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Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening conditions with high morbidity and mortality. Supportive care management of SJS/TEN is highly variable. A systematic review of the literature was performed by dermatologists, ophthalmologists, intensivists, and gynecologists with expertise in SJS/TEN to generate statements for supportive care guideline development. Members of the Society of Dermatology Hospitalists with expertise in SJS/TEN were invited to participate in a modified, online Delphi-consensus. Participants were administered 9-point Likert scale questionnaires regarding 135 statements. The RAND/UCLA Appropriateness Method was used to evaluate and select proposed statements for guideline inclusion; statements with median ratings of 6.5 to 9 and a disagreement index of ≤1 were included in the guideline. For the final round, the guidelines were appraised by all of the participants. Included are an evidence-based discussion and recommendations for hospital setting and care team, wound care, ocular care, oral care, urogenital care, pain management, infection surveillance, fluid and electrolyte management, nutrition and stress ulcer prophylaxis, airway management, and anticoagulation in adult patients with SJS/TEN. [ABSTRACT FROM AUTHOR]

Acute generalised exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction and is attributed to drugs in more than 90% of cases. It is a rare disease, with an estimated incidence of 1–5 patients per million per year. The clinical manifestations characterised by the rapid development of sterile pustular lesions, fever and leucocytosis. Number of drugs has been reported to be associated with AGEP, most common being the antibiotics. Histopathologically there is intraepidermal pustules and papillary dermal oedema with neutrophilic and eosinophilic infiltrations. Systemic involvement can be present in more severe cases. Early diagnosis with withdrawal of the causative drug is the most important step in the management. Treatment includes supportive care, prevention of antibiotics and use of a potent topical steroid.

Bullous drug eruptions are infrequent, but because they pose a challenge both to affected patients and to treating physicians they are considered to be the most severe cutaneous adverse reactions (SCAR). It is important to recognize these conditions and to differentiate them from other clinical entities involving blister formation. There may be early signs and symptoms that indicate a severe bullous drug eruption even before blisters and erosions of the skin and mucous membranes become obvious. Once the diagnosis is suspected, appropriate diagnostic procedures and adequate management must be initiated. The latter includes identification of the potentially inducing drug, although it should be taken into account that not all cases of bullous eruptions are drug-induced. In cases with drug causality the potentially culprit agent must be withdrawn, while in cases with other aetiology the underlying condition, e.g. an infection, must be treated appropriately. In addition to best supportive care, immunomodulating therapy may be considered.

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome belong to a family of severe cutaneous adverse reactions that can be life-threatening and carry a risk of significant morbidity and potential mortality in the event of re-exposure. Lifelong avoidance of the culprit agent is mandated, which can lead to the exclusion of multiple medications if the trigger is unclear. This can result in adverse health outcomes analogous to that of a penicillin allergy label. We present a case in which the patient would progress to fatal myeloma in the absence of treatment, however, multiple medications were administered prior to the occurrence of TEN following previous chemotherapy. Available risk stratification tools including human leucocyte antigen assessment and the algorithm of drug causality for epidermal necrolysis scoring system were utilized followed by patch testing which identified a lesser-suspected agent as possibly causative. Further evidence-based in vivo testing and subsequent challenges allowed for the reintroduction of life-saving chemotherapy., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2023. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.)

Introduction and Importance: Stevens-Johnson syndrome (SJS) is a rare and unusual hypersensitivity reaction to certain drugs like allopurinol, commonly used for treating gout. SJS is recognized by extensive necrosis and detachment of skin and mucus membranes. Pancytopenia, characterized by decreased levels of red blood cells, white blood cells and platelets, is an exceedingly rare occurrence in the rare disorder SJS., Case Presentation: The authors present a 61-year-old male who exhibited symptoms of fever and rash for 5 days accompanied by pancytopenia and liver injury., Clinical Discussion: The abdomen and bilateral lower extremities exhibited several well-defined dusky-colored hyperpigmented macular lesions. Initially, these lesions were small, tender, erythematous, and raised, later transitioning to a dark red. Multiple distinct ulcerations were present on the lips and buccal cavity. Additionally, there was denudation of the skin with bleeding observed between the toes of both legs. The causality was assessed as a definite adverse drug reaction according to the Naranjo and ALDEN algorithm. The patient received treatment consisting of intravenous steroid along with prophylactics antibiotics. The individual's pancytopenia was resolved without requiring any blood cells or plasma or platelet concentrate transfusion., Conclusion: The exact pathophysiology of SJS associated with pancytopenia has not yet been fully elucidated. The authors' study hypothesized that the cause of pancytopenia in SJS could be either the direct cytotoxicity of drugs or immune-mediated damage to the bone marrow cells. Additional studies are necessary to establish the precise pathophysiology of the condition. Moreover, our study also indicates that pancytopenia can resolve in SJS without the need for blood cells or plasma or platelet concentrate transfusion. Once more, further studies are required to establish precise management strategies for managing SJS associated with pancytopenia., Competing Interests: No conflict of interest.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Competing Interests: None disclosed.

