Generalized Pustular Psoriasis, Acute Generalized Exanthematous Pustulosis, and Other Pustular Reactions: A Clinical Review.

Generalized pustular rashes have various etiologies and can be challenging to diagnose and manage at first presentation. The authors provide an in-depth analysis of common pustular skin eruptions including generalized pustular psoriasis (GPP) and acute generalized exanthematous pustulosis, focusing on their pathophysiology, triggers, clinical presentation, diagnostic challenges, and management strategies. The article also highlights recent advances in genetic research and biologic therapies for GPP and the future directions in personalized medicine and prevention strategies.

Acute Generalized Exanthematous Pustulosis: Clinical Features, Differential Diagnosis, and Management.

Acute generalized exanthematous pustulosis (AGEP) is a rare, acute, severe cutaneous adverse reaction mainly attributed to drugs, although other triggers, including infections, vaccinations, ingestion of various substances, and spider bites, have also been described. AGEP is characterized by the development of edema and erythema followed by the eruption of multiple punctate, non-follicular, sterile pustules and subsequent desquamation. AGEP typically has a rapid onset and prompt resolution within a few weeks. The differential diagnoses for AGEP are broad and include infectious, inflammatory, and drug-induced etiologies. Diagnosis of AGEP depends on both clinical and histologic criteria, as cases of overlap with other disease processes have been reported. Management includes removal of the offending drug or treatment of the underlying cause, if necessary, and supportive care, as AGEP is a self-limited disease. This review aims to provide an overview and update on the epidemiology, pathogenesis, reported precipitating factors, differentials, diagnosis, and management of AGEP.

Acute Generalized Exanthematous Pustulosis: Clinical Characteristics, Pathogenesis, and Management.

BACKGROUND: Acute generalized exanthematous pustulosis (AGEP) is a potentially severe adverse cutaneous drug reaction, which typically occurs within 24-48 h after the intake of the culprit drug. SUMMARY: AGEP is characterized by numerous sterile subcorneal pustules on erythematous skin and in less than a third of cases it can be associated with organ manifestations possibly leading to life-threatening symptoms (e.g., cholestasis, nephritis, and lung and bone marrow involvement). In contrast to generalized pustular psoriasis, it can involve mucosal regions and typically resolves rapidly if the culprit drug is removed, and adequate therapy with topical or systemic steroids administered. Diagnosis based on patient history, clinical signs, and characteristic cutaneous histology is rarely challenging. Identification of the culprit drug may be aided by patch testing or lymphocyte transformation tests that are of limited value. KEY MESSAGES: Recent experimental data reviewed herein are supportive of an early role of drug-induced innate immune activation and innate cytokines such as interleukin (IL)-1, IL-36, and IL-17 in the pathogenesis of AGEP. This explains the rapid onset and neutrophilic character of the cutaneous inflammation, but also provides new avenues for in vitro tests aimed at better identifying the culprit drug.

Acute localized exanthematous pustulosis: Clinical features, pathophysiology, and therapy.

Acute localized exanthematous pustulosis (ALEP) is a rare disease characterized by the acute onset of multiple localized non-follicular, pinhead-sized pustules. ALEP is considered a localized form of acute generalized exanthematous pustulosis but its pathogeny is not well identified. We performed a systematic review of the literature of all publications regarding ALEP cases using the term "acute localized exanthematous pustulosis," to provide an update on this disease and its management. Results and conclusion ALEP is an uncommon skin condition attributed primarily to a hypersensitivity reaction to a systemic drug (classical or herbal); though a contact mechanism has been reported. It may be misdiagnosed as infectious or inflammatory disease but the clinico-pathological correlation in addition to the rapid response to withdrawal of the culprit agent supports this diagnosis. The pathogenesis of ALEP is still unclear, and there are no standardized treatment guidelines to manage this disease. Both AGEP and ALEP have a good prognosis if an early diagnosis is made.

Concurrent terbinafine-induced acute generalised exanthematous pustulosis and hepatitis.

