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Background: Serious adverse drug reactions (ADRs) can lead to hospital admission and can be fatal, but some of them are preventable. This study aimed to determine the types and frequencies of serious cutaneous ADRs and the methods employed to manage and prevent them, as well as to assess the factors related to their seriousness. Methods: A cross-sectional study was conducted retrospectively on inpatients and outpatients at a tertiary care hospital. All data were collected from the medical records database over a period of 3 years. Serious cutaneous ADRs were identified in the hospital database using the International Classification of Disease and Related Health Problems, 10th Revision (ICD-10). Results: A total of 2151 cases were retrieved using the ICD-10, and 436 patients were randomly selected for this study. Of these, 218 patients experienced ADRs (50.0%). The major clinical symptoms of the eight serious ADRs included anaphylaxis (38.5%) and urticaria (30.2%). The most commonly suspected drug group was antibiotics (45.0%). The main methods of ADR management were drug treatment (84.4%) and drug withdrawal (81.2%). The primary method of ADR prevention was patient drug allergy cards (52.3%). Factors affecting the severity of ADRs were having an underlying condition (p = 0.031) and the concomitant use of drugs (p = 0.044). Conclusions: Anaphylaxis was the most common serious ADR. Patients with underlying diseases and those taking concomitant drugs are more likely to present with serious ADRs. The prevention of serious ADRs should be promoted at all levels in hospitals to reduce harm and prevent their reoccurrence. [ABSTRACT FROM AUTHOR]

Trimethoprim/sulfamethoxazole is the first-line agent for oral eradication therapy for melioidosis but has been associated with toxicity in this context. This study aimed to quantify adverse drug reactions (ADRs) to trimethoprim/sulfamethoxazole when used for treatment of melioidosis, and assess risk factors for ADR development. A retrospective review of antimicrobial associated ADRs was performed in all patients treated for melioidosis in the Northern Territory of Australia from January 2017-September 2022. Over this time, 268 treatment episodes from 256 individuals were included. The frequency of clinician-attributed ADRs to trimethoprim/sulfamethoxazole (51% of exposed) was higher than for other antimicrobials used (ceftazidime 12%, meropenem 8%, and doxycycline 12% of those exposed; P < 0.0001). 44% of those treated with trimethoprim/sulfamethoxazole required drug cessation or dose reduction and 5 individuals (2%) had a severe cutaneous adverse reaction, with one fatality. Acute kidney injury was the most frequent ADR (25% of those exposed), with age and pre-existing renal disease independently associated with its development. Here we report very high rates of ADRs attributed to trimethoprim/sulfamethoxazole resulting in frequent discontinuation of this drug as part of oral eradication therapy for melioidosis. Further work is needed to balance the necessity and toxicity of this drug in this clinical context.

Abstract Drug hypersensitivity reactions are common in children. Risk factors predisposing to IgE-mediated drug allergies and delayed drug reactions are a matter of debate. Gender, age, previous reactions to the same drug or to another drug, reduced drug metabolism, chronic diseases, polypharmacy, drug doses are linked with the onset of hypersensitivity reactions in some children. Novel advances in genetic polymorphisms can rapidly change the approach to the prevention of reactions since gene testing can be a useful screening test for severe cutaneous adverse reactions. Viral infections may act as cofactors in susceptible individuals. Polypharmacy, high doses, repeated doses and parental route of administration are also risk factors. Clinicians should take into account risk factors to allow the risk–benefit balance to be maintained.

Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is classically considered a low-risk, self-limiting eruption lacking systemic manifestations and sparing facial and mucosal areas. We present 7 inpatients meeting diagnostic criteria for SDRIFE with concomitant systemic manifestations ± high-risk facial involvement acutely after antibiotic exposure (mean latency 6.71 days). These cases deviate from classic, self-limited SDRIFE and represent a unique phenotype of SDRIFE, characterized by coexisting extracutaneous manifestations. Onset of systemic stigmata coincided with or preceded cutaneous involvement in 4 and 3 patients, respectively. All patients developed peripheral eosinophilia and 6 patients had ≥ 2 extracutaneous systems involved. Facial involvement, a high-risk feature associated with severe cutaneous adverse reactions but atypical in classic SDRIFE, occurred in 4 cases. Patients had favorable clinical outcomes following drug cessation and treatment with 4–6 week corticosteroid tapers. We suggest that baseline labs be considered in hospitalized patients with antibiotic-induced SDRIFE. These patients may also necessitate systemic therapy given extracutaneous involvement, deviating from standard SDRIFE treatment with drug cessation alone. [ABSTRACT FROM AUTHOR]

Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute, life‐threatening and rare severe cutaneous adverse reactions induced by drugs in most cases. The drugs most often reported to be implicated in inducing TEN/SJS are allopurinol, antibacterial sulfonamides, antiepileptic drugs and oxicam. Pristinamycin is an oral streptogramin antibiotic with bactericidal activity against Gram‐positive bacteria that is rarely linked to TEN. Typically, this condition develops 4‐28 days after drug exposure, Herein, we report a case of a 71‐year‐old female who developed TEN within 3 days of administration of pristinamycin and was managed successfully with supportive care, including intravenous fluids, pain control, prophylactic antibiotics and intravenous methylprednisolone. This case of rapidly developing SJS/TEN after administration of pristinamycin highlights the possibility that these complications can develop within only a few days following ingestion of drugs thought to be probably safe. [ABSTRACT FROM AUTHOR]

