Acquired cutis laxa secondary to acute generalized exanthematous pustulosis: A case report and mini-review of literature.

Cutis laxa presents as loose redundant skin folds and loss of dermal elastic tissue. Acquired cutis laxa (ACL) is characterized by later onset. It has been reported in association with various kinds of neutrophilic dermatoses, drugs, metabolic disorders, and autoimmune disorders. Acute generalized exanthematous pustulosis (AGEP) is usually classified as a severe cutaneous adverse reaction characterized by T cell-mediated neutrophilic inflammation. We previously reported a mild case of AGEP caused by gemcitabine in a 76-year-old man. Here, we report a case of ACL secondary to AGEP in this patient. He developed AGEP 8 days after gemcitabine administration. Four weeks after beginning chemotherapy, his skin had become atrophic, loose, and darkly pigmented in areas previously affected by AGEP. Histopathological examination revealed edema and perivascular lymphocytic infiltration but no neutrophilic infiltration in the upper dermis. Elastica van Gieson staining showed that the elastic fibers in all layers of the dermis were sparse and shortened. Electron microscopy showed elevated numbers of fibroblasts and altered elastic fibers with irregular surfaces. Finally, he was diagnosed with ACL secondary to AGEP. He was treated with topical corticosteroids and oral antihistamines. Skin atrophy decreased over 3 months. We summarize 36 cases (including our case) with ACL secondary to neutrophilic dermatosis. We discuss these clinical manifestations, causative neutrophilic disorders, treatments, and outcomes. The mean age of patients was 3.5 years. Five patients had an aortic lesion as systemic involvement. The most common causative neutrophilic disorders were Sweet syndrome (24 cases), followed by urticaria-like neutrophilic dermatosis (11 cases). There were no cases of AGEP except for our case. Although treatment for ACL secondary to neutrophilic dermatosis, such as dapsone, oral prednisolone, adalimumab, and plastic surgery were reported, ACL is generally refractory and irreversible. Our patient was considered reversibly cured due to the absence of continuous neutrophil-mediated elastolysis.

Acute generalized exanthematous pustulosis complicated by cutaneous small vessel vasculitis: A case report and literature review.

Acute generalized exanthematous pustulosis (AGEP) is a rare skin eruption characterized by widespread erythematous lesions covered with numerous pustules. Leukocytoclastic vasculitis is now considered an uncommon but possible histopathological feature within the clinical and pathological spectrum of AGEP. Our report describes a rare case of AGEP overlapping with cutaneous small vessel vasculitis, a condition that has only been reported once in the literature.

Acute generalized exanthematous pustulosis.

BACKGROUND: Acute generalized exanthematous pustulosis is a rare disease. Although it is usually related to drug intake, it is occasionally associated with infections, especially in the pediatric age. It is characterized by the sudden onset of sterile non-follicular pustules on an erythematous fundus, fever, and leukocytosis, with frequent and prompt spontaneous resolution. It mainly affects adults and is uncommon in childhood. Complications have been reported in approximately 20% of cases. CASE REPORT: We report the case of a 10-year-old female patient with a 5-day history of fever and dermatosis characterized by countless non-follicular pustules, predominantly on the trunk, inguinal folds, and proximal thighs but not involving palms, soles, and mucous membranes. The patient reported an incident of upper respiratory tract infection that occurred 7 days earlier. Histopathological examination confirmed the diagnosis of acute generalized exanthematous pustulosis. Spontaneous resolution occurred within 2 weeks. CONCLUSIONS: This disease is one of the severe cutaneous adverse reactions that usually have a self-limited and benign course within a few weeks. We propose that a previous respiratory infection triggered the acute generalized exanthematous pustulosis in this pediatric case. Knowledge of this pathology by the medical professionals, in general, and the pediatricians, in particular, will prevent an aggressive and inappropriate approach and management.

