Drug Reaction With Eosinophilia and Systemic Symptoms: A Systematic Review.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a potentially life-threatening drug reaction; recognizing the diversity of its clinical presentations, implicated drugs, and management modalities can aid in diagnosis and reduce morbidity and mortality. OBJECTIVE: To review the clinical features, drug causes, and treatments deployed in DRESS. METHODS: This review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to review publications relating to DRESS published between 1979 and 2021. Only publications with a RegiSCAR score of 4 or greater were included (indicating "probable" or "definite" DRESS). The PRISMA guidelines were used for data extraction and the Newcastle-Ottawa scale for quality assessment (Pierson DJ. Respir Care 2009;54:1372-8). The main outcomes included implicated drugs, patient demographics, clinical manifestations, treatment, and sequelae for each included publication. RESULTS: A total of 1124 publications were reviewed, and 131 met the inclusion criteria, amounting to 151 cases of DRESS. The most implicated drug classes were antibiotics, anticonvulsants, and anti-inflammatories, although up to 55 drugs were implicated. Cutaneous manifestations were present in 99% of cases, with a median onset of 24 days and maculopapular rash the most common morphology. Common systemic features were fever, eosinophilia, lymphadenopathy, and liver involvement. Facial edema was present in 67 cases (44%). Systemic corticosteroids were the mainstay of DRESS-specific treatment. A total of 13 cases (9%) resulted in mortality. CONCLUSION: DRESS diagnosis should be considered in the presence of a cutaneous eruption, fever, eosinophilia, liver involvement, and lymphadenopathy. The class of implicated drug may influence outcome, as allopurinol was associated with 23% of cases that resulted in death (3 cases). Given potential DRESS complications and mortality, it is important that DRESS is recognized early so that any suspect drugs are ceased promptly.

Development and application of Adverse drug reactions reports QUality Algorithm (AQUA-12) score: a single-centre quality improvement initiative.

PURPOSE: To develop a reliable assessment tool to monitor the quality of adverse drug reaction (ADR) reports and evaluate its performance within a quaternary hospital setting. METHODS: Adverse drug reactions report QUality Algorithm (AQUA-12) was developed by a multidisciplinary team with the expertise in the management of ADRs. The design was based on data elements required to establish medication causality. Inter-rater reliability of AQUA-12 was evaluated over three rounds in two phases: development and prospective evaluation phases, by independent assessors both internal and external to the institutional ADR review processes. The characteristics and quality of ADR reports were subsequently assessed, and potential factors contributing to low-quality reports were identified. RESULTS: A total of 70 ADR reports were assessed, 20 in development and 50 in evaluation phases. The inter-rater reliability of AQUA-12 was found to be excellent in all three rounds (Cronbach's alpha of  ≥ 0.9, p < 0.001 for all). Approximately one in five reports concerned immediate hypersensitivity reactions while delayed hypersensitivity reactions constituted 60% of all reactions. AQUA-12 identified 18 (25.7%) reports as 'low-quality' with a score of  < 10. Identification of suspected medications (37.1%), description of index ADR (27.1%), and key events (ADR narrative, 35.7%) were the top data elements incomplete or missing from all reports. Univariable analyses identified the severity of the reaction as a factor associated with low quality of reports (p = 0.008). CONCLUSIONS: AQUA-12 is a practical and highly reliable assessment tool that can be utilised in hospital settings to regularly monitor the completeness of ADR reports to guide quality improvement initiatives.

The Current Treatment Landscape of Cutaneous Squamous Cell Carcinoma.

Non-melanoma skin cancers (NMSCs) are the most common form of skin cancer worldwide. The global incidence of cutaneous squamous cell carcinoma (CSCC) is rising, with an estimated 2.4 million cases diagnosed in 2019. Chronic exposure to ultraviolet (UV) radiation is a major risk factor for developing CSCC. Most early-stage CSCCs are treated successfully with surgery or radiotherapy; however, locally advanced or metastatic disease can be associated with significant morbidity or mortality. Recently, the treatment paradigm for advanced CSCC has been revolutionised by the introduction of immunotherapy, which can achieve a response rate of approximately 50% with durable cancer control, and significant improvement in quality of life. With the regulatory approval of programmed death-1 (PD-1)-targeting drugs since 2018, immunotherapy is now recognised as the standard of care for first-line systemic therapy in advanced or metastatic CSCC.

VEXAS syndrome: A dermatological perspective.

VEXAS (Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic mutation) syndrome is a genetically defined disorder identified in 2020, describing patients with inflammatory syndromes associated with haematological dysfunction. It is a severe, treatment-resistant condition, with estimated mortality between 40% and 63%. A wide range of cutaneous manifestations have been described. Here, we report on two patients with treatment-resistant neutrophilic dermatosis and myelodysplastic syndrome, who were subsequently diagnosed with VEXAS syndrome. Our cases highlight the need for dermatologists' awareness of this novel condition and to initiate early referral to haematologists for appropriate multidisciplinary care.

