Acute generalized exanthematous pustulosis
Acute generalized exanthematous pustulosis (AGEP) is a rare, severe cutaneous adverse reaction characterized by the acute onset of widespread, sterile, nonfollicular pustules on an erythematous base, typically accompanied by fever, neutrophilia, and mild systemic symptoms such as pruritus or malaise.[1] This condition usually develops rapidly, within 2–5 days of exposure to a triggering agent, and resolves spontaneously within 2 weeks after discontinuation of the trigger, often leaving postinflammatory desquamation.[2] AGEP has an estimated incidence of 1–5 cases per million people annually, with a female predominance and a mean age of onset around 56 years, though it can affect individuals of any age from infancy to elderly.[3] Over 90% of cases are drug-induced, most commonly by antibiotics such as β-lactams (e.g., amoxicillin), macrolides, or sulfonamides, but other medications like hydroxychloroquine, antifungals, and calcium channel blockers have also been implicated; non-drug triggers include infections (e.g., viral exanthems or COVID-19), vaccinations, and rarely spider bites or phototherapy. Recent studies as of 2024 have identified additional triggers such as certain biologics (e.g., nemolizumab, ixekizumab).[1][3][4] The pathogenesis involves a type IV hypersensitivity reaction mediated by drug-specific T cells, leading to cytokine release (e.g., IL-8, IL-17, IL-36) that recruits neutrophils and forms spongiform pustules; genetic factors such as mutations in the IL36RN gene may predispose susceptible individuals.[2] Clinically, the eruption often begins in intertriginous areas (e.g., axillae, groin) and rapidly generalizes to the trunk and extremities, sparing the face, palms, and soles in most cases; small (1–2 mm) pustules are pinpoint and superficial, with about 20% of patients experiencing mild mucosal involvement.[1] Laboratory findings typically include leukocytosis with neutrophilia (>7,000/mm³) and elevated C-reactive protein, while eosinophilia may be present in up to 30% of cases.[3] Diagnosis relies on clinical features validated by the EuroSCAR scoring system, which incorporates morphology, distribution, time course, and histopathology (e.g., subcorneal neutrophilic pustules with papillary dermal edema); scores of 8–12 confirm AGEP, distinguishing it from differentials like generalized pustular psoriasis, drug reaction with eosinophilia and systemic symptoms (DRESS), or Sweet syndrome. A 2024 European expert consensus provides updated guidance on diagnosis and management.[1][2][5] Management centers on immediate withdrawal of the suspected culprit agent, which leads to rapid improvement in most patients; supportive measures include emollients, topical corticosteroids for symptom relief, and antipyretics for fever, while severe cases with systemic involvement may require systemic corticosteroids or immunosuppressants like cyclosporine.[3] The prognosis is generally excellent, with full resolution in 15 days or less and a mortality rate under 5%, primarily from secondary infections or organ complications (e.g., renal or hepatic dysfunction in ~8% of cases); recurrence is rare but possible upon re-exposure to the trigger.[1]Overview
Definition
Acute generalized exanthematous pustulosis (AGEP) is a rare, acute, severe cutaneous adverse reaction characterized by the abrupt onset of widespread, nonfollicular, sterile pustules on an erythematous base.[1] It typically resolves within two weeks after removal of the trigger.[1] The condition was first described in 1968 as a pustular eruption in patients without a history of psoriasis, but it was formally recognized and named as a distinct drug eruption pattern in 1980 by Beylot et al.[6] AGEP is distinguished from other pustular eruptions, such as pustular psoriasis or subcorneal pustular dermatosis (Sneddon-Wilkinson disease), by its acute onset and self-limited course, in contrast to the chronic or relapsing nature of those conditions.[7] Most cases are associated with medications or infections.[1]Epidemiology