INTRODUCCIÓN: La pustulosis exantemática generalizada aguda es una enfermedad rara. Aunque usualmente se relaciona con el consumo de drogas, ocasionalmente se asocia con infecciones, sobre todo en edad pediátrica. Se caracteriza por el inicio súbito de pústulas no foliculares estériles sobre un fondo eritematoso, fiebre y leucocitosis, con frecuente y pronta resolución espontánea. Afecta principalmente a los adultos, y no es frecuente en la niñez. Se han reportado complicaciones en cerca del 20% de casos. CASO CLÍNICO: Se presenta el caso de una paciente de 10 años con fiebre e historia de dermatosis de 5 días de evolución caracterizada por incontables pústulas no foliculares de predominio en tronco, pliegues inguinales y parte proximal de muslos, respetando palmas, plantas y mucosas. Refirió antecedente de infección respiratoria alta 7 días antes. El examen histopatológico confirmó el diagnóstico de pustulosis exantemática generalizada aguda. Presentó resolución espontánea en el transcurso de 2 semanas. CONCLUSIONES: Esta enfermedad es una de las reacciones adversas cutáneas severas, que tiene un curso usualmente autolimitado y benigno en pocas semanas. Proponemos que la pustulosis exantemática generalizada aguda en este caso pediátrico fue desencadenada por la infección respiratoria previa. El conocimiento de esta patología por parte del gremio médico, en general, y del pediatra, en particular, evitará un abordaje y manejo agresivo e inapropiado.

Multisystem organ failure secondary to acute generalised exanthematous pustulosis (AGEP) with atypical presentation resembling septic shock.

A woman was admitted for sepsis secondary to cellulitis. After clinical improvement of sepsis, non-follicular small pustules were observed on the trunk, limbs and face while vesicles/bullae and skin exfoliation were noted on upper extremities. Larger systemic manifestations included fever, hypertension and tachycardia. Laboratory results revealed neutrophilic leukocytosis, eosinophilia, mild transaminitis and acute renal failure. Despite treatment for potential sepsis and discontinuation of offending agents, her condition worsened leading to haemodynamic instability and renal failure requiring vasopressor support, intubation and continuous veno-venous haemodialysis. Skin biopsy revealed a diagnosis of acute generalised exanthematous pustulosis (AGEP), a rare condition usually caused by antibiotic treatment. The suspected offending drug was clindamycin, with possible combined effects by metronidazole and/or vancomycin. Improvement of skin manifestations were seen within 48 hours of starting systemic steroids. Here, we present an uncharacteristic case of AGEP clinically presenting with atypical skin lesions, severe systemic involvement mimicking septic shock, which culminated in multisystem organ failure.

Clinical presentation and management of atypical and recalcitrant acute generalized exanthematous pustulosis.

Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction (SCAR) characterized by sterile nonfollicular pustules on an erythematous base that form rapidly after drug exposure. AGEP is mediated by numerous cytokines produced by drug-specific T cells that mediate neutrophilic intracorneal, subcorneal, or intraepidermal pustule development. Though genetic susceptibility is not fully understood, individuals with mutations in IL-36RN may be at increased risk of AGEP development. AGEP commonly presents with leukocytosis and fever in the acute pustular phase and follows a self-limited desquamative recovery phase upon removal of offending drug. Severe cases of AGEP may have multisystem organ involvement. Atypical presentations of AGEP include localized eruptions and cases with overlapping clinical and histopathologic features associated with Stevens-Johnson syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and generalized pustular psoriasis. Most cases of AGEP clear rapidly with systemic corticosteroids, but severe or recalcitrant cases may require other systemic therapies, such as cyclosporine, and intravenous immunoglobulin.

Drug triggered pruritus, rash, papules, and blisters - is AGEP a clash of an altered sphingolipid-metabolism and lysosomotropism of drugs accumulating in the skin?

Rash, photosensitivity, erythema multiforme, and the acute generalized exanthematous pustulosis (AGEP) are relatively uncommon adverse reactions of drugs. To date, the etiology is not well understood and individual susceptibility still remains unknown. Amiodarone, chlorpromazine, amitriptyline, and trimipramine are classified lysosomotropic as well as photosensitizing, however, they fail to trigger rash and pruritic papules in all individuals. Lysosomotropism is a common charcteristic of various drugs, but independent of individuals. There is evidence that the individual ability to respond to external oxidative stress is crosslinked with the elongation of long-chain fatty acids to very long-chain fatty acids by ELOVLs. ELOVL6 and ELOVL7 are sensitive to ROS induced depletion of cellular NADPH and insufficient regeneration via the pentose phosphate pathway and mitochondrial fatty acid oxidation. Deficiency of NADPH in presence of lysosomotropic drugs promotes the synthesis of C16-ceramide in lysosomes and may contribute to emerging pruritic papules of AGEP. However, independently from a lysosomomotropic drug, severe depletion of ATP and NAD(P)H, e.g., by UV radiation or a potent photosensitizer can trigger likewise the collapse of the lysosomal transmembrane proton gradient resulting in lysosomal C16-ceramide synthesis and pruritic papules. This kind of papules are equally present in polymorphous light eruption (PMLE/PLE) and acne aestivalis (Mallorca acne). The suggested model of a compartmentalized ceramide metabolism provides a more sophisticated explanation of cutaneous drug adverse effects and the individual sensitivity to UV radiation. Parameters such as pKa and ClogP of the triggering drug, cutaneous fatty acid profile, and ceramide profile enables new concepts in risk assessment and scoring of AGEP as well as prophylaxis outcome.