Introduction: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare yet life-threatening adverse events associated with immune checkpoint inhibitors (ICIs). This systematic review synthesizes the current literature to elucidate the clinical characteristics and outcomes of patients with ICI-related SJS/TEN. Methods: We conducted a thorough search across databases including Embase, Web of Science, Cochrane, MEDLINE, Scopus, and PubMed. Selection criteria focused on reports of SJS/TEN among cancer patients treated with ICIs, analyzing clinical manifestations, therapeutic interventions, and outcomes. Results: Our analysis included 47 articles involving 50 patients with ICI-related SJS/TEN. The cohort had a mean age of 63 years, with a slight male predominance (54%). Most patients had melanoma or non-small cell lung cancer. SJS/TEN typically occurred early, with a median onset of 23 days postICI initiation. Treatment primarily involved systemic corticosteroids and intravenous immunoglobulins. The overall mortality rate was 20%, higher for TEN at 32%, with infections and tumor progression as leading causes. Median time from onset to death was 28 days. Survivors experienced a median reepithelization time of 30 days, positively correlated with the extent of epidermal detachment (rs = 0.639, p = 0.009). Deceased patients exhibited a significantly higher proportion of TEN (90% vs. 48%, p = 0.029) and a larger epidermal detachment area (90% vs. 30% of the body surface area [BSA], p = 0.005) compared to survivors. The combination therapy group showed a higher proportion of TEN compared to corticosteroid monotherapy or noncorticosteroid therapy groups (72% vs. 29% and 50%, p = 0.01), with no significant differences in mortality or re-epithelization time. Dual ICI therapy resulted in a higher TEN rate than single therapy (100% vs. 50%, p = 0.028). Among single ICI therapies, the sintilimab-treated group trended towards a higher TEN rate (75% vs. 40-50%, p = 0.417), a larger detachment area (90% vs. 30-48% of BSA, p = 0.172), and a longer re-epithelization time (44 vs. 14-28 days, p = 0.036) compared to other ICI groups, while mortality rates remained similar. Conclusion: ICI-related SJS/TEN substantially impacts patient outcomes. Prospective clinical trials are critically needed to further clarify the pathogenesis and optimize therapeutic regimens. [ABSTRACT FROM AUTHOR]

Drug hypersensitivity reactions are common in children. Risk factors predisposing to IgE-mediated drug allergies and delayed drug reactions are a matter of debate. Gender, age, previous reactions to the same drug or to another drug, reduced drug metabolism, chronic diseases, polypharmacy, drug doses are linked with the onset of hypersensitivity reactions in some children. Novel advances in genetic polymorphisms can rapidly change the approach to the prevention of reactions since gene testing can be a useful screening test for severe cutaneous adverse reactions. Viral infections may act as cofactors in susceptible individuals. Polypharmacy, high doses, repeated doses and parental route of administration are also risk factors. Clinicians should take into account risk factors to allow the risk–benefit balance to be maintained. [ABSTRACT FROM AUTHOR]

Abstract Background Acute generalized exanthematous pustulosis (AGEP) is a rare and severe cutaneous drug eruption. Hydroxychloroquine (HCQ) is one of the known culprit drugs with less than 60 cases reported in the literature, and may have a more severe clinical presentation compared to AGEP induced by other drugs. There are no standardized management strategies for HCQ‐induced AGEP outside of drug discontinuation. Objectives Characterize the clinical presentation of HCQ‐induced AGEP and management strategies. Methods Retrospective chart review of nine patients clinically diagnosed with HCQ‐induced AGEP using the EuroSCAR score from 2017 to 2022 at four academic medical centres in the United States. Results All patients in our series were female and the median age was 52. Four patients initially presented with fever, and eight patients had neutrophilia. Median time to rash was 15 days. Biopsies obtained in six patients showed typical characteristics of AGEP. In most patients, rash morphology consisted of generalized pinpoint pustules atop atypical targetoid lesions and annular plaques. Five patients were hospitalized for AGEP. All patients were treated with methylprednisolone and/or prednisone, and the average days treated with systemic corticosteroids was 35. Conclusions Our case series is the largest to date describing HCQ‐induced AGEP. Clinicians should be wary that HCQ‐induced AGEP may present with a longer latency period after drug initiation and with atypical targetoid and annular lesions. Early initiation of systemic corticosteroids should be considered due to the severity of this drug reaction with addition of cyclosporine in refractory cases.

Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction, typically characterized by the appearance of multiple pinpoint non-follicular pustules, less than 5 mm, sterile, on an erythematous-edematous base, and can be disseminated. Up to 90% of cases are associated with drug administration. It usually resolves in less than 15 days with a good prognosis. We describe the case of a 31-year-old man who experienced drug-induced AGEP with multisystem involvement. However, at the onset, he presented with purpuric lesions on the skin and oral mucosal involvement, leading to the consideration of other differential diagnoses. The clinical evolution, including pustule formation and histopathological findings, led to the diagnosis of AGEP. He received standard supportive care, including topical and systemic corticosteroids, with a favorable clinical outcome. This case highlights an atypical presentation of AGEP and the possibility of overlap with other drug adverse reactions, emphasizing the need for timely and accurate diagnosis and management. [ABSTRACT FROM AUTHOR]