Acute generalized exanthematous pustulosis (AGEP) is a rare severe cutaneous adverse reaction, with an estimated incidence of 1 to 5 cases per million individuals annually.[8] This low rate underscores its rarity, though underreporting is likely due to diagnostic challenges and overlap with other pustular eruptions, leading to incomplete global surveillance.[1] The condition predominantly affects adults, with higher rates observed in those over 40 years of age and a mean onset age of approximately 56 years.[8] The condition shows a female predominance, with women accounting for 65–80% of cases.[1] Data from the EuroSCAR multinational case-control study, which validated 97 cases from European centers, highlight the condition's rarity, with potential underreporting globally due to diagnostic challenges and differences in pharmacovigilance.[9] Key risk factors include polypharmacy, which heightens exposure to potential triggering medications, and a history of prior drug reactions, increasing susceptibility through possible sensitization.[1] No strong genetic predispositions have been definitively identified, although weak associations with mutations in the IL36RN gene have been noted in some cohorts, without consistent evidence of broad heritability.[7] The majority of cases are linked to drug triggers such as antibiotics, though detailed etiologies are addressed elsewhere.[10]Clinical Presentation
Cutaneous Features
Acute generalized exanthematous pustulosis (AGEP) is characterized by a sudden onset of cutaneous manifestations, typically occurring within 2 to 5 days following exposure to a triggering agent. The eruption begins with diffuse, edematous erythema that initially appears in intertriginous and flexural areas, such as the axillae, groin, and major skin folds. This erythematous base rapidly progresses to involve the trunk, extremities, and often the entire body surface, typically achieving generalized distribution.[1][3][5] A hallmark feature is the development of numerous sterile, nonfollicular pustules, ranging from hundreds to thousands in number, superimposed on the edematous erythematous background. These pustules are pinpoint to small, measuring 1 to 4 mm in diameter, and contain neutrophils without evidence of infection. The pustules often arise within hours to days after the initial erythema and may coalesce in severe cases, contributing to a widespread appearance with possible superficial epidermal detachment. Distribution shows flexural accentuation, with the face involved in up to 20% to 30% of cases, sometimes extending to the tongue as part of limited mucosal involvement.[1][11][3] The eruption typically resolves spontaneously within 7 to 14 days after removal of the trigger, accompanied by desquamation in a reticulate or collarette pattern as the pustules dry and the erythema fades. Post-resolution, transient post-inflammatory hyperpigmentation may persist for weeks to months, particularly in areas of previous involvement, though scarring is uncommon.[1][5][3]Systemic and Laboratory Findings
Patients with acute generalized exanthematous pustulosis (AGEP) commonly experience systemic symptoms reflecting the condition's acute inflammatory response. Fever exceeding 38°C occurs in approximately 50-70% of cases, often developing rapidly alongside the pustular eruption and persisting for a median of 2 days.[1][12] Malaise is frequently reported as a mild systemic manifestation, contributing to overall discomfort.[1] Additionally, pruritus or a burning sensation accompanies the skin involvement in many patients, emphasizing the inflammatory nature of the reaction.[1] Laboratory investigations typically reveal markers of acute inflammation. Peripheral blood analysis shows neutrophilia, defined as a neutrophil count greater than 7,000/mm³, in 80-95% of cases, underscoring the neutrophil-driven pathology.[1][12] Eosinophilia may be present in 30-50% of patients, with variability across studies potentially linked to cytokine profiles involving IL-4 and IL-5.[12][13][5] Elevated levels of acute phase reactants, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), are commonly observed, aiding in confirming the systemic inflammatory process.[1][5] Extracutaneous involvement is uncommon but can occur in severe cases, affecting approximately 8-23% of patients. Hepatic enzyme elevations, such as transaminitis, and renal impairment, including acute kidney injury, have been documented in 8-12% and 8% of cases, respectively, typically resolving with supportive care.[1][12][13]Etiology