The similarity between pustular psoriasis (PP) and acute generalized exanthematous pustulosis (AGEP) poses problems in the diagnosis and treatment of these two conditions. Significant clinical and histopathologic overlap exists between PP and AGEP. PP is an inflammatory disorder that has numerous clinical subtypes, but all with sterile pustules composed of neutrophils. AGEP is a severe cutaneous adverse reaction that is also characterized by non-follicular sterile pustules. Clinical features that suggest a diagnosis of PP over AGEP include a history of psoriasis and the presence of scaling plaques. Histologically, eosinophilic spongiosis, vacuolar interface dermatitis, and dermal eosinophilia favor a diagnosis of AGEP over PP. Importantly, PP and AGEP vary in clinical course and treatment. PP treatment involves topical steroids, oral retinoids, and systemic immunosuppressants. Newer therapies targeting IL-36, IL-23, IL-1, and PDE-4 have been investigated. The removal of the offending agent is a crucial part of the treatment of AGEP.

Bullous drug eruptions are infrequent, but because they pose a challenge both to affected patients and to treating physicians they are considered to be the most severe cutaneous adverse reactions (SCAR). It is important to recognize these conditions and to differentiate them from other clinical entities involving blister formation. There may be early signs and symptoms that indicate a severe bullous drug eruption even before blisters and erosions of the skin and mucous membranes become obvious. Once the diagnosis is suspected, appropriate diagnostic procedures and adequate management must be initiated. The latter includes identification of the potentially inducing drug, although it should be taken into account that not all cases of bullous eruptions are drug-induced. In cases with drug causality the potentially culprit agent must be withdrawn, while in cases with other aetiology the underlying condition, e.g. an infection, must be treated appropriately. In addition to best supportive care, immunomodulating therapy may be considered. [ABSTRACT FROM AUTHOR]

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening conditions that may present with similar findings to other severe dermatologic diseases.Objective: The primary objective of this exploratory study was to explore factors associated with SJS/TEN and develop a model that provides the predicted probability of SJS/TEN for patients for whom the diagnosis of SJS/TEN is considered.Methods: Retrospective review of consultations for patients with suspected SJS, TEN, or overlap at 4 academic dermatology consultation services.Results: Overall, 208 patients were included; 59 (28.4%) had a final diagnosis of SJS/TEN, and 149 (71.6%) were given a different diagnosis. The most common mimickers were drug hypersensitivity syndrome (n = 21, 10.1%), morbilliform drug eruption (n = 18, 8.7%), erythema multiforme (n = 15, 7.2%), and acute generalized exanthematous pustulosis (n = 13, 6.2%). Nikolsky sign, atypical targets, fever, and lymphopenia were included in a model for predicting the probability of SJS/TEN.Limitations: All cases were obtained from academic centers, which may limit the generalization of findings to community-based settings. This was an exploratory study with a small number of cases, and external validation of the model performance is needed.Conclusion: Early dermatologic evaluation of patients with suspected SJS/TEN is key to separating patients with this condition from those who ultimately receive diagnoses of other serious skin diseases. [ABSTRACT FROM AUTHOR]

Keywords: AGEP/TEN overlap; ceftriaxone; COVID-19; patch test; SARS-CoV-2 infection; severe cutaneous adverse reaction EN AGEP/TEN overlap ceftriaxone COVID-19 patch test SARS-CoV-2 infection severe cutaneous adverse reaction 366 368 3 08/16/21 20210901 NES 210901 Adverse drug reactions (ADRs) are rarely reported in patients with coronavirus disease 2019 (COVID-19) despite the wide range of medications administered to slow the progression of the disease and relieve symptoms caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). AGEP/TEN overlap, ceftriaxone, COVID-19, patch test, SARS-CoV-2 infection, severe cutaneous adverse reaction Severe adverse drug reaction in SARS-CoV-2 infection: AGEP induced by ceftriaxone and confirmed by patch test. [Extracted from the article]

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous adverse reaction characterized by a morbilliform cutaneous eruption, fever, lymphadenopathy, and multiorgan involvement. Alopecia universalis is a variant of alopecia areata characterized by complete loss of hair on the entire body. Herein, we report a case of alopecia universalis that presented after DRESS. [ABSTRACT FROM AUTHOR]