Toxic epidermal necrolysis (TEN) is a life-threatening mucocutaneous disorder commonly caused by drugs. TEN is often treated with corticosteroids, intravenous immunoglobulin (IVIG), or cyclosporine; however, the efficacy of these treatments is controversial. Etanercept (a TNF-a antagonist) was proven to decrease skin-healing time in a randomized clinical trial. Herein, we report the case of a 44-month-old boy who developed TEN due to deflazacort as the probable culprit drug and was successfully treated with etanercept. The patient presented to the emergency department complaining of erythematous maculopapular rashes and vesicles all over the face and body, with vesicles on the hands, feet, and trunk. Symptoms started 4 days before presentation, with edema of the upper lip, which progressed to erythematous macules over the body. He was started on deflazacort for nephrotic syndrome 21 days before the visit. Approximately 20% of the body surface area (BSA) was covered by vesicular lesions. Under the diagnosis of Steven Johnson syndrome/TEN, deflazacort was discontinued, and intravenous dexamethasone (1.5 mg/kg/day), a 5-day course of IVIG (0.4 mg/kg/day), and cyclosporine (3 mg/kg/day) were administered. The lesions seemed to be stationary for 3 days, but on the 6th day of hospitalization, when IVIG was discontinued, the vesicular lesions progressed to approximately 60% of the BSA. Etanercept 0.8 mg/kg was administered subcutaneously. Lesions stopped progressing, and bullous lesions started epithelialization. However, on the 15th day, around 30% of the BSA was still involved; thus, a second dose of etanercept was administered. No acute or sub-acute complications were observed. In conclusion, the use of etanercept in children with TEN that is not controlled with conventional therapy is both effective and safe. [ABSTRACT FROM AUTHOR]

Purpose Levetiracetam is an antiepileptic drug known for its high tolerability, and severe adverse drug reactions are rare. We report the case of a severe cutaneous adverse drug reaction in a patient who was switched from brand-name to generic levetiracetam. Summary A 29-year-old woman undergoing contrast-enhanced computed tomography developed lesions over her trunk starting 6 hours after imaging. Although initially diagnosed as an allergy to the radiocontrast agent, the condition progressively worsened into toxic epidermal necrolysis-drug reaction with eosinophilia and systemic symptoms overlap syndrome, despite adequate hydration and treatment. Investigation of the patient's medications revealed that she had been switched from brand-name to generic levetiracetam a week before the onset of symptoms. Levetiracetam was immediately discontinued, with the patient recovering after 2 weeks of intensive care. Adverse drug reaction analysis identified excipients in generic levetiracetam as the likely cause of the severe reaction. Conclusion This is the first reported case of severe cutaneous drug allergy after a brand-to-generic switch for levetiracetam. Brand-to-generic switches of medications can potentially cause severe allergic reactions due to differences in excipients. [ABSTRACT FROM AUTHOR]

Idiosyncratic drug-induced liver injury (DILI) associated with drug reactions with eosinophilia and systemic symptoms (DRESS) is poorly characterized among patients of Western countries. We aimed to comprehensively assess the clinical characteristics, outcomes, and causative agents in a prospective, well-vetted cohort of DILI patients with DRESS (DILI-DRESS). We identified 53 DILI-DRESS cases from the Spanish DILI Registry and the Latin American DILI Network. For comparison purposes, we defined a group of DILI patients (n = 881). DILI-DRESS cases were younger (47 vs. 53 years, respectively; p = 0.042) and presented more frequently with cholestatic/mixed damage (p = 0.018). Most DILI-DRESS patients showed moderate liver injury, 13% developed severe damage, and only one patient (with hepatocellular injury due to anti-tuberculosis drugs) progressed to acute liver failure and died. DILI-DRESS cases showed a distinctive causative drug pattern compared to DILI cases. The most frequent drugs were carbamazepine (13%), anti-tuberculosis drugs (13%), amoxicillin-clavulanate (11%), and allopurinol and lamotrigine (7.6% each). Among all cases of DILI due to allopurinol and lamotrigine, 67% presented with a DILI-DRESS phenotype, respectively. Higher total bilirubin (TBL) levels at DILI recognition (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.04–1.45) and absence of eosinophilia (OR 8.77; 95% CI 1.11–69.20) increased the risk for developing a severe-fatal injury in DILI-DRESS patients. DILI-DRESS patients have a more frequent cholestasis/mixed pattern of injury at presentation, with antiepileptics as distinctive causative drug class. Most of the lamotrigine and allopurinol cases present with this phenotype. Higher TBL levels and absence of eosinophilia at DILI recognition are markers of poor outcomes. [ABSTRACT FROM AUTHOR]

Background: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) are potentially life-threatening severe cutaneous adverse reactions (SCARs). Although the classical causal agents of SCARs (antibiotics, anticonvulsants, nonsteroidal anti-inflammatory drugs, and allopurinol) are well characterized, there has been little update to this list to account for newly marketed medications. Objective: To provide an updated and stratified list of medications with significant reporting odds ratios (RORs) of SCARs. Methods: A case/non-case analysis using the United States FDA Adverse Event Reporting System was performed. Results: As expected, the prototypical medication classes made up the majority of reported cases of SJS, TEN, AGEP, and DRESS (77%, 64%, 75%, and 72%, respectively). In addition, several infrequently or previously undescribed classes/medications implicated in SCARs were identified to have significant ROR signals, including acetylcysteine, anticoagulants, diuretics, immunotherapies, proton pump inhibitors, antivirals, and antifungals. Among these reported for SJS were acetylcysteine (ROR: 64.38) and fluconazole (ROR: 17.13). For TEN, we identified furosemide (ROR: 26.32), spironolactone (ROR: 14.45), fluconazole (ROR: 30.21), amphotericin B (39.06), and acetylcysteine (ROR: 93.12). For AGEP, we identified acyclovir (ROR: 61.72), valacyclovir (ROR: 30.76), and enoxaparin (ROR: 27.37). For DRESS, we identified vemurafenib (ROR: 17.35), acyclovir (ROR: 30.63), abacavir (ROR: 26.62), raltegravir (ROR: 23.27), and valacyclovir (ROR: 21.77) to have strong reporting odds. Conclusion: Our analysis provides an updated tool for physicians to reference when identifying suspected SCARs and a basis for future studies to investigate atypical medication causality. [ABSTRACT FROM AUTHOR]