Study protocol: Australasian Registry of Severe Cutaneous Adverse Reactions (AUS-SCAR).

INTRODUCTION: Severe cutaneous adverse reactions (SCAR) are a group of T cell-mediated hypersensitivities associated with significant morbidity, mortality and hospital costs. Clinical phenotypes include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP). In this Australasian, multicentre, prospective registry, we plan to examine the clinical presentation, drug causality, genomic predictors, potential diagnostic approaches, treatments and long-term outcomes of SCAR in Australia and New Zealand. METHODS AND ANALYSIS: Adult and adolescent patients with SCAR including SJS, TEN, DRESS, AGEP and another T cell-mediated hypersensitivity, generalised bullous fixed drug eruption, will be prospectively recruited. A waiver of consent has been granted for some sites to retrospectively include cases which result in early mortality. DNA will be collected for all prospective cases. Blood, blister fluid and skin biopsy sampling is optional and subject to patient consent and site capacity. To develop culprit drug identification and prevention, genomic testing will be performed to confirm human leukocyte antigen (HLA) type and ex vivo testing will be performed via interferon-γ release enzyme linked immunospot assay using collected peripheral blood mononuclear cells. The long-term outcomes of SCAR will be investigated with a 12-month quality of life survey and examination of prescribing and mortality data. ETHICS AND DISSEMINATION: This study was reviewed and approved by the Austin Health Human Research Ethics Committee (HREC/50791/Austin-19). Results will be published in peer-reviewed journals and presented at relevant conferences. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12619000241134).

A long-term cohort study of acitretin for prevention of keratinocyte carcinoma in solid organ transplant recipients.

BACKGROUND: Solid organ transplant recipients (SOTR) are at high risk of keratinocyte carcinoma (KC). Long-term evidence for acitretin as chemoprophylaxis in this population is lacking. OBJECTIVE: To determine the benefit of long-term acitretin for KC chemoprevention in SOTR. METHODS: A retrospective cohort study of SOTR treated with acitretin at an Australian transplant dermatology clinic was performed. General estimating equations were used to evaluate change in rates of histologically confirmed KC in the 6-12 months prior to acitretin and following a minimum 6 months of treatment. A control group of patients within the same service was included, comprising SOTR who were not treated with acitretin. RESULTS: Twenty-two patients received acitretin treatment for at least 6 months, eighteen for at least 5 years and four for at least 9 years. The median KC rate pretreatment was 3.31 per year (IQR 1.93, 5.40). There was a significant reduction in the rate of KC in the first year of acitretin treatment (IRR 0.41, 95% CI 0.22, 0.76, P = 0.005), and this effect was observed for 5 years (IRR at 5 years 0.34, 95% CI 0.17, 0.67, P = 0.002). The control group had no statistically significant change in KC rate over time in the study. CONCLUSIONS: Acitretin appears to be well-tolerated and effective in reducing KC in SOTR for at least 5 years. Study limitations include its retrospective nature, small sample size and lack of blinding.

Blister fluid as a cellular input for ex vivo diagnostics in drug-induced severe cutaneous adverse reactions improves sensitivity and explores immunopathogenesis.

Background: Drug-induced severe cutaneous adverse reactions (SCARs) are presumed T-cell-mediated hypersensitivities associated with significant morbidity and mortality. Traditional in vivo testing methods, such as patch or intradermal testing, are limited by a lack of standardization and poor sensitivity. Modern approaches to testing include measurement of IFN-γ release from patient PBMCs stimulated with the suspected causative drug. Objective: We sought to improve ex vivo diagnostics for drug-induced SCARs by comparing enzyme-linked immunospot (ELISpot) sensitivities and flow cytometry-based intracellular cytokine staining and determination of the cellular composition of separate samples (PBMCs or blister fluid cells [BFCs]) from the same donor. Methods: ELISpot and flow cytometry analyses of IFN-γ release were performed on donor-matched PBMC and BFC samples from 4 patients with SCARs with distinct drug hypersensitivity. Results: Immune responses to suspected drugs were detected in both the PBMC and BFC samples of 2 donors (donor patient 1 in response to ceftriaxone and case patient 4 in response to oxypurinol), with BFCs eliciting stronger responses. For the other 2 donors, only BFC samples showed a response to meloxicam (case patient 2) or sulfamethoxazole and its 4-nitro metabolite (case patient 3). Consistently, flow cytometry revealed a greater proportion of IFN-γ-secreting cells in the BFCs than in the PBMCs. The BFCs from case patient 3 were also enriched for memory, activation, and/or tissue recruitment markers over the PBMCs. Conclusion: Analysis of BFC samples for drug hypersensitivity diagnostics offers a higher sensitivity for detecting positive responses than does analysis of PBMC samples. This is consistent with recruitment (and enrichment) of cytokine-secreting cells with a memory/activated phenotype into blisters.