Recognition and Management of Severe Cutaneous Adverse Drug Reactions (Including Drug Reaction with Eosinophilia and Systemic Symptoms, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis).

Severe cutaneous adverse reactions to medications (SCARs) include drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis. They are all non-immunoglobulin E mediated hypersensitivity reaction patterns, distinguished from simple cutaneous drug eruptions by immunologic pathogenesis and internal organ involvement. Herein the clinical features, diagnostic workup, and management considerations are presented for each of these major SCARs.

Acute localized exanthematous pustulosis caused by enoxaparin.

Notably, enoxaparin has not been described to cause acute localized exanthematous pustulosis (ALEP). Herein, we present a case of a woman with a cutaneous drug reaction consistent with ALEP that occurred after enoxaparin. This case highlights enoxaprin as a novel causative agent for this type of drug reaction.

Terbinafine-Induced Acute Generalized Exanthematous Pustulosis.

Severe cutaneous adverse drug reactions are uncommon but potentially critical clinical situations demanding prompt diagnosis and treatment. We report a rare and severe case of terbinafine-induced acute generalized pustulosis. The patient was directly referred to a Burn Unit where she underwent diagnostic confirmation, systemic supportive care, and wound care treatments. Clinical and histopathological differential diagnosis of severe cutaneous adverse drug reactions is fundamental due to their significantly different management and prognosis.

Diagnostic utility of plasmacytoid dendritic cells in dermatopathology.

Differentiating cutaneous diseases that mimic each other clinically and histopathologically can at times be a challenging task for the dermatopathologist. At the same time, differentiation of entities with overlapping features may be crucial for patient management. Although not seen in normal skin, plasmacytoid dendritic cells usually infiltrate the skin in several infectious, inflammatory/autoimmune and neoplastic entities. Plasmacytoid dendritic cells can be identified in tissue using specific markers such as CD123 and/or blood-derived dendritic cell antigen-2. Plasmacytoid dendritic cells are the most potent producers of type I interferons and their activity may therefore be assessed indirectly in tissue using human myxovirus resistance protein A, a surrogate marker for type I interferon production. In recent years, accumulating evidence has established the utility of evaluating for specific plasmacytoid dendritic cell-related parameters (plasmacytoid dendritic cell content, distribution and clustering and/ or human myxovirus resistance protein A expression) as a diagnostic tool in differentiating cutaneous diseases with overlapping features such as the alopecias, lupus and its mimics, and neoplastic entities. In this review, we provide an update on the current evidence on this topic and on the contexts where this can be a useful adjunct to reach the histopathological diagnosis.

Widespread pustular eruption following probiotic use.

A 26-year-old woman with Crohn disease and palmoplantar psoriasis on ustekinumab presented with a diffuse and intensely pruritic rash with a few pin-point pustules within days after initiation of an over-the-counter Align brand probiotic. Biopsy revealed psoriasiform and spongiotic dermatitis with spongiform subcorneal pustules and scattered eosinophils, consistent with acute generalized exanthematous pustulosis. Our case highlights a unique presentation of acute generalized exanthematous pustulosis following probiotic exposure with fewer than usual pustular lesions. IL23 suppression by ustekinumab may have contributed to the patient's reduced pustular presentation.

A Case of Acute Generalized Exanthematous Pustulosis by Cefixime with Oral Mucosal Involvement.

Acute generalized exanthematous pustulosis (AGEP) is a rare severe cutaneous adverse reaction characterized by the development of numerous sterile and non-follicular pustules on an erythematous base with no or minimal mucous membrane involvement associated with fever and leucocytosis. Cefixime is a cephalosporin-type beta-lactam antibiotic commonly used for the management of several infections. The Cefixime-induced AGEP cases are known to be rare. Here, we present the case report of a 26-year old female who developed Cefixime-induced AGEP with mucosal membrane involvement. To the best of our knowledge, this is the first case to report the mucosal membrane involvement in Cefixime-induced AGEP. We are presenting this case report to draw the attention on the existence and plethora of symptoms of Cefixime-induced AGEP hoping that the clinicians will reckon these in their differential diagnosis and implement the appropriate management strategies for this rare adverse event in their clinical practice.