A severe medical condition known as Stevens-Johnson syndrome (SJS) is marked by a cutaneous and mucosal reaction from the use of specific medications. The prodromal illness is followed by severe mucocutaneous symptoms in this immune-mediated disease. We describe the clinical history of a 55-year-old Caucasian woman who was exposed to cephalosporins. In resource-constrained countries and hospitals where cutaneous biopsy is not readily available, it is not easy to diagnose Steven Johnson Syndrome. This is particularly true in countries where the incidence of infectious diseases such as scarlet fever and measles is high and the early symptoms of SJS can be mistaken for these conditions. We used the Naronjo scale to confirm the probable association of the drug with the syndrome. Physicians while writing prescriptions for their patients need to warn them of potential side effects and they should keep in mind conditions like Stevens-Johnson syndrome. This case report highlights the need for improved knowledge and understanding of SJS among healthcare practitioners in resource-limited communities where the prevalence of infectious diseases is high. [ABSTRACT FROM AUTHOR]

Meifang Wang,&ast; Li Lin,&ast; Leyi Wang, Linfeng Li Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Linfeng Li, Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China, Tel +86-13693620186, Email zoonli@sina.comAbstract: Severe cutaneous adverse reactions (SCARs) to drugs are associated with morbidity, mortality, healthcare costs, and challenges in drug development. It is important to identify the SCAR type early by using strict diagnostic criteria because they may require different treatments, follow-ups, and short- or long-term prognoses. A 68-year-old woman admitted to our hospital presented with fever and rashes for 10 days. This case exhibited many features that suggested acute generalized exanthematous pustulosis (AGEP). However, the course of treatment and verified clinical features led to a diagnosis of AGEP and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome that was induced by carbamazepine and levofloxacin after a herpes zoster infection. AGEP combined with DRESS syndrome is a complicated and rare drug-induced dermatological eruption that follows a course similar to DRESS syndrome and more recalcitrant than the course seen with typical AGEP. The associated factors for the SCARs in our patient included age, history of allergy, viral infection, and drugs interacting with specific HLA loci. Improving our understanding of these factors can improve the treatment and prevention of SCARs in these patients.Keywords: severe cutaneous adverse reaction, SCARs, acute generalized exanthematous pustulosis, AGEP, drug reaction with eosinophilia and systematic syndrome, DRESS syndrome, overlapping feature, carbamazepine, varicella zoster virus infection

Generalized bullous fixed drug eruption (GBFDE) is a rare type of life‐threatening severe cutaneous adverse reaction that is considered a medical emergency because of its potential lethality. Currently, only a few cases of bullous adverse reactions have been reported after coronavirus disease 2019 (COVID‐19) vaccination. We describe a patient with distinct clinical, histopathological, and immunological findings that are consistent with severe GBFDE, after Pfizer messenger RNA COVID‐19 vaccination. An 83‐year‐old man presented with a fever and well‐demarcated multiple erythematous patches that occurred only 4 h after receiving the first dose of COVID‐19 Pfizer vaccination. Over the next few days, the patches became generalized and turned into blisters covering approximately 30% of the body surface. The patient was started on intravenous methylprednisolone and oral cyclosporine. There were no additional blistering lesions after 10 days of treatment, prompting a gradual dose reduction. Our case suggests that a stepwise vaccination adhering to the standard dosing schedule should be warranted with close monitoring for possible significant side effects. [ABSTRACT FROM AUTHOR]

Introduction: Human herpesvirus-6 (HHV-6) is a ubiquitous lymphotropic betaherpesvirus that can reactivate in drug rash with eosinophilia and systemic symptoms (DRESS). Despite recent publications advancing our understanding of HHV-6 in DRESS, the exact role of HHV-6 in disease pathogenesis remains unclear. Methods: A scoping review with the PubMed query "(HHV 6 AND (drug OR DRESS OR DIHS)) OR (HHV6 AND (drug OR DRESS OR DIHS))" was conducted in accordance with PRISMA guidelines. Articles containing original data on at least one DRESS patient with HHV-6 testing were included. Results: Our search returned a total of 373 publications, of which 89 met eligibility criteria. HHV-6 reactivation occurred in 63% of DRESS patients (n = 748), which was significantly more often than other herpesviruses. HHV-6 reactivation was associated with worse outcomes and greater severity in controlled studies. Case reports have demonstrated sometimes fatal HHV-6-related multi-organ involvement. Temporally, HHV-6 reactivation typically occurs 2 to 4 weeks after DRESS onset and has been linked to markers of immunologic signaling, such as OX40 (CD134), an HHV-6 entry receptor. Efficacy of antiviral or immunoglobulin treatment has only been demonstrated anecdotally, and steroid use may affect HHV-6 reactivation. Conclusion: HHV-6 is implicated in DRESS more than in any other dermatologic condition. It is still unclear whether HHV-6 reactivation is cause or consequence of DRESS dysregulation. Similar pathogenic mechanisms precipitated by HHV-6 in other contexts may be relevant in DRESS. Future randomized controlled studies to assess effects of viral suppression on clinical outcomes is needed. [ABSTRACT FROM AUTHOR]

The Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome can be potentially life-threatening. The diagnosis is sometimes difficult since the clinical manifestations may be incomplete or non-specific. Insulinoma is a rare functioning neuroendocrine tumor (NET) of the pancreas. Medical therapy may be needed when surgery is contraindicated, delayed or refused. Diazoxide is widely used to control hypoglycemia in patients with insulinoma. We report a clinical case of an insulinoma in a 85-year-old patient treated with diazoxide with a fatal outcome due to a delayed diagnosis of a DRESS syndrome. This is the first case of DRESS syndrome reported after using diazoxide for insulinoma treatment in our knowledge.