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous adverse reaction to drugs with varied clinical manifestations. Diffuse morbilliform rash with facial edema and systemic involvement in the form of lymphadenopathy, eosinophilia and hepatic involvement are the commonest clinical presentation. Features mimicking Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN), sepsis, Kawasaki disease andhyper-eosinophilic syndrome can cause immense diagnostic dilemma. We report a case of DRESS which is unique as the triggering drug being leflunomide that has rarely been reported and atypical presentation wherein exfoliative dermatitis and erythema multiforme like lesions which evolved sequentially. A 56-year-old lady, a known case of rheumatoid arthritis on treatment, developed diffuse exanthematous rash over body with fever and hepatic dysfunction, a month after administration of leflunomide. She was diagnosed as DRESS partially managed with steroids to rebound back a week later with severe and atypical manifestations. The uniqueness of the case lies in the fact that DRESS resulted after an uncommon incriminating drug and polymorphic presentation appearing sequentially, besides, highlighting the need of slow tapering of steroids. [ABSTRACT FROM AUTHOR]

Background: Severe cutaneous adverse reactions (SCARs) are frequent in inpatient oncology. Early intervention might reduce morbidity, mortality, and hospitalization costs; however, current clinical and histologic features are unreliable SCAR predictors. There is a need to identify rational markers of SCARs that could lead to effective therapeutic interventions.Objective: To characterize the clinical and serologic features of hospitalized patients with cancer who developed SCARs.Methods: Retrospective review of 49 hospitalized cancer patients with a morbilliform rash, recorded testing for serum cytokines (interleukin [IL] 6, IL-10, and tumor necrosis factor [TNF] α) or elafin, and a prior dermatology consultation. Patients were categorized as having a simple morbilliform rash without systemic involvement or complex morbilliform rash with systemic involvement.Results: Fifteen out of 49 patients (30.6%) were deceased at 6 months from time of dermatologic consultation. Elafin, IL-6, and TNF-α were significantly higher in patients who died compared with patients who were still alive at 6 months. IL-6 and IL-10 were significantly higher in patients with a drug-related complex rash.Limitations: Retrospective design, limited sample size, and high-risk patient population.Conclusion: In cancer patients with SCARs, elafin, IL-6, and TNF-α levels might predict a poor outcome. Agents directed against these targets might represent rational treatments for the prevention of fatal SCARs. [ABSTRACT FROM AUTHOR]

Acute generalised exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction and is attributed to drugs in more than 90% of cases. It is a rare disease, with an estimated incidence of 1-5 patients per million per year. The clinical manifestations characterised by the rapid development of sterile pustular lesions, fever and leucocytosis. Number of drugs has been reported to be associated with AGEP, most common being the antibiotics. Histopathologically there is intraepidermal pustules and papillary dermal oedema with neutrophilic and eosinophilic infiltrations. Systemic involvement can be present in more severe cases. Early diagnosis with withdrawal of the causative drug is the most important step in the management. Treatment includes supportive care, prevention of antibiotics and use of a potent topical steroid. [ABSTRACT FROM AUTHOR]

Toxic epidermal necrolysis (TEN) is a rare fatal mucocutaneous blistering disorder that can have varied underlying triggers. The percentage of body surface area (BSA) that is impacted by erosive blistering is what separates it from Steven Johnson syndrome (SJS), both of which have the same underlying pathogenesis and are thought to exist on a continuum of disease with TEN being the more serious of the two. Medications are the most frequent cause of TEN/SJS and typically cause disease in both adults and children within eight weeks; however, the median exposure window is four days to four weeks. Nonsteroidal anti-inflammatory drugs, allopurinol, anticonvulsants including lamotrigine, phenytoin, levetiracetam and carbamazepine, antimicrobial sulfonamides, and the antiviral nevirapine are examples of medications that frequently cause TEN/SJS. Here, we are reporting a case of phenytoin-induced TEN highlighting the patient's excellent response to immunomodulating treatment despite 100% involvement of the BSA., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Tunuguntla et al.)