Terbinafine is a commonly used antifungal medication. Its side effects, while widely known, are rarely described and can be missed by the medical community. We present a 55-year-old woman who visited her primary care physician with onychomycosis. She started treatment with terbinafine, and 1 week later developed a rash in the left flank that extended to the chest, back, and upper part of lower extremities. Laboratory results showed elevated liver enzymes. A treatment with steroids did not improve the rash and she was admitted to our institution. She was started with intravenous dexamethasone, topical hydrocortisone and triamcinolone. Seven days later the liver enzymes normalised, and the rash resolved on the chest and back. Our patient had concurrent acute generalised exanthematous pustulosis and hepatitis that together has been very rarely associated with terbinafine.

Acute generalized exanthematous pustulosis and Stevens-Johnson syndrome overlap due to hydroxychloroquine: a case report.

BACKGROUND: Since the World Health Organization declared a global pandemic due to the novel coronavirus disease2019, there have been targeted efforts to establish management modalities. Hydroxychloroquine has been suggested as a possible treatment; however, it is associated with multiple adverse reactions. We report a rare case of a patient with acute generalized exanthematous pustulosis with Stevens-Johnson syndrome due to hydroxychloroquine. Acute generalized exanthematous pustulosis is characterized by acute onset of a generalized rash that is pustular and erosive in nature, affecting limbs; trunk; face; and, less often, mucosal membranes. Although rare, it is important to be mindful of this side effect because the diagnosis is often delayed, and the disease has the potential to be life-threatening. CASE PRESENTATION: A 68-year-old American woman presented to our hospital with a painful, rapidly spreading rash. Its morphologic features included erythema multiforme-like lesions with extensive skin sloughing in various regions of the head, neck, and trunk and mucosal involvement. Her Nikolsky sign was negative, and she had no evidence of lesions on areas of skin trauma. Four weeks prior, she had been initiated on hydroxychloroquine for a presumed diagnosis of cutaneous sarcoidosis. Three punch biopsies of the head and neck area revealed subcorneal pustules consistent with acute generalized exanthematous pustulosis. Treatment began with high doses of methylprednisolone, leading to only minimal improvement of existing areas and ongoing spread to new areas. Treatment with intravenous immunoglobulin was initiated, at which point disease stability was achieved. The patient's rash ultimately resolved, as did her cutaneous pain and pruritus. CONCLUSIONS: Among many potential adverse reactions involving hydroxychloroquine, cutaneous side effects are varied and can lead to significant morbidity or even death. The drug is currently being investigated in a multitude of trials for coronavirus disease2019 treatment, prevention, and prophylaxis after exposure to severe acute respiratory syndrome coronavirus 2. Acute generalized exanthematous pustulosis is a rare side effect of hydroxychloroquine, and even fewer cases demonstrate histologic evidence of acute generalized exanthematous pustulosis while clinically presenting with Stevens-Johnson syndrome. Patients who develop Stevens-Johnson syndrome/toxic epidermal necrolysis require best supportive care with aggressive fluid and electrolyte replacement and prevention of further breakdown of the skin barrier. With the potential of widespread hydroxychloroquine use, it is important that providers be aware of its potential severe adverse drug reactions.

Aetiopathogenesis of severe cutaneous adverse reactions (SCARs) in children: A 9-year experience in a tertiary care paediatric hospital setting.

BACKGROUND: Severe cutaneous adverse reactions (SCARs) are delayed-type hypersensitivity reactions to drugs including as follows: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Acute Generalized Exanthematous Pustulosis (AGEP). Incidence, triggers and management of SCARs have not been investigated in large-scale epidemiological studies on children. OBJECTIVE: The aim of our study was to collect epidemiological, clinical and aetiological data from children with SCARs referred to our tertiary care paediatric hospital of Florence. METHODS: From 2010 to 2018 charts of children with diagnosis of SCAR were reviewed, and data collected during the acute phase and/or the subsequent allergy evaluation. Patients underwent patch tests, intradermal tests and lymphocyte transformation tests. All children were investigated for infectious diseases. RESULTS: Incidence of SCARs in hospitalized children was 0.32% over a 9-year period. Fifty-four children were enrolled (31 M; 23 F; median age 6.5 years): 17 cases of DRESS, 30 SJS, 3 TEN, 2 AGEP, 1 linear immunoglobulin A bullous disease (LABD) and 1 pemphigus. Twenty-eight out of 54 patients underwent drug allergy investigations, and 50% of them resulted positive. Combining clinical history and results of allergy work-up, 74% SCARs seem to be caused by drugs, 18.6% by both drugs and infections, 3.7% by infections, and 3.7% remained idiopathic. No deaths occurred. CONCLUSIONS: In this study, SCARs incidence is in line with literature data. Drugs were most commonly the leading cause. Management of SCARs requires cooperation among professional figures for an early diagnosis and a prompt treatment. Mortality rate seems to be lower in children.