The document titled "Severe Cutaneous Adverse Reactions Associated with Immune Checkpoint Inhibitors: A Systematic Review of Clinical Characteristics and Management" published in the Journal of Cutaneous Medicine & Surgery explores rare and potentially fatal skin reactions linked to immune checkpoint inhibitors (ICI) used in cancer treatment. The review includes data from 164 patients who developed severe cutaneous adverse reactions (SCARs) during ICI therapy, with common reactions being Stevens-Johnson syndrome and toxic epidermal necrolysis. Treatment success was achieved in 63.7% of cases with a combination of biologic, corticosteroid, and immunosuppressive therapies, and further research is needed to optimize monitoring and treatment strategies. [Extracted from the article]

IntroductionDrug Reaction with Eosinophilia Systemic Symptoms (DRESS) is more common in persons living with HIV (PLHIV), and first-line anti-TB drugs (FLTDs) and cotrimoxazole are the commonest offending drugs. Limited data is available on the skin infiltrating T-cell profile among DRESS patients with systemic CD4 T-cell depletion associated with HIV.Materials and methodsHIV cases with validated DRESS phenotypes (possible, probable, or definite) and confirmed reactions to either one or multiple FLTDs and/or cotrimoxazole were chosen (n = 14). These cases were matched against controls of HIV-negative patients who developed DRESS (n = 5). Immunohistochemistry assays were carried out with the following antibodies: CD3, CD4, CD8, CD45RO and FoxP3. Positive cells were normalized to the number of CD3+ cells present.ResultsSkin infiltrating T-cells were mainly found in the dermis. Dermal and epidermal CD4+ T-cells (and CD4+/CD8+ ratios) were lower in HIV-positive vs. negative DRESS; p

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), a severe cutaneous adverse reaction (SCAR), represents a diagnostic and therapeutic challenge due to its varied, evolving clinical presentation, complex pathophysiology, and potential for severe systemic involvement. This article explores DRESS syndrome through three illustrative cases from diverse populations and with different background co-morbidities. Cases highlight different challenges in DRESS care, including: i) the need for early diagnosis and severity scoring, ii) identification of offending drugs and risk stratification to consider a possible drug challenge, and iii) best practice management including long-term monitoring for emergent autoimmunity. Recent developments in our understanding of clinical spectrum of disease, genomic and non-genomic biomarkers, severity groupings, and pharmacological and longer-term management strategies are described. Critical gaps remain in several of these domains, particularly in vulnerable groups such as the immune-compromised. In this absence of robust evidence, we aim for this article to assist attending clinicians with current expert opinion in DRESS management. Finally, we highlight areas for further research needed to improve the clinical care and outcomes of DRESS., (Copyright © 2025. Published by Elsevier Inc.)

Background: In end-stage renal disease (ESRD), reduced renal function affects medication response and clearance, increasing risk of adverse drug reactions. Renal disease is a risk factor for poor prognosis in severe cutaneous adverse reactions (SCARs). The effects of SCARs in ESRD patients are less understood., Methods: This retrospective analysis of the United States Renal Data System (USRDS) evaluated whether SCARs are an independent risk factor for mortality in ESRD patients, controlling for demographic and clinical factors, including malnutrition, sepsis, pneumonia, secondary autoimmune conditions and Charlson Comorbidity Index (CCI). We examined whether Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) or drug reaction with eosinophilia and systemic symptoms (DRESS) was associated with all-cause mortality in subjects enrolled in the USRDS from 2005-2018., Results: Patients with DRESS were more often female (OR=1.37), with catheter (OR=1.08) or graft (OR=1.15) access and a higher CCI (OR=1.21). Those with SJS/TEN were more likely to be black (OR=2.43) or other race (OR=2.06) and female (OR=1.55), with catheter access (OR=1.36) and a higher CCI (OR=1.18). DRESS and SJS/TEN were associated with higher risk of malnutrition (OR=1.64, OR=2.61), sepsis (OR=1.93, OR=3.38), pneumonia (OR=1.82, OR=1.80), and secondary autoimmune conditions (OR=1.47, OR=1.47). Patients with DRESS (HR=2.05) or SJS/TEN (HR=3.12) had increased mortality across 12 months following diagnosis. Increasing age (HR=1.04), hemodialysis (HR=1.76), catheter (HR=2.58) or graft (HR=1.52) access, malnutrition (HR=1.07), and sepsis (HR=1.26) increased mortality risk., Conclusion: ESRD patients' risk for SCARs varied by age, race, sex, comorbidities, and dialysis modality. Patients with a SCAR had increased mortality across 12 months following diagnosis., Competing Interests: Declaration of competing interest The authors state that they have no conflicts of interest. Further, there is no financial/personal interest or belief that could affect their objec?vity with regards to the research presented, (Copyright © 2025. Published by Elsevier Inc.)