Drug-Induced Causes
Acute generalized exanthematous pustulosis (AGEP) is primarily triggered by medications in approximately 90% of cases.[5] Among these, antibiotics represent the most common culprits, accounting for 75-90% of reported instances, with beta-lactam antibiotics such as penicillins (e.g., amoxicillin) and cephalosporins being particularly frequent, alongside macrolides (e.g., erythromycin), sulfonamides, and other antibiotics like pristinamycin and lincosamides (e.g., clindamycin).[14] The onset of symptoms typically occurs rapidly after drug initiation, within 1-5 days for antibiotic-induced cases, often manifesting as 24-48 hours post-exposure.[3] Non-antibiotic medications are implicated in the remaining drug-related cases, including calcium channel blockers such as diltiazem, antimalarials like hydroxychloroquine, antifungals including terbinafine, and anticonvulsants such as carbamazepine or phenytoin.[7][15] These agents generally exhibit a longer latency period compared to antibiotics, with symptom onset up to 2 weeks or more after starting therapy; for instance, diltiazem-associated AGEP has a mean delay of about 11 days, while terbinafine cases range from 2 to 44 days, and hydroxychloroquine may extend to 12-40 days.[16][17][5] Cross-reactivity risks exist within drug classes, particularly among beta-lactam antibiotics, where exposure to one agent (e.g., piperacillin) may provoke reactions to structurally related compounds like cephalosporins (e.g., ceftazidime) or carbapenems (e.g., meropenem).[18] Case reports document rapid recurrence upon rechallenge, underscoring the need for avoidance of the offending drug and related classes; for example, sequential beta-lactam administrations in septic patients have led to multiple episodes of AGEP within days of each exposure.Infection-Associated Causes
Infections represent a rare etiology of acute generalized exanthematous pustulosis (AGEP), accounting for approximately 1% of cases in large cohorts, though they are more frequently implicated in pediatric patients where viral triggers predominate.[19] In children, infections may contribute to a substantial proportion of AGEP episodes based on case series (e.g., up to 60% in small series), contrasting with the predominance of drug-induced causes in adults.[20] Viral infections are the most commonly reported microbial triggers of AGEP, particularly in younger patients. Examples include parvovirus B19, which has been associated with pustular eruptions resolving after viral clearance; cytomegalovirus; Epstein-Barr virus; and enteroviruses such as coxsackievirus, often presenting in outbreaks among children.[21][3] Additional viral associations encompass herpes simplex virus type 1, varicella-zoster virus, and more recently, SARS-CoV-2, with cases reported shortly after infection onset.[3] Bacterial infections linked to AGEP are less frequent but well-documented, primarily involving atypical pathogens. Mycoplasma pneumoniae has been implicated in multiple pediatric cases, with pustulosis emerging during acute respiratory illness, while Chlamydia pneumoniae has triggered similar reactions in adults.[3] These associations typically occur without concurrent antibiotic exposure, distinguishing them from drug-related hypersensitivity.[22] Fungal triggers are exceptionally rare, with isolated reports of AGEP following coccidioidomycosis infection, resolving upon antifungal therapy. The onset of infection-associated AGEP generally coincides with or follows shortly after the acute phase of the underlying infection, often within days, and the eruption tends to resolve spontaneously or with antimicrobial treatment within 1-2 weeks, mirroring the self-limited course of drug-induced cases but without rechallenge risks.[3]Other Triggers