Allopurinol, an inhibitor of xanthine oxidase, is a frequent cause of severe cutaneous adverse reactions (SCARs) in humans, including drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome and toxic epidermal necrolysis. Although SCARs have been suspected to be immune-mediated, the mechanisms of allopurinol-induced SCARs remain unclear. In this study, we examined whether allopurinol has the ability to induce innate immune responses in vitro using human dendritic cell (DC)-like cell lines, including HL-60, THP-1 and K562, and a human keratinocyte cell line, HaCaT. In this study, we demonstrate that treatment of HL-60 cells with allopurinol significantly increased the mRNA expression levels of interleukin-8, monocyte chemotactic protein-1 and tumor necrosis factor α in a time- and concentration-dependent manner. Furthermore, allopurinol induced the phosphorylation of mitogen-activated protein kinases (MAPK), such as c-Jun N-terminal kinase and extracellular signal-regulated kinase, which regulate cytokine production in DC. In addition, allopurinol-induced increases in cytokine expression were inhibited by co-treatment with the MAPK inhibitors. Collectively, these results suggest that allopurinol has the ability to induce innate immune responses in a DC-like cell line through activation of the MAPK signaling pathways. These results indicate that innate immune responses induced by allopurinol might be involved in the development of allopurinol-induced SCARs. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: The term chronic kidney disease (CKD) is used to describe abnormal kidney function (or structure). People with CKD have an increased prevalence of cardiovascular disease (CVD). Evidence is emerging that allopurinol may have a role to play in slowing down the progression of CKD and reducing the risk of CVD. Objectives: This systematic review addresses the research question: does allopurinol reduce mortality, the progression of chronic kidney disease or cardiovascular risk in people with CKD? Data sources: The following databases were searched on 7 January 2013: MEDLINE (1946 to 7 January 2013), EMBASE (1974 to 28 December 2012), The Cochrane Library (Issue 1, 2013) and ClinicalTrials.gov. Bibliographies of retrieved citations were also examined and two manufacturers of allopurinol were approached for data. Review methods: Two reviewers independently screened all titles and abstracts to identify potentially relevant studies for inclusion in the review. Full-text copies were assessed independently by two reviewers. Data were extracted and assessed for risk of bias by one reviewer and independently checked for accuracy by a second. Summary statistics were extracted for each outcome and, where possible, data were pooled. Meta-analysis was carried out using fixed-effects models. Results: Efficacy evidence was derived solely from four randomised controlled trials (RCTs). Adverse event (AE) data were derived from the RCTs and 21 observational studies. Progression of CKD was measured by estimated glomerular filtration rate (eGFR) in three trials and by changes in serum creatinine in the other. No significant differences in eGFR over time were reported. The only significant difference between groups was reported in one trial at 24 months favouring allopurinol [eGFR: 42.2 ml/minute/1.73 m2, standard deviation (SD) 13.2 vs. 35.9 ml/minute/1.73 m2, SD 12.3 ml/minute/1.73 m2; p

Competing Interests: Conflicts of interest None disclosed.

Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a life-threatening, multi-organ adverse drug reaction with an incidence of 1 in 1000 to 1 in 10 000 high-risk drug exposures., Case Presentation: An elderly female presented to the hospital with progressive weakness and a diffuse erythematous macular rash covering most of her body that started 3 days prior. Over the next 3 days, the patient quickly deteriorated, developing disorientation with acute onset left-sided weakness, leukocytosis, thrombocytopenia, eosinophilia, liver and kidney failure, and hypoxia. Clinical and histological changes supported the diagnosis of DRESS syndrome caused by intravenous (IV) ampicillin administered during a prior hospitalization for a urinary tract infection. Systemic corticosteroids were initiated quickly thereafter, but the patient ultimately succumbed to complications caused by DRESS syndrome., Conclusion: There are currently no randomized trials evaluating treatments for DRESS, and evidenced-based guidelines are lacking. Viral reactivation has also been suggested as a possible complication of DRESS syndrome, though the true incidence and association remain unclear. Although we started our patient on high-dose IV corticosteroids early in her course, she still succumbed to complications of DRESS syndrome. Further research into the treatment of DRESS syndrome and its association with viral reactivation is essential., Competing Interests: Conflicts of Interest The authors declare that they have no conflicts of interest., (© 2023 HCA Physician Services, Inc. d/b/a Emerald Medical Education.)

Toxic epidermal necrolysis ( TEN) is an adverse reaction that can be induced by various drugs; the associated mortality rate is 20-25%. A previous report showed a weak association between TEN and acetaminophen. Recently, the US Food and Drug Administration declared that acetaminophen is associated with a risk of serious skin reactions, including TEN. Here, we describe the case of a 43-year-old Japanese woman with TEN caused by acetaminophen. She had poorly controlled ulcerative colitis and was treated with high doses of prednisolone, infliximab, acetaminophen and lansoprazole. Nine days after administrating acetaminophen, targetoid erythematous and bullous lesions appeared on the patient's trunk, palms and the soles of her feet. The skin lesions expanded rapidly; within 3 weeks, skin detachment was detected across nearly 100% of the patient's body. However, no mucosal involvement of the eyes, oral cavity or genitalia was found. We performed lymphocyte transformation tests using various drugs; however, a high stimulation index was obtained only with acetaminophen. The patient recovered following treatment with plasmapheresis, i.v. immunoglobulin therapy, topical medication and supportive therapy. Acetaminophen is included in many prescription and over-the-counter products; thus, clinicians should monitor their patients for severe drug reactions, including TEN. [ABSTRACT FROM AUTHOR]