Outpatient management and follow-up recommendations for adverse drug reactions: guidelines for posthospitalization care.

Acute generalized exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are types of adverse drug reactions (ADRs), each with their own set of characteristic symptoms and sequelae. Although guidelines for inpatient management of these conditions exist, guidelines for outpatient follow-up are lacking. Based on the existing literature, we propose guidelines for outpatient follow-up of AGEP, DRESS, and SJS/TEN.

Treatment of severe drug reactions by hemodialysis.

BACKGROUND: Extracorporeal treatments such as hemodialysis and plasma exchange are lifesaving measures in the treatment of drug poisoning. This treatment method generally is not used for severe cutaneous and systemic drug reactions. METHODS: Here, we describe three cases wherein hemodialysis therapy was instrumental in reversing the adverse drug reaction. RESULTS: In the cases of severe cutaneous drug reactions reviewed, patients presented with linear immunoglobulin A bullous dermatosis, acute generalized exanthematous pustulosis, and toxic epidermal necrolysis. Salvage treatment with hemodialysis therapy drastically influenced the course of disease, resulting in remission. CONCLUSIONS: This novel and highly effective treatment option is not considered in current algorithms for adverse drug reactions. Hence, in addition to the rarity of these reactions, the main limitation of the study is the small number of patients. Hemodialysis can substantially alter the prognosis and, in some cases, be a lifesaving treatment for patients with severe adverse cutaneous drug reaction associated with systemic toxicity.

Cutaneous adverse drug reactions: Kids are not just little people.

Cutaneous adverse drug reactions are a common complication of drug therapy and affect patients of all ages. Despite the daunting frequency at which these reactions occur, there are no scientific contributions comparing cutaneous adverse drug reactions in adults to those occurring in children. Literature delineating such differences is important given that there are significant age-related differences in the pharmacokinetics of many drugs and that most of the package-insert data on adverse drug reactions are based on preclinical trials that do not include children as participants. This contribution attempts to bridge the literature gap by examining five cutaneous adverse drug reactions that occur in both adults and children, highlighting the many types of age-related differences, with a special emphasis on comparisons of (1) epidemiology, (2) etiology, (3) clinical presentation, (4) workup, and (5) treatment.

Treatments for Severe Cutaneous Adverse Reactions.

Severe cutaneous adverse reaction (SCAR) is life-threatening. It consists of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and generalized bullous fixed drug eruptions (GBFDE). In the past years, emerging studies have provided better understandings regarding the pathogenesis of these diseases. These diseases have unique presentations and distinct pathomechanisms. Therefore, theoretically, the options of treatments might be different among various SCARs. However, due to the rarity of these diseases, sufficient evidence is still lacking to support the best choice of treatment for patients with SCAR. Herein, we will provide a concise review with an emphasis on the characteristics and treatments of each SCAR. It may serve as a guidance based on the current best of knowledge and may shed light on the directions for further investigations.

Acute Generalized Exanthematous Pustulosis: Pathogenesis, Genetic Background, Clinical Variants and Therapy.

Acute generalized exanthematous pustulosis (AGEP) is a severe, usually drug-related reaction, characterized by an acute onset of mainly small non-follicular pustules on an erythematous base and spontaneous resolution usually within two weeks. Systemic involvement occurs in about 20% of cases. The course is mostly benign, and only in rare cases complications lead to life-threatening situations. Recent studies highlight the importance of genetic variations in interleukin-36 receptor antagonist gene (IL-36RN) in the pathogenesis of this disease. The physiopathology of AGEP remains unclear, but an involvement of innate and acquired immune cells together with resident cells (keratinocytes), which recruit and activate neutrophils via production of cytokines/chemokines such as IL-17, IL-36, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor alpha (TNFα) and chemokine (C-X-C motif) ligand 8 (CXCL8)/IL-8, has been postulated. Treatment is based on the removal of the causative drug, supportive care, infection prevention and use of potent topical or systemic steroids.