While the majority of acute generalized exanthematous pustulosis (AGEP) cases are attributed to drug exposure, rare instances have been linked to contact with certain substances such as mercury, as reported in isolated cases of systemic exposure leading to pustular eruptions mimicking drug reactions.[23] Similarly, herbal remedies, including essential oils like those from Pistacia lentiscus and turmeric supplementation, have been implicated in triggering AGEP through hypersensitivity responses in sporadic reports.[24][25] Environmental factors, such as spider bites—particularly from species like the brown recluse (Loxosceles reclusa)—have been documented as precipitants in multiple case series, with onset occurring rapidly after envenomation and presenting characteristic pustular features.[26][27] Vaccinations, such as influenza and COVID-19 vaccines, have also been reported as rare triggers.[28] Evidence for other environmental exposures, including food additives like oral blue dyes or shiitake mushrooms, remains anecdotal and supported only by individual case reports, lacking robust epidemiological confirmation.[29] UV exposure has been noted as a potential exacerbator in select cases, often in combination with photosensitizing factors, though isolated UV-induced AGEP is exceedingly rare.[30] AGEP has been reported during pregnancy and the postpartum period, potentially influenced by immune changes, though it remains rare and direct causation is not established.[31] Up to 10% of AGEP cases are idiopathic, lacking an identifiable trigger and potentially associated with underlying immune dysregulation, as suggested by genetic factors like IL36RN mutations in some patients.[32][33]Pathophysiology
Immune Mechanisms
Acute generalized exanthematous pustulosis (AGEP) is primarily driven by a type IV hypersensitivity reaction, specifically the subtype IVd, characterized by a T-cell-mediated inflammatory response involving both adaptive and innate immunity components.[34] Drug-specific CD4+ and CD8+ T cells are activated upon recognition of the offending agent, often presented in a cell-bound manner without processing, leading to clonal expansion and migration to the skin.[35] This activation triggers the release of pro-inflammatory cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), which amplify the immune cascade and promote epidermal inflammation.[34] Cytotoxic CD8+ T cells play a central role in tissue damage, secreting perforin and granulysin, which induce keratinocyte apoptosis and contribute to the formation of intraepidermal vesicles that evolve into pustules.[35] Granulysin, expressed by both CD4+, CD8+, and natural killer cells, further exacerbates keratinocyte death and neutrophil infiltration.[36] Concurrently, activated T cells produce interleukin-8 (IL-8, also known as CXCL8) and other chemokines, which recruit neutrophils to the epidermis, resulting in the characteristic sterile pustular eruptions.[35] This neutrophil accumulation, driven by the chemokine gradient, is essential for the acute pustular morphology observed in AGEP.[34] Genetic predispositions influence susceptibility, with associations reported between certain human leukocyte antigen (HLA) alleles and AGEP triggered by specific drugs; for instance, HLA-B*51 and HLA-DR11 have been linked to increased risk in some populations.[1] Additionally, mutations in genes such as IL36RN and CARD14, which regulate innate immune responses, may enhance cytokine production and neutrophil activation in susceptible individuals.[5] Elevated levels of Th17-related cytokines like IL-17 further support neutrophil recruitment and inflammation, highlighting the interplay between adaptive T-cell responses and innate pathways.[5]Histological Features
The histological hallmark of acute generalized exanthematous pustulosis (AGEP) is the presence of spongiform subcorneal or intraepidermal pustules filled with neutrophils, typically without evidence of acantholysis or viral inclusions.[1][5] These nonfollicular pustules are often located in the upper epidermis and may show spongiosis, with papillary dermal edema contributing to the intraepidermal separation.[3][34] In the dermis, a perivascular lymphocytic infiltrate is accompanied by neutrophils and eosinophils, forming a mixed inflammatory response without associated fibrosis or hyperkeratosis.[1][5] Exocytosis of neutrophils into the epidermis is common, and necrotic keratinocytes may occasionally be observed, further supporting the acute nature of the eruption.[3][34] Histologically, AGEP evolves from early papillary edema and isolated spongiform pustules to more diffuse intraepidermal spongiosis in later stages, a progression that helps distinguish it from chronic pustular dermatoses.[1][37] Neutrophil recruitment in these lesions is mediated by cytokines such as IL-8 and IL-36, enhancing the inflammatory milieu.[34]Diagnosis