Introduction Recent publications have described drug reaction with eosinophilia and systemic symptoms (DRESS) with topiramate. Topiramate has been associated with other severe cutaneous adverse reactions, including Stevens-Johnson syndrome, but a relationship to DRESS has not been established. To determine if there is a causal association between topiramate and DRESS, we conducted a comprehensive review of the data in the Janssen Research & Development Global Safety Database (GSD), signaling databases, and the literature. Methods The primary data were post-marketing reports of DRESS in the Janssen topiramate GSD (cumulative through 1 July 2022), representing >14,000,000 patient-years (PY) exposure. Cases were reviewed, assigned a Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) score, and assessed for overall contribution of topiramate to DRESS based on temporality, concomitant medications, dechallenge/rechallenge, and baseline patient factors. Statistical disproportionality was evaluated in European Medicines Agency's EudraVigilance (EV) safety database and the United States Food and Drug Administration Adverse Event Reporting System (FAERS). For EV, the overall disproportionality threshold was the lower limit of the 95% confidence interval (CI) for the reporting odds ratio (ROR025) >1 and N ≥5. The overall threshold for FAERS was the Empirical Bayesian Geometric Mean (EBGM) ≥2, lower bound of the 90% CI (EB05) of >1, and N ≥3. To account for the role of concomitant drugs, Empirical Bayes regression-adjusted arithmetic mean (ERAM) scores were calculated, with a threshold ≥2, a lower bound of the 90% CI (ER05) of >1, and N ≥3. An integrated search of major biomedical literature was performed for reports of topiramate and DRESS. Results There were 17 reports of DRESS in the GSD (reporting rate 0.12/100,000 PY). RegiSCAR scores ranged from -3 to 7 (average -0.4). No cases met full diagnostic criteria and were highly confounded by the presence of other suspect drugs. Disproportionality scores exceeded thresholds for statistical significance in FAERS (N=72, EBGM=2.06, EB05=1.69), but not in EV (N=33, ROR025=0.79). When accounting for co-administered drugs, ERAM was statistically significant for carbamazepine (4.53), lamotrigine (ERAM=6.54), phenytoin (ERAM=2.91), and zonisamide (ERAM=2.25) exceeding disproportionality thresholds, but the score of topiramate was no longer significant (0.25). Conclusion A comprehensive review of all available evidence does not support a causal association between topiramate and DRESS., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2023, Thoms et al.)

Strontium ranelate is a relatively new medication with good safety profile for the treatment of postmenopausal osteoporosis. However, severe cutaneous adverse drug reactions have been reported, such as drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). We report the case of a 70-year-old woman who developed multiple itching erythematous macules and plaques about 1 month after beginning strontium ranelate medication. The cutaneous lesions progressed over the entire body with severe oral and ocular mucosa involvement. Probable mild SJS was diagnosed, compatible with the pathology findings, and strontium ranelate was discontinued immediately. Systemic methylprednisolone was administered to suppress the overactive immune system and ameliorate cutaneous symptoms. With early recognition and prompt treatment, the patient's prognosis was good. [ABSTRACT FROM AUTHOR]

Drug reaction with eosinophilia and systemic symptoms ( DRESS), also known as drug-induced hypersensitivity syndrome ( DIHS), is a rare, severe cutaneous adverse reaction characterised by fever, rash, lymphadenopathy, eosinophilia and/or other leukocyte abnormalities, and internal organ involvement and often has a relapsing-remitting course despite withdrawal of the drug. The drugs that are most implicated include aromatic anticonvulsants, allopurinol, sulphonamides, antiretrovirals (abacavir and nevirapine), and minocycline. The pathogenesis of DRESS/ DIHS is far from clear but probably involves a combination of impaired pharmacokinetics and the accumulation of drug metabolites, the sequential reactivation of the herpesvirus family and genetic susceptibility conferred by the association with certain human leukocyte antigen ( HLA) class I alleles. The strong association between abacavir and HLA - B *5701 has enabled pharmacogenetics screening to be employed successfully to minimise the occurrence of hypersensitivity. A prolonged course of oral corticosteroids is required to treat DRESS/ DIHS, given the relapsing-remitting nature of the condition with i.v. immunoglobulin and valgangciclovir reserved for refractory or life-threatening cases. [ABSTRACT FROM AUTHOR]