Toxic epidermal necrolysis and Stevens‐Johnson Syndrome describe a spectrum of severe cutaneous skin reactions constituting a medical emergency, and no formal treatment guidelines exist to direct systemic immunosuppressive therapy although referral to a burns unit and wound management remains a mainstay of treatment. We performed a retrospective chart review on all patients at a single centre with TEN between 2017 to 2021 to compare clinical characteristics and outcomes of those treated with the tumour necrosis factor‐alpha (TNF‐α) inhibitor adalimumab against non‐TNF‐α immunosuppressants such as glucocorticoids, intravenous immunoglobulin and cyclosporine. All patients treated with adalimumab had successful resolution of their TEN, resulting in a mean duration of hospital admission of 22.5 days compared to 33 days for patients treated with non‐TNF‐α inhibitors. We highlight adalimumab as a promising systemic immunomodulator in the treatment of TEN with efficacy comparable to other immunosuppressive agents and associated with a shorter duration of hospital admission. [ABSTRACT FROM AUTHOR]

Aims: Allopurinol is known to cause severe cutaneous adverse drug reactions (SCAR) in Malaysia. However, the incidence of allopurinol‐induced SCAR is unknown. Therefore, we aimed to determine the incidence of allopurinol‐induced SCAR in Malaysia over 5 years from 2015 to 2019. Methods: This retrospective analysis was done in collaboration with the National Pharmaceutical Regulatory Agency (NPRA). All allopurinol‐induced adverse drug reaction cases reported to NPRA from 2015 to 2019 were extracted. Allopurinol‐induced SCAR cases were identified and the incidence over the 5 years was calculated. Results: Incidence of allopurinol‐induced SCAR averaged at 2.5 cases per 1000 new users over the 5‐year period, with a reducing trend from 3.2 per 1000 new users in 2015 to 2.25 per 1000 in 2019; despite the increasing number of adverse drug reaction cases being reported over the years. Stevens–Johnson syndrome was the commonest form of allopurinol‐induced SCAR reported, at 143 cases (46.8% of total SCAR reported). Among Malaysia's 3 main ethnicities, the Chinese had the highest percentages of allopurinol‐induced SCAR when compared to the Bumiputera and Indians (3.18 × 10−4%). Conclusion: The estimated incidence of allopurinol‐induced SCAR in Malaysia from 2015 to 2019 was 2.5 cases per 1000 new users. This figure is consistent with the incidence reported in other Asian countries, namely Taiwan and Thailand. [ABSTRACT FROM AUTHOR]

Sulfonamides, particularly antimicrobial sulfonamides, have been implicated as a common cause of a spectrum of hypersensitivity reactions. Immediate IgE-mediated reactions have been reported but are much less common than delayed cutaneous reactions. Delayed cutaneous reactions range from benign exanthems to severe cutaneous reactions such as Stevens Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms. Sulfonamides can be subclassified as antimicrobial sulfonamides and non-antimicrobial sulfonamides, which are also distinguished by key structural differences, resulting in very low risk of cross-reactivity between these two subclasses. Immediate and delayed skin testing and in vitro testing remain limited as options in evaluating antimicrobial sulfonamide hypersensitivity. Drug challenges continue to play an important role in the evaluation of both immediate and delayed reactions, with a growing body of evidence for the safety of direct challenges regardless of human immunodeficiency virus infection status. While numerous "desensitization" protocols have been described for the management of antimicrobial sulfonamide hypersensitivity, there is limited evidence that such procedures are successful because of an induction of tolerance. [ABSTRACT FROM AUTHOR]

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe, idiosyncratic reaction to a drug which presents after a prolonged latency period. Although it most commonly occurs with aromatic anticonvulsants, antibiotics are also occasionally implicated. A 50-year-old male was admitted for left pyopneumothorax. He was started on intravenous piperacillin-tazobactam (Pip/Taz) and clindamycin. After 10 days of treatment, he developed high grade fever with maculopapular rashes with areas of scaling. He had elevated WBC counts with eosinophils of 21% and raised serum transaminases. After excluding other possible etiologies for febrile illness, a possibility of DRESS was considered. Naranjo scale, used for causality assessment, yielded a total score of 6, pointing toward probable adverse drug reaction. Also, the patient had 6 out of the 7 inclusion criteria for DRESS as per European Registry of Severe Cutaneous Adverse Reaction (RegiScar) scoring. Pip/Taz was found to be causative drug and was discontinued. He was conservatively managed with antipyretics and topical steroids. Fever subsided the day after stopping Pip/Taz and his rashes resolved gradually. In conclusion the possibility of antibiotics-induced DRESS should be considered and high index of vigilance is advised. [ABSTRACT FROM AUTHOR]

