Acute generalized exanthematous pustulosis associated with clindamycin in a patient with Hailey-Hailey disease.

A 61-year-old African-American female with moderately controlled Hailey-Hailey disease (HHD) presents to the emergency department with a rash and fever. One day prior to her presentation, she was started on oral clindamycin for a tooth extraction procedure. Her physical examination shows diffuse erythema on the trunk and extremities with multiple nonfollicular pustules. A punch biopsy of her upper extremity revealed intraepidermal acantholysis, neutrophilic spongiosis, and subcorneal pustules. The perivascular and interstitial superficial dermal infiltrate is mixed and composed of predominantly neutrophils, with lymphocytes and rare eosinophils. These findings suggest a superimposed acute generalized exanthematous pustulosis (AGEP) in the background of HHD. AGEP is a potentially severe cutaneous condition characterized by the abrupt onset of numerous nonfollicular pustules in a background of pruritic edematous erythroderma. To date, only two case reports have described AGEP in patients with HHD. Early diagnosis of AGEP is essential to initiate prompt and aggressive systemic therapy, prompt medication cessation, close monitoring for end-organ damage, and improve overall morbidity and mortality.

Múltiples reacciones adversas graves a fármacos en un paciente luego de la infección por COVID-19: informe de un caso / Drug-induced severe cutaneous adverse reactions in a patient after COVID-19 infection: case report

Durante la pandemia por COVID-19 se observaron diversas reacciones adversas a fármacos. Esto pudo haber estado relacionado con una mayor susceptibilidad inmunológica de los pacientes con SARS-CoV-2 a presentar este tipo de cuadros, así como también con la exposición a múltiples medicamentos utilizados en su tratamiento. Comunicamos el caso de un paciente con una infección respiratoria grave por COVID-19, que presentó 2 reacciones adversas graves a fármacos en un período corto de tiempo. (AU)

During the COVID-19 pandemic, various adverse drug reactions were observed. This could have been related to a greater immunological susceptibility of patients with SARS-CoV-2 to present this type of symptoms, as well as exposure to multiple drugs used in their treatment. We report the case of a patient with a severe respiratory infection due to COVID-19, who presented 2 serious adverse drug reactions associated with paracetamol in a short period of time. (AU)

Initiation of hydroxychloroquine therapy during pregnancy can cause adverse effects and alter pregnancy outcomes: A case of acute generalised exanthematous pustulosis induced by hydroxychloroquine in a patient with systemic lupus erythematosus.

Hydroxychloroquine (HCQ) is effective for treating a number of autoimmune diseases, including systemic lupus erythematosus. HCQ is generally safe and may be prescribed to pregnant women. Although current guidelines recommend initiating HCQ when considering pregnancy, the drug can cause adverse effects such as acute generalised exanthematous pustulosis (AGEP), which should be carefully evaluated. A 30-year-old pregnant woman with systemic lupus erythematosus at 16 + 5 gestational weeks was referred to National Center for Child Health and Development for persistent proteinuria and alopecia. Tacrolimus was initiated, and the dose of prednisone was increased. At 20 + 3 weeks of gestation, HCQ was administered to allow for a dose reduction of prednisolone. Proteinuria gradually improved as the pregnancy course stabilised. At 27 + 1 weeks of gestation, generalised pustular exanthema developed, presumably due to HCQ. Based on the clinical course and the analysis of the skin lesions, she was diagnosed to have either AGEP or generalised pustular psoriasis. Despite discontinuing HCQ, the skin lesions worsened dramatically, and infliximab therapy was required. After one course of infliximab treatment, exanthema gradually subsided. The final diagnosis was AGEP, based on the clinical course and pathological findings. At 30 weeks, pyothorax developed because of the pyogenic skin lesion and the compromised immune system, and long-term antibiotic therapy was required until 32 + 4 weeks, after which she underwent caesarean section. Although introducing HCQ is occasionally necessary during pregnancy, it is preferable to initiate HCQ in the preconception period and not after pregnancy because of the possible adverse effect, which can alter perinatal prognosis. Rheumatologists should consider the potential risks of HCQ.

Patient Care Outcomes in Hospitalized Patients with Acute Generalized Exanthematous Pustulosis: A Cross-Sectional Database Study.

