Multiomic single-cell sequencing defines tissue-specific responses in Stevens-Johnson Syndrome and Toxic epidermal necrolysis.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) is a rare but life-threatening cutaneous drug reaction mediated by human leukocyte antigen (HLA) class I-restricted CD8+ T-cells. To obtain an unbiased assessment of SJS/TEN cellular immunopathogenesis, we performed single-cell (sc) transcriptome, surface proteome, and TCR sequencing on unaffected skin, affected skin, and blister fluid from 17 SJS/TEN patients. From 119,784 total cells, we identified 16 scRNA-defined subsets, confirmed by subset-defining surface protein expression. Keratinocytes upregulated HLA and IFN-response genes in the affected skin. Cytotoxic CD8+ T-cell subpopulations of expanded and unexpanded TCRαß clonotypes were shared in affected skin and blister fluid but absent or unexpanded in SJS/TEN unaffected skin. SJS/TEN blister fluid is a rich reservoir of oligoclonal CD8+ T-cells with an effector phenotype driving SJS/TEN pathogenesis. This multiomic database will act as the basis to define antigen-reactivity, HLA restriction, and signatures of drug-antigen-reactive T-cell clonotypes at a tissue level.

Comment on: Proposal for a new diagnostic classification of photodistributed Stevens-Johnson syndrome and toxic epidermal necrolysis.

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap (SJS/TEN), collectively referred to SJS/TEN, form a spectrum of severe life-threatening adverse drug reactions whose pathomechanism is not fully understood. The article "Photodistributed Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Systematic Review and Proposal for a New Diagnostic Classification" by McKinley et. al., discusses a distinct distribution of epidermal necrosis in SJS/TEN, attributable to preceding exposure to ultraviolet radiation (UVR), and relative sparing of photo-protected areas. After reviewing numerous cases within the Immune-mediated Adverse drug Reactions in African HIV endemic setting Register and Biorepository (IMARI-SA) at the University of Cape Town with a similar clinical pattern as those published by McKinley et. al., we propose that the relative sparing of some areas giving an impression of photo-distribution is due to localised increase in skin pressure that reduces the blood supply in that area below a critical threshold. A dip in blood supply below this critical threshold quantitively limited T lymphocytes and cytokines that drive SJS/TEN to reach and damage the skin.

Management of Adult Patients With Drug Reaction With Eosinophilia and Systemic Symptoms: A Delphi-Based International Consensus.

Importance: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but potentially fatal drug hypersensitivity reaction. To our knowledge, there is no international consensus on its severity assessment and treatment. Objective: To reach an international, Delphi-based multinational expert consensus on the diagnostic workup, severity assessment, and treatment of patients with DRESS. Design, Setting, and Participants: The Delphi method was used to assess 100 statements related to baseline workup, evaluation of severity, acute phase, and postacute management of DRESS. Fifty-seven international experts in DRESS were invited, and 54 participated in the survey, which took place from July to September 2022. Main Outcomes/Measures: The degree of agreement was calculated with the RAND-UCLA Appropriateness Method. Consensus was defined as a statement with a median appropriateness value of 7 or higher (appropriate) and a disagreement index of lower than 1. Results: In the first Delphi round, consensus was reached on 82 statements. Thirteen statements were revised and assessed in a second round. A consensus was reached for 93 statements overall. The experts agreed on a set of basic diagnostic workup procedures as well as severity- and organ-specific further investigations. They reached a consensus on severity assessment (mild, moderate, and severe) based on the extent of liver, kidney, and blood involvement and the damage of other organs. The panel agreed on the main lines of DRESS management according to these severity grades. General recommendations were generated on the postacute phase follow-up of patients with DRESS and the allergological workup. Conclusions and Relevance: This Delphi exercise represents, to our knowledge, the first international expert consensus on diagnostic workup, severity assessment, and management of DRESS. This should support clinicians in the diagnosis and management of DRESS and constitute the basis for development of future guidelines.

Updates in SJS/TEN: collaboration, innovation, and community.

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is a predominantly drug-induced disease, with a mortality rate of 15-20%, that engages the expertise of multiple disciplines: dermatology, allergy, immunology, clinical pharmacology, burn surgery, ophthalmology, urogynecology, and psychiatry. SJS/TEN has an incidence of 1-5/million persons per year in the United States, with even higher rates globally. One of the challenges of SJS/TEN has been developing the research infrastructure and coordination to answer questions capable of transforming clinical care and leading to improved patient outcomes. SJS/TEN 2021, the third research meeting of its kind, was held as a virtual meeting on August 28-29, 2021. The meeting brought together 428 international scientists, in addition to a community of 140 SJS/TEN survivors and family members. The goal of the meeting was to brainstorm strategies to support the continued growth of an international SJS/TEN research network, bridging science and the community. The community workshop section of the meeting focused on eight primary themes: mental health, eye care, SJS/TEN in children, non-drug induced SJS/TEN, long-term health complications, new advances in mechanisms and basic science, managing long-term scarring, considerations for skin of color, and COVID-19 vaccines. The meeting featured several important updates and identified areas of unmet research and clinical need that will be highlighted in this white paper.