Delayed Response After Confirmed Progression (DR) and Other Unique Immunotherapy-Related Treatment Concepts in Cutaneous Squamous Cell Carcinoma.

Non-melanoma skin cancers are one of the most common cancers diagnosed worldwide, with the highest incidence in Australia and New Zealand. Systemic treatment of locally advanced and metastatic cutaneous squamous cell carcinomas has been revolutionized by immune checkpoint inhibition with PD-1 blockade. We highlight treatment issues distinct to the management of the disease including expansion of the traditional concept of pseudoprogression and describe delayed responses after immune-specific response criteria confirmed progressive disease with and without clinical deterioration. We term this phenomenon "delayed response after confirmed progression (DR)". We also discuss the common development of second primary tumors, heterogeneous disease responses, and expanding clinical boundaries for immunotherapy use.

The Role of In Vivo and Ex Vivo Diagnostic Tools in Severe Delayed Immune-Mediated Adverse Antibiotic Drug Reactions.

BACKGROUND: The use of in vivo and ex vivo diagnostic tools for delayed immune-mediated adverse drug reactions is currently ill defined. OBJECTIVE: To determine whether the combination of skin testing and/or IFN-γ enzyme-linked immunoSpot assay (ELISpot) can aid diagnosis of these allergy phenotypes. METHODS: Patients with antibiotic-associated severe delayed immune-mediated adverse drug reaction hypersensitivity, including Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis, generalized bullous fixed drug eruption, and severe maculopapular exanthema, were prospectively recruited. In vivo testing was completed to the implicated drug(s), and ex vivo testing was performed with the patient's PBMCs stimulated with the relevant antibiotic concentrations for IFN-γ release ELISpot measurement. RESULTS: Eighty-one patients met the inclusion criteria, with DRESS (42; 51.9%) accounting for most cases. Among the 63 (78%) who had an ELISpot assay performed, 34 (54%) were positive to at least 1 implicated antibiotic (median spot-forming units/million cells, 99.5; interquartile range, 68-187), with glycopeptide being a strong predictor of positivity (adjusted odds ratio, 6.11; 95% CI, 1.74-21.42). In combination (in vivo and ex vivo), 51 (63%) of those tested were positive to an implicated antibiotic. For DRESS and severe maculopapular exanthema associated with penicillins and cephalosporins, this combination confirmed the culprit agent in 11 of the 12 cases and in 6 of 7 for DRESS associated with glycopeptides. CONCLUSIONS: This study demonstrates that using in vivo in combination with ex vivo testing can enhance the diagnostic approach in these severe phenotypes by assisting with the identification of possible culprit antibiotics.

Melanoma in a cohort of organ transplant recipients: Experience from a dedicated transplant dermatology clinic in Victoria, Australia.

BACKGROUND: There is limited information on the profile of melanomas diagnosed in a specialist transplant dermatology clinic. OBJECTIVE: To describe the incidence and characteristics of incident primary melanomas in a cohort of organ transplant recipients (OTRs) attending a specialized transplant dermatology clinic and determine the number of pigmented lesions needed to excise for every melanoma diagnosed. METHODS: A retrospective study of 327 OTRs monitored by an Australian clinic during a 10-year period. RESULTS: There were 11 incident melanomas diagnosed during a total follow-up of 1280 patient-years. The mean interval between the first transplant and diagnosis was 5.5 years. Only 2 melanomas were >1 mm in Breslow thickness. Seven melanomas (64%) arose de novo. A contiguous nevus was present in 4 cases. Metastatic disease did not develop in the melanoma patients during the follow-up period, and all remain alive. The needed to excise for every melanoma diagnosed ratio was 16:1. LIMITATIONS: The crude incidence rates were age standardized, unlike the comparison rates of melanoma in the general population, and the cohort was small. CONCLUSION: Most melanomas diagnosed in OTR patients attending a specialized transplant dermatology service were detected early. Our data suggest early detection may reduce the proportion of OTRs presenting with thick melanomas, thus improving prognosis and patient outcomes. A needed to excise for every melanoma diagnosed ratio of 16:1 is not unreasonable for this cohort of high-risk patients. To our knowledge, this is the first time this ratio has been calculated for a cohort of OTRs.

Prolonged survival with the early use of a novel extracorporeal photopheresis regimen in patients with Sézary syndrome.