Background Allopurinol is a main cause of severe cutaneous adverse reactions ( SCAR). How allopurinol induces hypersensitivity remains unknown. Pre-disposing factors are the presence of the HLA-B*58:01 allele, renal failure and possibly the dose taken. Objective Using an in vitro model, we sought to decipher the relationship among allopurinol metabolism, HLA-B*58:01 phenotype and drug concentrations in stimulating drug-specific T cells. Methods Lymphocyte transformation test ( LTT) results of patients who had developed allopurinol hypersensitivity were analysed. We generated allopurinol or oxypurinol-specific T cell lines ( ALP/ OXP- TCLs) from allopurinol naïve HLA-B*58:01+ and HLA-B*58:01− individuals using various drug concentrations. Their reactivity patterns were analysed by flow cytometry and 51Cr release assay. Results Allopurinol allergic patients are primarily sensitized to oxypurinol in a dose-dependent manner. TCL induction data show that both the presence of HLA-B*58:01 allele and high concentration of drug are important for the generation of drug-specific T cells. The predominance of oxypurinol-specific lymphocyte response in allopurinol allergic patients can be explained by the rapid conversion of allopurinol to oxypurinol in vivo rather than to its intrinsic immunogenicity. OXP- TCLs do not recognize allopurinol and vice versa. Finally, functional avidity of ALP/ OXP- TCL is dependent on both the induction dose and HLA-B*58:01 status. Conclusions and Clinical Relevance This study establishes the important synergistic role of drug concentration and HLA-B*58:01 allele in the allopurinol or oxypurinol-specific T cell responses. Despite the prevailing dogma that Type B adverse drug reactions are dose independent, allopurinol hypersensitivity is primarily driven by oxypurinol-specific T cell response in a dose-dependent manner, particular in the presence of HLA-B*58:01 allele. [ABSTRACT FROM AUTHOR]

Toxic epidermal necrolysis (TEN) is a severe cutaneous adverse reaction to drugs, characterized by extensive detachment of epidermis and mucous membranes with a mortality of 30-40%. An increased occurrence of cutaneous drug reactions is seen in patients with human immunodeficiency virus (HIV) infection. We present this case of TEN caused by ondansetron in an HIV-infected patient. A 24-year-old HIV-1-infected man on antitubercular therapy and cotrimoxazole, presented with extensive and confluent erosions involving the face, trunk, extremities and mucous membranes following the intake of oral ondansetron, ofloxacin and ornidazole. All the drugs were withdrawn and he was treated with intravenous dexamethasone and antibiotics with consequent healing of the erosions. However, the lesions recurred on inadvertent intake of oral ondansetron. He was treated with intravenous antibiotics, fluid resuscitation and supportive care. The skin lesions healed completely over 2 months with postinflammatory depigmentation and scarring, and the eye lesions healed with corneal opacities. We would like to emphasize that the drug most frequently associated with adverse drug reactions may be innocent in a given patient and the physician dealing with a suspected drug reaction must always remain unbiased regarding the causative drug. [ABSTRACT FROM AUTHOR]

This review focuses on the current applications of telemedicine for drug hypersensitivity reactions. Telemedicine holds promise as a tool to risk-stratify patients with drug hypersensitivity, for both evaluation of penicillin allergies and severe cutaneous adverse reactions. Although telemedicine may not fully replace in-person assessment owing to the need for testing, challenges, and in-person physical examination or skin biopsy, it may allow for risk stratification whereby some in-person visits may not be necessary. Electronic consults have also emerged along with telemedicine as a tool for drug allergy evaluations., Competing Interests: Disclosure D. Wells: No relevant disclosures. K. DeNiro: No relevant disclosures. A. Ramsey: Speakers Bureau for Sanofi/Regeneron and GlaxoSmithKline (not relevant for article)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are severe mucocutaneous bullous disorders characterized by widespread skin and mucosal necrosis and detachment, which are most commonly triggered by medications. Despite their rarity, these severe cutaneous adverse drug reactions will result in high mortality and morbidity as well as long-term sequela. The immunopathologic mechanisms is mainly cell-mediated cytotoxic reaction against keratinocytes leading to massive skin necrolysis. Subsequent studies have demonstrated that immune synapse composed of cytotoxic T cells with drug-specific human leukocyte antigen (HLA) class I restriction and T cell receptors (TCR) repertoire is the key pathogenic for SJS/TEN. Various cytotoxic proteins and cytokines such as soluble granulysin, perforin, granzyme B, interleukin-15, Fas ligand, interferon-γ, tumor necrosis factor-α have been as mediators involved in the pathogenesis of SJS/TEN. Early recognition and immediate withdrawal of causative agents, and critical multidisciplinary supportive care are key management of SJS/TEN. To date, there is yet to be a sufficient consensus or recommendation for the immunomodulants of the treatment in SJS/TEN. Systemic corticosteroids remain one of the most common treatment options for SJS/TEN, though the efficacy remain uncertain. Currently, there is increasing evidence showing that cyclosporine and TNF-α inhibitors decrease the mortality of SJS/TEN. Further multicenter double-blinded, randomized, placebo-controlled trials are required to confirm the efficacy and safety., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Keywords: delayed hypersensitivity reaction; drug allergy; severe cutaneous adverse reaction; t-cell; enzyme link immunospot; cytotoxicity; flow cytoametry; lactate dehydrogenase EN delayed hypersensitivity reaction drug allergy severe cutaneous adverse reaction t-cell enzyme link immunospot cytotoxicity flow cytoametry lactate dehydrogenase 1 1 1 09/06/21 20210902 NES 210902 In the original article, we mistakenly omitted a statement from the Funding section. Delayed hypersensitivity reaction, drug allergy, severe cutaneous adverse reaction, t-cell, enzyme link immunospot, cytotoxicity, flow cytoametry, lactate dehydrogenase The statement reads as follows: "JP receives financial support from National Institutes of Health, award K43TW011178-02; the EDCTP2 programme supported by the European Union, grant number TMA2017SF-1981 and the South African National Research Foundation (NRF). [Extracted from the article]

