organ involvement, most commonly liver, kidney or lung disease.

Liver: Liver findings are elevated enzyme levels that are either hepatocellular (elevated aspartate aminotransferase and alanine aminotransferase up to twice the normal value) or cholestatic (elevated alkaline phosphatase and γ-glutamyltransferase). Abdominal ultrasonography may show steatosis or hepatomegaly, both of which are non-specific.

Kidneys: Renal findings may include a creatinine >1.5 times baseline, indicating severe acute kidney injury.

Pulmonary: Pulmonary findings may include pleural effusions, hypoxemia and increased oxygen demand.

Systemic symptoms usually resolve with discontinuation of the causative drug, treatment of the underlying disease and supportive care. AGEP cases associated with systemic symptoms are usually associated with higher morbidity and mortality than AGEP cases with only cutaneous features.

Remember. Coarse lamellar corneolytic desquamation is diagnostically indicative of subcorneal pustulation!

In an atypical course, clinically evident pustule formation may be absent in this clinical picture. It is then only seen in the histological preparation; however, even in these cases a lesional corneolytic scaly ruff is found on healing.

The literature reports positive patch test results in AGEP. Ninety-three drugs were identified in a larger study, which together caused 259 positive patch tests in 248 patients with AGEP. The following drug classes showed the most frequent reactions (de Groot AC 2022):

Beta-lactam antibiotics (25.9%)

other antibiotics (20.8 %)

contrast media containing iodine (7.3 %)

corticosteroids (5.4 %)

Together, these drugs account for almost 60% of all reactions

ESR elevation, CRP elevation, always marked leukocytosis (leukocytes > 10,000-12,000/mm³; sine qua non), marked neutrophilia, usually mild to marked relative lymphopenia, possibly eosinophilia. Not obligatory are elevations of transaminases and alk. phosphatase.

Exocytosis with intraepidermal, immediate subcorneal accumulations of neutrophil granulocytes.

Formation of spongiform to unicompartmental (nonfollicular)pustules.

Focal loss of str. granulosum. Mostly orthokeratotic epithelium. Occasionally, admixtures of eosinophilic granulocytes and erythrocyte extravasations are also present.

Pattern: Superficial perivascular and diffuse neutrophilic dermatitis with subcorneal pustule formation.

In contrast to TEN (subepidermal cleft formation with necrotic epidermis), biopsy in pustulosis acuta generalisata shows subcorneal pustules.

Immunohistology: Immunoglobulins (IgG) and complement factors (C3) in the vessel walls of the capillaries of the stratum papillare and in the basement membrane zone

The "AGEP validation score" of the EuroSCAR study group (Sidoroff et al. 2001) is helpful for validating the diagnosis. A score of 8-12 points speaks for the diagnosis:

AGEP validation score of EuroSCAR study group (Sidoroff A et al. 2001)

Symptom Score

• Pustule
  • Typical +2
  • Compatible +1
  • Not compatible 0
• Erythema
  • Typical +2
  • Compatible +1
  • Non-compatible 0
• Distribution pattern
  • Typical +2
  • Compatible +1
  • Non-compatible 0
• Postpustular desquamation
  • Typical +1
  • Non-compatible 0
• Mucosal infestation
  • Yes +1
  • No 0
• Acute course (<10 days)
  • Yes +1
  • No 0
• Healing (<15 days)
  • Yes +1
  • No 0
• Fever
  • Yes +1
  • No 0
• Neutrophilic leukocytosis (>7,000)
  • Yes +1
  • No 0

• Clinical differential diagnoses:
  • Pyoderma (microbiological detection of the purulent cocci)
  • Psoriasis pustulosa generalisata (anamnesis; chronic recurrent course, recurrences without fever symptoms and without the severe general symptoms of AGEP)
  • Dermatosis, acute febrile neutrophils (Sweet-Syndrome) (analogous acute and general symptoms, but primarily reddish-livid, succulent papules, nodules and plaques. Intralesional, grafting pustular formation possible. Pustules, however, not in the density as in AGEP.
  • Hand-foot-mouth disease (few acral localized painful blisters; only moderate or no disturbance of the AZ)
  • Erythema exsudativum multiforme (not pustular)
  • Lyell syndrome (large-area exfoliative, not pustular)
  • Subcorneal pustulose (chronic recurrent course; similar clinical morphology! The occurrence of larger and flaccid pustules - hypopyon formation is indicated). Entity is increasingly disputed!
  • Impetigo herpetiformis (occurrence in the last trimester of pregnancy)
  • Pityrosporum folliculitis (always follicular papules and pustules; no severe course of the disease).
• Histological differential diagnoses:
  • Psoriasis pustulosa generalisata (no reliable histological differentiation; medical history)
  • Pustular tinea (subcorneal pustular formation possible; detection of hyphae in the PAS preparation; in the upper dermis dense diffuse, sometimes perivasally accentuated lymphocytic infiltrate with few neutrophils and eosinophil granulocytes)
  • Impetigo contagiosa (subcorneal pustule; detection of bacteria)
  • Impetiginized eczema (eczema picture with broad-based acanthosis and extensive parakeratosis, broad spongiosis; focal penetration of the epithelium with neutrophil granulocytes).

Stopping the triggering medication.

Healing is usually described 10-14 days after discontinuation of the triggering drug. Until then symptomatic therapy, e.g. with dimetindene or other H1-blockers.

Important: control of protein and electrolyte balance.

Internal steroid medication can be initiated in the eruption phase of the disease: Initially 250-150 mg prednisolone/day i.v.; reduce by 50 mg daily depending on the acuity, oralize from 50 mg and reduce in 5 mg steps.

Spontaneous healing after 10-28 days

The disease also heals spontaneously after discontinuation of the triggering medication. The extent to which glucocorticoid therapy is useful is currently unclear.

In individual cases, a positive epicutaneous test against the causative medication can be achieved after the clinical symptoms have subsided (the non-irritant concentration of the medication in epicutaneous testing of drugs varies).

The 63-year-old patient, who had always been in good health, had been suffering for 4 days from a rash affecting his trunk and extremities, accompanied by malaise, loss of appetite, and a moderate fever (38.5 °C). This was preceded by a 2-week course of oral terbinafine for tinea unguium.

• Findings: The patient was in a markedly debilitated, febrile (38.7 °C) condition. A dense rash was diffusely distributed over the trunk and extremities, consisting of red papules and plaques measuring 0.2–0.5 cm in size, some isolated and others confluent into larger areas. Particularly on the confluent plaques, isolated pustules barely 0.1 cm in size are visible, confluent in places to form larger pools of pus. Oral mucosa unremarkable. No hepatosplenomegaly, no lymph node enlargement.
• Histology: Intraepidermal, superficial, spongiform to single-chambered pustules. Laboratory: CRP 65 mg/L; leukocytosis (16,400/µL), neutrophilia (87%), lymphopenia (1,200/µL), GGT (54 U/L).
• Treatment: Systemic glucocorticoids (prednisolone 250 mg/day IV, with a 50 mg reduction in dose in a tapering regimen). Additionally, a sedating antihistamine ( dimetindene 4 mg IV twice daily). Topical therapy with a thin application of Lotio alba or Lotio alba aquosa, skin-colored (NRF 11.22).
• Course: Fever subsided after 2 days; lesions began to fade after 4 days, followed by coarse lamellar desquamation, initially on the trunk and much later on the lower extremity. After 7 days, CRP 35 mg/L, leukocytosis at 11,400 µ/L. After 14 days, extensive recovery. The patient was permitted to take lukewarm showers during every phase of the illness.

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