Skin infiltrating T-cell profile of drug reaction with eosinophilia and systemic symptoms (DRESS) reactions among HIV-infected patients.

Introduction: Drug 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 methods: HIV 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. Results: Skin 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 < 0.001 and p = 0.004, respectively; without correlation to whole blood CD4 cell counts. In contrast, no difference in dermal CD4+FoxP3+ T-cells was found in HIV-positive vs. negative DRESS, median (IQR) CD4+FoxP3+ T-cells: [10 (0-30) cells/mm2 vs. 4 (3-8) cells/mm2, p = 0.325]. HIV-positive DRESS patients reacting to more than one drug had no difference in CD8+ T-cell infiltrates, but higher epidermal and dermal CD4+FoxP3+ T-cell infiltrates compared to single drug reactors. Conclusion: DRESS, irrespective of HIV status, was associated with an increased skin infiltration of CD8+ T-cells, while CD4+ T-cells were lower in HIV-positive DRESS compared to HIV-negative DRESS skin. While inter-individual variation was high, the frequency of dermal CD4+FoxP3+ T-cells was higher in HIV-positive DRESS cases reacting to more than one drug. Further research is warranted to understand the clinical impact of these changes.

HIV-associated photodermatitis in African populations.

Photosensitive dermatoses are seen in 5% of HIV-infected persons. These include drug- and chemical-induced photoallergic and phototoxic reactions, chronic actinic dermatitis of HIV, photo lichenoid drug eruptions, and porphyria. Data on photodermatitis in HIV are limited to case reports and series. The pathogenesis is not completely understood and includes a th2 phenotype in HIV which results in impaired barrier function and resultant allergen sensitisation as well as immune dysregulation. The objective of this manuscript is to review the literature on the clinical phenotype, pathogenesis, role of photo and patch testing, outcomes, and treatment of photodermatitis in HIV in an African population.

HIV-Associated Immune Dysregulation in the Skin: A Crucible for Exaggerated Inflammation and Hypersensitivity.

Skin diseases are hallmarks of progressive HIV-related immunosuppression, with severe noninfectious inflammatory and hypersensitivity conditions as common as opportunistic infections. Conditions such as papular pruritic eruption are AIDS defining, whereas delayed immune-mediated adverse reactions, mostly cutaneous, occur up to 100-fold more during HIV infection. The skin, constantly in contact with the external environment, has a complex immunity. A dense, tightly junctioned barrier with basal keratinocytes and epidermal Langerhans cells with antimicrobial, innate-activating, and antigen-presenting functions form the frontline. Resident dermal dendritic, mast, macrophage, and innate lymphoid cells play pivotal roles in directing and polarizing appropriate adaptive immune responses and directing effector immune cell trafficking. Sustained viral replication leads to progressive declines in CD4 T cells, whereas Langerhans and dermal dendritic cells serve as viral reservoirs and points of first viral contact in the mucosa. Cutaneous cytokine responses and diminished lymphoid populations create a crucible for exaggerated inflammation and hypersensitivity. However, beyond histopathological description, these manifestations are poorly characterized. This review details normal skin immunology, changes associated with progressive HIV-related immunosuppression, and the characteristic conditions of immune dysregulation increased with HIV. We highlight the main research gaps and several novel tissue-directed strategies to define mechanisms that will provide targeted approaches to prevention or treatment.