BACKGROUND: Current understanding of the etiology, natural history, and outcomes of acute generalized exanthematous pustulosis (AGEP) has been limited, with most available studies consisting of small or heterogenous cohorts. OBJECTIVES: The aim of this study was to further characterize associated factors and disease outcomes of AGEP. METHODS: A cross-sectional study design was employed with formal inclusion and causality criteria. Patients were identified from an inpatient database at an academic medical center, including 65 patients with AGEP and a control group of 61 patients with non-severe cutaneous adverse reactions. RESULTS: Increased age and body mass index (BMI) were associated with higher risk of AGEP (p < 0.001). Length of stay was longer for both the overall AGEP cohort (13.1 days) and a subcohort with a primary discharge diagnosis of AGEP (9.7 days) compared with the control group (3.6 days) [p < 0.001]. Patients with AGEP were more likely to be discharged to a long-term care facility compared with control patients (p < 0.001). CONCLUSIONS: AGEP was associated with longer length of hospitalization, higher rates of discharge to long-term care facilities, and higher mortality compared with non-severe cutaneous adverse drug reaction (SCAR) medication reactions. Future research should examine the association between morbid obesity and this particular drug reaction, and the possibility of decreasing hospitalization length given the relatively low risk of mortality among patients with AGEP.

Clinical features, diagnosis and management of cephalosporin-induced acute generalized exanthematous pustulosis.

WHAT IS KNOWN AND OBJECTIVE: Acute generalized exanthematous pustulosis (AGEP) is a serious and rare adverse reaction of cephalosporins. We aimed to describe the clinical features of cephalosporin-induced AGEP and provide a reference for rational clinical use of cephalosporins. METHODS: We systematically searched Chinese and English databases for cephalosporin-induced TGEP-related case reports, retrospective studies, clinical studies, and review articles published before May 2022. RESULTS AND DISCUSSION: A total of 43 patients from 35 articles were eligible, of which 28 (65.1%) were female, with a median age of 69 years. A total of 11 cephalosporins were suspected, the most commonly involved were ceftriaxone (41.9%), cephalexin (16.3%), and cefepime (9.3%). AEGP erupted primarily within 14 days after administration, manifested as nonfollicular pustules on an erythematous base, distributed favourably to the extremities (44.2%), trunk (23.3%), face (23.3%), and could involve the oral mucosa (11.6%). During AGEP resolution, the affected area had desquamation (39.5%). The acute phase of the disease may be accompanied by fever (>38.0°C) and elevated neutrophil count (>7500/mm3 ). Histology of AGEP showed subcorneal pustules (56.3%), intraepidermal cavernous pustules (37.5%), with papillary dermal edema (37.5%), containing neutrophils and eosinophilic infiltration (71.9%). After drug discontinuation, the median time to resolution of AGEP symptoms was 10 days (range 2, 90). WHAT IS NEW AND CONCLUSION: Cephalosporin-induced AGEP is rare and should be properly diagnosed. This serious cutaneous adverse reaction is self-limiting and has a favourable prognosis, usually resolves with drug interruption, and may require additional interventions, such as topical steroids.

Dupilumab-induced Acute Generalized Exanthematous Pustulosis in a 17-year-old Female Chinese Patient with Atopic Dermatitis.

is missing (Short communication).

Results of patch testing in acute generalized exanthematous pustulosis (AGEP): A literature review.

The literature on positive patch-test results in acute generalized exanthematous pustulosis (AGEP) is reviewed. Ninety-three drugs were identified that have together caused 259 positive patch tests in 248 patients with AGEP. The drug classes causing the highest number of reactions are beta-lactam antibiotics (25.9%), other antibiotics (20.8%), iodinated contrast media (7.3%), and corticosteroids (5.4%), together accounting for nearly 60% of all reactions. The highest number of reactions to individual drugs was to amoxicillin (n = 36), followed by pristinamycin (n = 25), diltiazem (n = 14), amoxicillin-clavulanic acid (n = 13), clindamycin (n = 11), and iomeprol (n = 8); 59 of the 93 drugs each caused a single case only. The "Top-10" drugs together caused over 50% of all reactions. The sensitivity of patch testing (percentage of positive reactions) in patients with AGEP is largely unknown, but may generally be ~50%, which also applies to pristinamycin. Patch testing in AGEP appears to be safe, although mild recurrence of AGEP skin symptoms or other rashes may occur occasionally. Clinical aspects of AGEP, including epidemiology, etiology and pathophysiology, clinical features, histology, treatment, and prognosis are briefly presented, as are diagnosing the disease and identifying the culprit drugs with patch tests, intradermal tests, in vitro tests, and challenge tests.

Generalized Pustular Figurate Erythema in Patients with COVID-19 Treated with Hydroxychloroquine: A Systematic Review.

severe distinctive cutaneous drug reaction, generalized pustular figurate erythema, closely linked with hydroxychloroquine (HCQ), has been documented. It is distinguishable from AGEP by its longer incubation, more varied morphology (initially urticarial and later targetoid, arcuate plaques), recalcitrance to therapy and longer disease course. Aim of the article is to review the recognized entity associated with ingestion of hydroxychloroquine in patients infected with COVID-19. A systematic review using electronic search was performed. Inclusion criteria: n patients with COVID-19 demonstrated by PCR, with typical clinical features of AGEP/GPFE or atypical features associated with typical histopathology. We used the (JBI) Critical Appraisal Checklist for Case Reports for the qualitive assessment. We included 13 publications. Their overall quality was good to moderate. Only 27.3% of the patients had a severe COVID-19 course. The mean lag time between trigger exposure and rash development was 24 days. Only 15.38% of the reported AGEP were clinically typical, while the remaining 69.23 % were suggestive of GPFE. Unfortunately, 2 patients died secondary to massive pulmonary embolism. In COVID-19 infection, we suggest reconsidering treating established COVID-19 empirically with HCQ, as both triggers can augment the subsequent cytokine storm, inducing a severe drug reaction and possibly increasing the risk of thrombo-embolic events.