Extracorporeal photopheresis (ECP) has demonstrated therapeutic benefit in patients with Sézary syndrome (SS) and erythrodermic mycosis fungoides (e-MF). To examine the efficacy of ECP in the modern era of novel therapies, we conducted a retrospective analysis of 65 patients with a diagnosis of SS or e-MF with blood involvement who were treated with ECP at our institute. Overall survival (OS), time to next treatment (TTNT), and skin response rate (RR) were used as the study end points to determine patient outcome. The median follow-up from diagnosis was 48 months (range 1-225 months), with a median predicted OS of 120 months. The majority (88%) of patients commenced ECP at treatment lines 1 to 3, either as a monotherapy or in conjunction with other systemic agents. The use of ECP monotherapy resulted in a significantly longer median TTNT when compared with interferon-α (P = .0067), histone deacetylase inhibitors (P = .0003), novel immunotherapy agents (P = .028), low-dose methotrexate (P < .0001), and chemotherapy (P < .0001). In particular, early commencement of ECP at treatment lines 1 to 3 yielded a TTNT of 47 months. The results of our study support the utilization of ECP for SS/e-MF, and we recommend that ECP should be considered as early as possible in the treatment paradigm for these patients.

Drug-induced liver injury is frequently associated with severe cutaneous adverse drug reactions: experience from two Australian tertiary hospitals.

BACKGROUND: Drug-induced liver injury (DILI) can be associated with certain cutaneous adverse drug reaction (cADR). AIMS: To demonstrate the prevalence of DILI in patients with cADRs. Severity and patterns of liver injury, risk factors, causal medications and outcomes are also examined. METHODS: A retrospective cohort study of patients with cADRs was conducted across two hospitals in Australia. Patients were identified through cross-linkage of multiple databases. RESULTS: One hundred and four patients with cADRs were identified. Of these, 33 (31.7%) had liver injury, representing 50% of patients with drug reaction with eosinophilia and systemic symptoms, and 30.2% of patients with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Most cases of liver injury (69.7%) were of a cholestatic/mixed pattern with severe disease in 18.2%. No significant risk factors for development of liver injury were noted, but peripheral lymphocytosis may represent a risk in patients with SJS (odds ratio, OR = 6.0, 95% confidence interval, CI: 1.8-19.7, P = 0.003). Antimicrobials were the most common class to be implicated in DILI. The median length of inpatient stay was longer in patients with liver injury compared to those without (19 vs 11 days, P = 0.002). The mortality rate in those with liver injury was 15.2% and 9.9% in those without. No patients required liver transplantation. CONCLUSIONS: DILI commonly occurs in patients with cADRs and is associated with longer inpatient stay. Patients with SJS/TEN and peripheral lymphocytosis appear to be at higher risk for developing associated liver injury.

Retrospective audit of patients referred for further treatment following Mohs surgery for non-melanoma skin cancer.

BACKGROUND/OBJECTIVES: To describe the characteristics, subsequent management and outcomes of patients referred for further management following Mohs micrographic surgery (MMS) for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). METHODS: Retrospective analysis of patients referred to a quaternary cancer centre from 2000 to 2015. RESULTS: In total, 83 lesions in 82 patients were referred for further management; 52 (62%) were SCC and 80 (96%) were located in the head and neck. Reasons for referral included high-risk disease for consideration for adjuvant radiotherapy (37/83, 45%), inadequate resection (28/83, 34%) or recurrence following previous MMS (15/83, 17%). Fewer than 40% of the 69 referrals received from MMS surgeons included photos or an operative report and diagram. There was discordance in pathology opinion in 11 (13%) of cases. Histopathology from MMS was reviewed in eight cases and there was discordance with the in-hospital pathology opinion in six of these. In-hospital re-excision was performed in 19 cases and in five of these the pathology report on the paraffin-sectioned re-excised tissue was discordant with prior MMS assessment. Significantly, two cases were associated with a misinterpretation of lymphocytic infiltrate as residual disease in patients with chronic lymphocytic leukaemia (CLL). CONCLUSION: This study highlights some of the challenges and limitations of MMS. Early referral for multidisciplinary management is recommended when MMS resection margins are inadequate or uncertain, especially for high-risk SCC. We recommend that referrals be accompanied by histological material, as well as a detailed report with operative photos and diagrams. CLL can pose an intraoperative diagnostic challenge. Discrepancies in the interpretation of MMS slides present an opportunity for improvement, and our findings support the role of ongoing quality assurance programs.

Two cases of amoxycillin-induced follicular acute localised exanthematous pustulosis.

We report two cases of Caucasian women who developed folliculocentric pustulosis after exposure to amoxycillin. A literature review found that most amoxycillin-related pustular eruptions were reported as acute generalised exanthematous pustulosis (AGEP) or acute localised exanthematous pustulosis (ALEP). Histopathology from both our cases showed sterile suppurative folliculitis, which resolved on the cessation of amoxycillin.