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare delayed-type hypersensitivity reaction that causes skin abnormalities and mucosal involvement of the entire body. This is a case report of DRESS occurring in a liver transplantation recipient after taking drugs. A 57-year-old female patient with hepatocellular carcinoma underwent living donor liver transplantation in April 2019. She had no previous medical histories relevant to allergic diseases. There were no adverse events during hospitalization. She was admitted to evaluate and treat a headache occurring at one month after transplantation. However, she suffered from adverse drug reactions after taking anticonvulsants, showing skin rash, itching sense, and fever with eosinophilia. Piperacillin/Tazoperan was administered for ten days as an empirical antibiotic. Skin biopsy was performed on postoperative day 106 for erythematous maculopapular rash in the arms, legs, and torso. Her symptoms improved after discontinuation of the suspected medication with conservative skin treatment and high-dose steroid treatment. This case suggests that suspicion of drug history is essential for early diagnosis and management of DRESS.

Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and acute generalized exanthematous pustulosis (AGEP) are two separate pathological entities of severe cutaneous adverse reactions (SCARs) with different etiologies and treatment strategies. Diagnosis is, however, complicated by the similarity in their clinical presentation. Although there are few claims of AGEP-SJS/TEN overlap, a simultaneous true overlap of SJS/TEN and AGEP has rarely been described in the literature. Here, we report a case study of a 61-year-old female with a known allergy to sulfa drugs presenting with altered mental status, generalized weakness, and erythematous and excoriated purulent wounds. Based on initial workup and extensive consultation, the patient was diagnosed with severe sepsis secondary to diffuse purulent cellulitis, community-acquired pneumonia, and acute renal failure due to prerenal azotemia from dehydration. She was treated with several antibiotics, starting with vancomycin, piperacillin/tazobactam. Six days later, antibiotics were de-escalated to ceftriaxone and metronidazole because of the patient's improved status. The medications were withheld when the patient started developing extensive blistering on day 8. Blood cultures ruled out any bacterial etiology. Skin biopsy confirmed overlapping features of AGEP and SJS/TEN. Due to the uncontrolled progression of her rash, she was transferred to the burn unit of a higher care center. This is potentially the first histologically confirmed case of AGEP-SJS/TEN overlap in the United States. In this case study, a conclusive diagnosis would have never been made without a biopsy, especially because the condition presented clinically as SJS/TEN. We, therefore, recommend considering a potential overlap of multiple pathologies at each presentation or suspicion of a SCAR and performing an early skin biopsy in order to provide definitive diagnosis and treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Chowdhury et al.)

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Allopurinol is the most common cause of severe cutaneous adverse reactions (SCARs) in Korea due to the relatively high prevalence of the HLA-B*58:01 genotype (8%-13%)., Objective: We aimed to reveal the clinical characteristics and risk factors for death in allopurinol-induced SCARs in Korea., Methods: We retrospectively reviewed the medical records of 106 subjects with allopurinol-induced SCARs and 639 subjects with other drug-induced SCARs who were enrolled in the Korean SCARs Registry (collected from 34 nationwide medical institutions) from January 2010 to December 2015., Results: Subjects with allopurinol-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) were older and had more comorbidities, longer latent periods, longer disease durations, more deranged laboratory findings, and increased disease severity resulting in a higher mortality rate (17.6% vs 7.6%; P = .020) compared with the subjects with other drug-induced SCARs. There was no significant difference in age or mortality in drug reaction with eosinophilia and systemic symptoms (DRESS). Subjects with allopurinol-induced SJS/TEN were older and had shorter latent periods and a higher mortality rate (17.6% vs 3.7%; P = .044) than those with allopurinol-induced DRESS. In allopurinol-induced SJS/TEN, significant risk factors for death included chronic renal insufficiency, intensive care unit (ICU) admission, increased blood urea nitrogen levels on admission day, serum peak eosinophil counts, baseline and peak creatinine levels, baseline and peak alanine aminotransferase levels, and decreased lowest platelet counts. In allopurinol-induced DRESS, significant risk factors for death included ICU admission and increased glucose levels on admission day., Conclusions: Allopurinol-induced SCARs have unique characteristics and poor prognoses with important predictive factors of death., (Copyright © 2019. Published by Elsevier Inc.)

Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but severe hypersensitivity reaction that remains poorly characterized in the United States., Objective: To identify and describe DRESS syndrome cases in an integrated health care system using electronic health record (EHR) allergy module free-text searches., Methods: We identified DRESS syndrome cases with rash, absolute eosinophil count of 500/L or more, organ involvement, and a European Registry of Severe Cutaneous Adverse Reactions to Drugs and Collection of Biological Samples score of 2 or more by reviewing those patients from 1980 to 2016 whose EHR allergic reaction matched DRESS-related key words. Liver injury required alanine aminotransferase level of 100 U/L or more, and renal injury required creatinine increase by 0.5 mg/dL (or 50%) or more. Patient and DRESS characteristics were described, resource use was determined, and cost was estimated., Results: Among 3,162,562 patients with 3,319,387 million allergy entries, 538 reactions matched key words, and 69 were DRESS syndrome cases (prevalence 2.18 per 100,000). Patients with DRESS had liver (42%) or renal (42%) injury; 11 (16%) had both liver and renal injury. Primary drug culprits were antibiotics (74%) (vancomycin [39%], β-lactams [23%], fluoroquinolones [4%], tetracyclines [4%], and sulfonamides [3%]) and anticonvulsants (20%). Of 65 (94%) hospitalized patients with DRESS, 43 (66%) were hospitalized for DRESS syndrome management with median length of stay of 9 days (interquartile range, 6-17 days) and cost approximately $17,101 per patient., Conclusions: Using free-text search of the EHR allergy module identified a large US DRESS syndrome cohort. DRESS prevalence was 2.18 per 100,000 patients. Both liver and kidney injury were frequent, and vancomycin was the most common drug culprit. DRESS cases were morbid and resource-intensive., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

All beta-lactam use is associated with a certain rate of adverse reactions. Many of these adverse reactions result in an allergy to the beta-lactam being entered into the patient's medical record. Unfortunately, only a small minority of these recorded allergies are clinically significant immunologically mediated drug hypersensitivity. An unconfirmed allergy to beta-lactams is a significant public health risk, because patients so labeled typically do not receive narrow-spectrum penicillins and cephalosporins when clinically indicated. The alternative antibiotics they receive result in poorer clinical outcomes, increased incidence of serious antibiotic-resistant infections, prolonged hospitalizations, and greater health care utilization. There is a wide variation in beta-lactam allergy incidence and prevalence around the world, based in part on the specific beta-lactams used and overused. There is a wide variation in specific protocols used to confirm current tolerance of beta-lactams and remove these inaccurate allergy reports. Harmonizing testing protocols, when possible, may lead to more widespread use of narrow-spectrum beta-lactams, when clinically indicated, and improve patient safety worldwide. Further research is needed to better understand the regional differences in reporting beta-lactam allergy as this relates to regional differences in beta-lactam use and overuse, the frequency of clinically significant immunologically mediated beta-lactam hypersensitivity, and the optimal testing strategies to confirm current tolerance, based on presenting clinical symptoms., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

An association between drug treatment for viral infections and severe cutaneous adverse reactions has been noted. We investigated six patients diagnosed with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) after being prescribed acetaminophen for suspected viral illnesses. Multiplex analysis was performed to measure cytokine levels in sera before and after treatment. IL-2Rα levels significantly decreased during the convalescence phase. Although acetaminophen is relatively safe, the drug can trigger SJS/TEN in patients with suspected viral infections. T-cells and monocytes may be key components of the link between viral infection and acetaminophen-induced SJS/TEN., Competing Interests: The authors declare no conflict of interest.

Severe cutaneous adverse reactions include syndromes such as drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS) and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). An important advance has been the discovery of associations between HLA alleles and many of these syndromes, including abacavir-associated hypersensitivity reaction, allopurinol-associated DRESS/DIHS and SJS/TEN, and SJS/TEN associated with aromatic amine anticonvulsants. These HLA associations have created the promise for prevention through screening and have additionally shed further light on the immunopathogenesis of severe cutaneous adverse reactions. The rollout of HLA-B∗5701 into routine clinical practice as a genetic screening test to prevent abacavir hypersensitivity provides a translational roadmap for other drugs. Numerous hurdles exist in the widespread translation of several other drugs, such as carbamazepine, in which the positive predictive value of HLA-B∗1502 is low and the negative predictive value of HLA-B∗1502 for SJS/TEN might not be 100% in all ethnic groups. International collaborative consortia have been formed with the goal of developing phenotypic standardization and undertaking HLA and genome-wide analyses in diverse populations with these syndromes. [ABSTRACT FROM AUTHOR]

An abstract of the article "Medications as Risk Factors of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Children: A Pooled Analysis," by Natacha Levi, Sylvie Bastuji-Garin, Maja Mockenhaupt, Jean-Claude Roujeau, Antoine Flahault, Judith P. Kelly, Elvira Martin, David W. Kaufman, and Patrick Maison is presented.