Cefixime is a third-generation cephalosporin that has been used for the treatment of a wide range of infections in children and adults. The incidence of cefixime induced toxic epidermal necrolysis (TEN) is less than 2% in adults, but it is infrequent among pediatric patients. We report a rare case of cefixime induced TEN in a 7-year-old boy. In this case, the child presented with symptoms of TEN after 2 days of administration of cefixime. This case highlights the need to select structurally different antibiotics in case of antibiotic-induced severe cutaneous adverse reaction (SCAR) to avoid recurrence of SCAR. Furthermore, concluded that irrational use of antibiotics could be disastrous as it can result in TEN as the incidence of antibiotics induced TEN ranges from 29% to 42%. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction:Ex vivo and in vitro diagnostics, such as interferon-γ (IFN-γ) release enzyme linked ImmunoSpot (ELISpot) and flow cytometry, are increasingly employed in the research and diagnostic setting for severe T-cell mediated hypersensitivity. Despite an increasing use of IFN-γ release ELISpot for drug causality assessment and utilization of a range of antimicrobial concentrations ex vivo, data regarding antimicrobial-associated cellular cytotoxicity and implications for assay performance remain scarcely described in the literature. Using the measurement of lactate dehydrogenase (LDH) and the 7-AAD cell viability staining, we aimed via an exploratory study, to determine the maximal antimicrobial concentrations required to preserve cell viability for commonly implicated antimicrobials in severe T-cell mediated hypersensitivity.Method: After an 18-h incubation of patient peripheral blood monocytes (PBMCs) and antimicrobials at varying drug concentrations, the cell cytotoxicity was measured in two ways. A colorimetric based assay that detects LDH activity and by flow cytometry using the 7-AAD cell viability staining. We used the PBMCs collected from three healthy control participants with no known history of adverse drug reaction and two patients with a rifampicin-associated drug reaction with eosinophilia and systemic symptoms (DRESS), confirmed on IFN-γ ELISpot assay. The PBMCs were stimulated for the investigated drugs at the previously published drug maximum concentration (Cmax), and concentrations 10- and 100-fold above.Results: In a human immunodeficiency virus (HIV) negative and a positive rifampicin-associated DRESS with positive ex vivo IFN-γ ELISpot assay, use of 10- and 100-fold Cmax drug concentrations decreased spot forming units/million cells by 32–100%, and this corresponded to cell cytotoxicity of more than 40 and 20% using an LDH assay and 7-AAD cell viability staining, respectively. The other antimicrobials (ceftriaxone, flucloxacillin, piperacillin/tazobactam, and isoniazid) tested in healthy controls showed similar dose-dependent increased cytotoxicity using the LDH assay, but cytotoxicity remained lower than 40% for all Cmax and 10-fold Cmax drug concentrations except flucloxacillin. All 100-fold Cmax concentrations resulted in cell death >40% (median 57%), except for isoniazid. 7-AAD cell viability staining also confirmed an increase in lymphocyte death in PBMCs incubated with 10-fold and 100-fold above Cmax for ceftriaxone, and flucloxacillin; however, piperacillin/tazobactam and isoniazid indicated no differences in percentages of viable lymphocytes across concentrations tested.Conclusion: The LDH cytotoxicity and 7-AAD cell viability staining techniques both demonstrate increased cell death corresponding to a loss in ELISpot sensitivity, with use of higher antimicrobial drug concentrations for ex vivo diagnostic IFN-γ ELISpot assays. For all the antimicrobials evaluated, the use of Cmax and 10-fold Cmax concentrations impacts cell viability and potentially affects ELISpot performance. These findings inform future approaches for ex vivo diagnostics such as IFN-γ release ELISpot.

Introduction: Ex vivo and in vitro diagnostics, such as interferon-γ (IFN-γ) release enzyme linked ImmunoSpot (ELISpot) and flow cytometry, are increasingly employed in the research and diagnostic setting for severe T-cell mediated hypersensitivity. Despite an increasing use of IFN-γ release ELISpot for drug causality assessment and utilization of a range of antimicrobial concentrations ex vivo , data regarding antimicrobial-associated cellular cytotoxicity and implications for assay performance remain scarcely described in the literature. Using the measurement of lactate dehydrogenase (LDH) and the 7-AAD cell viability staining, we aimed via an exploratory study, to determine the maximal antimicrobial concentrations required to preserve cell viability for commonly implicated antimicrobials in severe T-cell mediated hypersensitivity. Method: After an 18-h incubation of patient peripheral blood monocytes (PBMCs) and antimicrobials at varying drug concentrations, the cell cytotoxicity was measured in two ways. A colorimetric based assay that detects LDH activity and by flow cytometry using the 7-AAD cell viability staining. We used the PBMCs collected from three healthy control participants with no known history of adverse drug reaction and two patients with a rifampicin-associated drug reaction with eosinophilia and systemic symptoms (DRESS), confirmed on IFN-γ ELISpot assay. The PBMCs were stimulated for the investigated drugs at the previously published drug maximum concentration (Cmax), and concentrations 10- and 100-fold above. Results: In a human immunodeficiency virus (HIV) negative and a positive rifampicin-associated DRESS with positive ex vivo IFN-γ ELISpot assay, use of 10- and 100-fold Cmax drug concentrations decreased spot forming units/million cells by 32–100%, and this corresponded to cell cytotoxicity of more than 40 and 20% using an LDH assay and 7-AAD cell viability staining, respectively. The other antimicrobials (ceftriaxone, flucloxacillin, piperacillin/tazobactam, and isoniazid) tested in healthy controls showed similar dose-dependent increased cytotoxicity using the LDH assay, but cytotoxicity remained lower than 40% for all Cmax and 10-fold Cmax drug concentrations except flucloxacillin. All 100-fold Cmax concentrations resulted in cell death >40% (median 57%), except for isoniazid. 7-AAD cell viability staining also confirmed an increase in lymphocyte death in PBMCs incubated with 10-fold and 100-fold above Cmax for ceftriaxone, and flucloxacillin; however, piperacillin/tazobactam and isoniazid indicated no differences in percentages of viable lymphocytes across concentrations tested. Conclusion: The LDH cytotoxicity and 7-AAD cell viability staining techniques both demonstrate increased cell death corresponding to a loss in ELISpot sensitivity, with use of higher antimicrobial drug concentrations for ex vivo diagnostic IFN-γ ELISpot assays. For all the antimicrobials evaluated, the use of Cmax and 10-fold Cmax concentrations impacts cell viability and potentially affects ELISpot performance. These findings inform future approaches for ex vivo diagnostics such as IFN-γ release ELISpot. [ABSTRACT FROM AUTHOR]