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.

COVID-19 presenting as acute generalized exanthematous pustulosis associated with multiorgan dysfunction in a 44-year-old female patient.

Acute generalised exanthematous pustulosis (AGEP) is an unusual cutaneous reaction, most often related with a hypersensitivity reaction to commonly used drugs. It is characterized by an abrupt onset of a pustular rash within hours or days after drug exposure and usually resolves spontaneously within 1-2 weeks after drug discontinuation. Some cases associated with systemic involvement and shock have been reported. We present the case of a severe AGEP, manifesting in association with systemic involvement and haemodynamic instability resulting in shock and multiorgan dysfunction in an adult female patient diagnosed with COVID-19 infection. There were no identifiable associated drugs, and the patient was not initiated on antimalarial drugs. Our patient improved rapidly, both hemodynamically and dermatologically with no directed therapy.

Acute Generalized Exanthematous Pustulosis (AGEP) in 12 Patients Treated for SARS-CoV-2 Positive Pneumonia.

ABSTRACT: The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is rapidly spreading throughout the world. The study describes 12 patients with SARS-CoV-2 pneumonia, who developed an acute erythematous rash with nonfollicular pinhead-sized pustules, without mucosal involvement. The clinical differential diagnosis was viral rash, acute generalized exanthematous pustulosis (AGEP), or multiform erythema. computed tomography with a diagnosis of interstitial pneumonia and a respiratory tract sample positive for SARS-CoV-2 in a reverse transcriptase polymerase chain reaction assay. Patients had signs of respiratory distress and were treated with hydroxychloroquine, darunavir, ritonavir, heparin, ceftriaxone, and azithromycin. Punch biopsies showed subcorneal pustules typical of AGEP. Dermal microvascular injury and thrombosis as described in skin damage by SARS-CoV-2 infection was not observed. The direct immunofluorescence for IgG, IgA, IgM, and C3 was negative in 8 patients investigated. A polymerase chain reaction for RNA SARS-CoV-2 performed on frozen skin was negative in 5 of 6 patients. Most of our patients were treated with systemic corticosteroids. After some days (4-10), the diffuse erythema and pustules had improved. AGEP is classified as a severe cutaneous adverse reaction, provoked by drugs and acute infections. Characteristically, removal of the offending agent leads to spontaneous resolution typically in less than 15 days. The recognition of AGEP is important, in order to avoid confusion with a systemic infection and consequently to avoid incorrect treatment. Cutaneous adverse reactions to drugs are common and are major health problems worldwide causing considerable costs for health care systems. We suggest that in the patients with AGEP during SARS-CoV-2 pneumonia, viral infection is a risk factor for developing drug reaction.

Clindamycin-induced acute generalized exanthematous pustulosis: A case report.

RATIONALE: Acute generalized exanthematous pustulosis (AGEP) is a severe pustular cutaneous adverse drug reaction. Sterile, non-follicular pustules overlying the erythematous skin characterize this reaction. PATIENT CONCERNS: A 30-year-old Asian women presented with sterile, non-follicular lesions with pus-fluid levels on her back 2 days after taking clindamycin. Skin biopsy revealed a spongiotic change in the epidermis with a focal subcorneal pustule and perivascular eosinophil and lymphocyte infiltration. DIAGNOSIS: Clindamycin-induced AGEP. INTERVENTIONS: We discontinued clindamycin treatment and prescribed systemic corticosteroids. OUTCOMES: The pustule stopped spreading within 1 day and the rash improved within 2 days. LESSONS: AGEP is a pustular cutaneous adverse drug reaction that can appear with pus-fluid levels, clinically mimicking Sneddon-Wilkinson disease. The differentiation between both conditions is a history of drug use, characteristic skin lesions and histopathology.

Generalized pustular figurate erythema: A newly delineated severe cutaneous drug reaction linked with hydroxychloroquine.

A severe cutaneous drug reaction resembling acute generalized exanthematous pustulosis resulting from ingestion of hydroxychloroquine has been documented. It is distinguishable by its longer incubation period, more varied morphology with initially urticarial and later targetoid and arcuate plaques, recalcitrance to therapy and longer duration. Given the anticipated surge in the use of hydroxychloroquine due to its reported benefits in those with coronavirus disease 2019, specific recognition of this entity is pivotal. We delineate it as generalized pustular figurate erythema.