Clinical Evaluation
The clinical evaluation of suspected acute generalized exanthematous pustulosis (AGEP) begins with a thorough patient history, emphasizing potential triggers within the preceding two weeks. A detailed medication reconciliation is essential, as drugs account for approximately 85-90% of cases, with antibiotics such as β-lactams and macrolides being the most common culprits, typically leading to onset within 1-10 days of exposure.[1][19][5] Inquiry into recent infections is also critical, though these are implicated in fewer than 1-2% of adult cases and more commonly in pediatric presentations, such as viral illnesses.[1][19] The timing and progression of the eruption should be assessed, noting its acute onset and characteristic resolution within 15 days after trigger removal.[5] Additionally, evaluation of the rash's distribution is key, often starting in intertriginous areas before generalizing to the trunk, extremities, and face while sparing the palms and soles.[1] On physical examination, the focus is on the morphology and extent of cutaneous involvement to characterize the eruption. The hallmark is widespread erythema overlaid with numerous sterile, nonfollicular pustules measuring less than 5 mm in diameter, which may coalesce and lead to desquamation in a collarette pattern.[1][19] Erythema typically affects more than 50% of the body surface, often beginning in flexural regions and progressing diffusely.[5] Mucosal involvement is uncommon, occurring in under 6-20% of cases and usually limited to the oral or buccal mucosa without severe erosions.[1][19][5] Fever may accompany these findings in about half of patients, supporting the acute inflammatory nature.[19] Baseline laboratory investigations complement the history and exam by confirming acute inflammation. A complete blood count (CBC) often reveals leukocytosis with neutrophilia in over 85% of cases, typically exceeding 7,000 neutrophils per mm³.[1][19][5] Inflammatory markers such as C-reactive protein are commonly elevated, further indicating the systemic response.[1][5] These findings help differentiate AGEP from chronic or infectious processes but are not specific.[19]Diagnostic Criteria
The diagnosis of acute generalized exanthematous pustulosis (AGEP) relies on validated diagnostic tools, primarily the EuroSCAR validation score developed by the EuroSCAR study group, which evaluates morphological, clinical course, laboratory, and histopathological features to classify cases as no AGEP (score ≤0), possible (1–4), probable (5–7), or definite (8–12).[5] This score emphasizes typical non-follicular pustules on erythematous skin, acute onset within 10 days, resolution within 15 days, fever ≥38°C, neutrophilia ≥7000/mm³, and specific histological patterns, while deducting points for atypical features such as mucosal involvement or prolonged course.[5] The following table outlines the EuroSCAR AGEP validation score criteria and points:| Category | Criteria | Points |
|---|---|---|
| Morphology: Pustules | Typical (dozens of small, nonfollicular pustules on edematous erythema) | +2 |
| Compatible (atypical but not suggestive of other diseases) | +1 | |
| Insufficient (cannot be judged, e.g., late stage or poor photos) | 0 | |
| Morphology: Erythema | Typical (widespread, often flexural) | +2 |
| Compatible | +1 | |
| Insufficient | 0 | |
| Morphology: Distribution/Pattern | Typical (generalized or linear in folds) | +2 |
| Compatible | +1 | |
| Insufficient | 0 | |
| Morphology: Post-pustular Desquamation | Present | +1 |
| Absent or insufficient | 0 | |
| Course: Mucosal Involvement | Present | -2 |
| Absent | 0 | |
| Course: Onset | Acute (≤10 days after drug exposure) | 0 |
| >10 days | -2 | |
| Course: Resolution | ≤15 days | 0 |
| >15 days | -4 | |
| Fever | ≥38°C | +1 |
| Absent | 0 | |
| Laboratory: Neutrophils | ≥7000/mm³ | +1 |
| <7000/mm³ | 0 | |
| Histology | Other disease (e.g., pustular psoriasis) | -10 |
| Not representative or absent | 0 | |
| Neutrophilic exocytosis | +1 | |
| Subcorneal/intraepidermal non-spongiform pustules with papillary dermal edema or without | +2 | |
| Spongiform subcorneal/intraepidermal pustules with papillary edema | +3 |