Toxic epidermal necrolysis is an uncommon but potentially life-threatening adverse cutaneous drug reaction characterized by variable degrees of epidermal necrosis and detachment leading to morbidity and risk of mortality. We describe a 67-year-old woman who underwent allogeneic peripheral blood stem cell transplantation as treatment for chronic lymphocytic leukemia. She developed toxic epidermal necrolysis after she was transitioned to voriconazole, which was a component of her post-transplant regimen. The diagnosis of toxic epidermal necrolysis in our patient was made clinically and confirmed histologically. Based on the temporal initiation of voriconazole therapy and the development of her adverse cutaneous reaction, we concluded that voriconazole was the offending agent. There are limited reported cases of voriconazole-induced toxic epidermal necrolysis; we report this case to increase awareness of this potential life-threatening complication.

Toxic epidermal necrolysis (TEN) is a rare, acute inflammatory skin reaction that results in skin blistering and extensive epidermal detachment. Stevens-Johnson syndrome (SJS) and TEN are unified aspects on a spectrum varying in the severity of vesiculobullous cutaneous eruptions with mucosal involvement of the oral cavity, genitourinary tract, gastrointestinal tract, and conjunctiva. The inciting event is usually caused by an exaggerated hypersensitivity reaction in response to triggering medications, including nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, urate-lowering drugs (such as allopurinol), anticonvulsants, and antipsychotics. We report a case of clindamycin-induced TEN in a 79-year-old African-American female following the recent administration of clindamycin for a developing sacral decubitus ulcer. However, lincosamide antibiotics like clindamycin are rarely associated with precipitating SJS or TEN. This report highlights the treatment and prognostic challenges faced throughout the patient's clinical course and seeks to highlight the importance of recognizing the development of SJS/TEN following novel drug administration and promptly addressing the management of the condition to improve long-term patient outcomes., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. HCA Healthcare Institutional Review Board issued approval 2024-189. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: This research was supported (in whole or in part) by the HCA Healthcare and/or an HCA Healthcare-affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities., (Copyright © 2024, Scally et al.)

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.

Background: Acute generalized exanthematous pustulosis (AGEP) is a rare, severe, cutaneous adverse reaction. Although most commonly caused by drugs, it can also be triggered by infections, especially in children. Methods: This is a retrospective study involving children and adolescents aged 16 years or younger, diagnosed with AGEP between January 2010 and March 2020 in our tertiary pediatric hospital. Information pertaining to the patient's demographics, clinical presentation and progress, biochemical, microbiological, and histopathological investigations, treatment, and outcomes was analyzed. Results: Eight patients were diagnosed with AGEP with mean age 8.2 years (range: 1.7‐16.0 years). None of the patients had a personal or family history of psoriasis. Almost all patients had fever (n = 7, 87.5%). Although all 8 patients had intercurrent illness, 5 cases were attributed to infection, while the other 3 were likely precipitated by drugs. Abnormal hematological and biochemical parameters included a raised absolute neutrophil count (mean: 11.5 × 109/L, range: 5.0‐30.9 × 109/L), C‐reactive protein (mean: 52.5 mg/L, range: 5.0‐143.7 mg/L), and erythrocyte sedimentation rate (mean: 38.6 mm/h, range: 6‐64 mm/h). All patients developed post‐pustular desquamation and subsequently recovered. The mean duration from onset to cessation of acute pustulation was 5.6 days (range: 3.0‐10.0 days). One patient developed a recurrent episode of AGEP. Conclusion: AGEP is rare and may be more commonly caused by infections in children. The condition is self‐limiting with overall good outcomes in this age‐group. In cases with concomitant infection and drug use, formal allergy testing should be arranged after resolution of the infection to confirm the underlying etiology. [ABSTRACT FROM AUTHOR]

Background: Severe cutaneous adverse reactions (SCARs) are associated with high morbidity and mortality in patients with cancer. Early identification and treatment of SCARs may improve outcomes.Objective: To identify biomarkers to predict outcomes in hospitalized patients with cancer who developed SCARs.Methods: Retrospective review of 144 hospitalized patients with cancer with a morbilliform rash, recorded testing for serum cytokines (interleukin [IL]-6, IL-10, and tumor necrosis factor [TNF]-α) or elafin, and a dermatology consultation. Rashes were categorized as simple morbilliform rash without systemic involvement or complex morbilliform rash with systemic involvement.Results: Fifty-four of 144 (37.5%) patients died during follow-up. Elevated levels of IL-6, IL-10, and TNF-α were associated with decreased survival. Overall survivals in patients with elevated levels of IL-6, IL-10, and TNF-α were 53.7%, 56.6%, 53.6%, respectively, compared with 85.7%, 82.5% and 83.6%, respectively, in those with lower levels. Patients with increased levels of both IL-6 and TNF-α had a nearly 6-fold increase in mortality (hazard ratio, 5.82) compared with patients with lower levels.Limitations: Retrospective design, limited sample size, and high-risk population.Conclusions: Hospitalized patients with cancer with rash and elevated IL-6 and TNF-α were nearly 6 times more likely to die over the course of follow-up. These biomarkers may serve as prognostic biomarkers and therapeutic targets for this high-risk population. [ABSTRACT FROM AUTHOR]