Toxicodermias graves: ¿existen las formas combinadas? / Severe Cutaneous Drug Reactions: Do Overlapping Forms Exist?

La pustulosis exantemática generalizada aguda, el síndrome de Stevens-Johnson, la necrólisis epidérmica tóxica y el síndrome de hipersensibilidad a fármacos con síntomas sistémicos y eosinofilia son reacciones de hipersensibilidad grave a fármacos. Aunque cada una de ellas se describe como una entidad bien constituida con criterios diagnósticos propios, en la práctica clínica se encuentran algunos casos que manifiestan características de 2 de estas entidades, abriendo el diálogo ante la posible existencia de formas combinadas. La existencia de estas formas solapadas entre 2 toxicodermias graves es motivo de controversia en los últimos años en diferentes foros de dermatología. En el artículo se aportan 2 nuevos casos de formas solapadas entre pustulosis exantemática generalizada aguda y síndrome de Stevens-Johnson/necrólisis epidérmica tóxica, se revisan los casos previos publicados y el estado actual de esta controversia en la literatura

Acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms are all severe hypersensitivity reactions to medications. While each of these reactions is a well-established entity with specific diagnostic criteria, clinicians see cases that fulfill criteria for more than one form, prompting discussion on the possibility of combined forms. Such overlapping clinical pictures meeting the criteria for 2 conditions have thus become a topic of debate in dermatology in recent years. We describe 2 patients with cutaneous drug reactions having the characteristics of both acute generalized exanthematous pustulosis and Stevens-Johnson syndrome -toxic epidermal necrolysis. We also review previously published cases and current thinking on such overlapping conditions

Adverse cutaneous drug eruptions: current understanding.

Adverse cutaneous drug reactions are recognized as being major health problems worldwide causing considerable costs for health care systems. Most adverse cutaneous drug reactions follow a benign course; however, up to 2% of all adverse cutaneous drug eruptions are severe and life-threatening. These include acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Physicians should be aware of specific red flags to rapidly identify these severe cutaneous drug eruptions and initiate appropriate treatment. Besides significant progress in clinical classification and treatment, recent studies have greatly enhanced our understanding in the pathophysiology of adverse cutaneous drug reactions. Genetic susceptibilities to certain drugs have been identified in SJS/TEN patients, viral reactivation in DRESS has been elucidated, and the discovery of tissue resident memory T cells helps to better understand the recurrent site-specific inflammation in patients with fixed drug eruption.

Probable fenofibrate-induced acute generalized exanthematous pustulosis.

PURPOSE: The case of a patient who experienced a severe adverse reaction requiring emergency treatment after a single dose of fenofibrate is described. SUMMARY: A 58-year-old woman with type 1 diabetes was hospitalized for treatment of an extensive blistering rash on the buttocks and trunk accompanied by fever, hypotension, tachycardia, neutrophilia, impaired renal function, and liver enzyme abnormalities. She reported that two days previously she had developed fever and vomiting four hours after taking her first dose of fenofibrate (145 mg). The patient required vasopressor support and was initially treated with broad-spectrum antibiotics for 3 days and a course of immune globulin. On hospital day 4, histopathology returned results consistent with acute generalized exanthematous pustulosis (AGEP), and the patient was subsequently treated with topical steroids. Gradual resolution of AGEP was noted at the time of her discharge from the hospital on day 7 and at one-week follow-up. Analysis of the case using the adverse drug reaction probability scale of Naranjo et al. yielded a score of 5, indicating a probable association between fenofibrate use and AGEP development. AGEP is a predominantly drug-induced condition but is not typically associated with fenofibrate use. Cutaneous eruptions in AGEP are often accompanied by systemic symptoms (e.g., fever, leukocytosis), and the disorder can also be associated with impaired creatinine clearance and elevated aminotransaminase levels. CONCLUSION: A woman with type 1 diabetes developed AGEP after taking a single dose of fenofibrate. Her cutaneous symptoms began to resolve within days of discontinuation of fenofibrate use.