Disease severity and status in Stevens-Johnson syndrome and toxic epidermal necrolysis: Key knowledge gaps and research needs.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are on a spectrum of cutaneous drug reactions characterized by pan-epidermal necrosis with SJS affecting < 10% of body surface area (BSA), TEN > 30%, and SJS/TEN overlap between 10 and 30%. Severity-of-illness score for toxic epidermal necrolysis (SCORTEN) is a validated tool to predict mortality rates based on age, heart rate, BSA, malignancy and serum urea, bicarbonate, and glucose. Despite improved understanding, SJS/TEN mortality remains constant and therapeutic interventions are not universally accepted for a number of reasons, including rarity of SJS/TEN; inconsistent definition of cases, disease severity, and endpoints in studies; low efficacy of interventions; and variations in treatment protocols. Apart from mortality, none of the other endpoints used to evaluate interventions, including duration of hospitalization, is sufficiently standardized to be reproducible across cases and treatment centers. Some of the gaps in SJS/TEN research can be narrowed through international collaboration to harmonize research endpoints. A case is made for an urgent international collaborative effort to develop consensus on definitions of endpoints such as disease status, progression, cessation, and complete re-epithelialization in interventional studies. The deficiencies of using BSA as the sole determinant of SJS/TEN severity, excluding internal organ involvement and extension of skin necrosis beyond the epidermis, are discussed and the role these factors play on time to healing and mortality beyond the acute stage is highlighted. The potential role of artificial intelligence, biomarkers, and PET/CT scan with radiolabeled glucose as markers of disease status, activity, and therapeutic response is also discussed.

IFN-γ ELISpot in Severe Cutaneous Adverse Reactions to First-Line Antituberculosis Drugs in an HIV Endemic Setting.

Severe cutaneous adverse reactions related to first-line antituberculosis drugs are associated with high mortality and long-term morbidity. Oral sequential drug challenge, as a form of drug provocation testing, helps to salvage therapy by identifying culprit drugs but is associated with risk and is costly. IFN-γ enzyme-linked immune absorbent spot (ELISpot), an adjunctive in vitro diagnostic tool, may help to guide risk-stratification approaches. To determine the diagnostic accuracy of IFN-γ ELISpot against full-dose sequential drug challenge, we analyzed samples collected prospectively at multiple time points in 32 patients with first-line antituberculosis drug‒associated severe cutaneous adverse reaction (81% HIV infected, 25 with drug reaction with eosinophilia and systemic symptoms, and 7 with Stevens‒Johnson syndrome/toxic epidermal necrolysis). Sensitivity of IFN-γ ELISpot was 33% (4 of 12), 13% (1 of 8), 11% (1 of 9), and 0% (0 of 4) for rifampicin, isoniazid, pyrazinamide, and ethambutol, respectively (positivity threshold ≥50 spot forming units/million cells). Specificity was 100% for all the four drugs. Rifampicin IFN-γ ELISpot sensitivity increased to 58% (7 of 12) if a threshold of 20 spot forming units was used and to 75% (3 of 4) when restricted to samples <12 weeks after acute severe cutaneous adverse reaction event; specificity remained 100% for both. IFN-γ ELISpot offers adequate risk stratification of rifampicin severe cutaneous adverse reaction using acute samples and lowered threshold for positivity. Given the low sensitivity of IFN-γ ELISpot for other first-line antituberculosis drugs, additional optimization is needed to improve risk-stratification potential.

Recognizing Drug Hypersensitivity in Pigmented Skin.

The imagery of pigmented skin is underrepresented in teaching materials such as textbooks, journals, and online references, and this has resulted in poorer diagnostic and management outcomes of skin pathology, including delayed cutaneous drug hypersensitivity reactions. In this review, we use clinical images to highlight factors that impact clinical presentations and sequelae of drug hypersensitivity reactions in pigmented skin compared with nonpigmented skin. We describe clinical features in some anatomic sites that aid diagnosis or are associated with more severe sequelae. Finally, we discuss strategies that may aid the diagnosis and management of these reactions in pigmented skin.

Delabeling Delayed Drug Hypersensitivity: How Far Can You Safely Go?

Delayed immune-mediated adverse drug reactions (IM-ADRs) are defined as reactions occurring more than 6 hours after dosing. They include heterogeneous clinical phenotypes that are typically T-cell-mediated reactions with distinct mechanisms across a wide spectrum of severity from benign exanthems through to life-threatening cutaneous or organ-specific diseases. For mild reactions such as benign exanthem, considerations for delabeling are similar to immediate reactions and may include a graded or single-dose drug challenge with or without preceding skin or patch testing. Evaluation of challenging cases such as the patient who is on multiple drugs at the time a severe delayed IM-ADR occurs should prioritize clinical ascertainment of the most likely phenotype and implicated drug(s). Although not widely available and validated, procedures such as patch testing, delayed intradermal skin testing, and laboratory-based functional drug assays or genetic (human leukocyte antigen) testing may provide valuable information to further help risk stratify patients and identify the likely implicated and/or cross-reactive drug(s). The decision to use a drug challenge as a diagnostic or delabeling tool in a patient with a severe delayed IM-ADR should weigh the risk-benefit ratio, balancing the severity and priority for the treatment of the underlying, and the availability of alternative efficacious and safe treatments.

SJS/TEN 2019: From science to translation.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening, immune-mediated adverse reactions characterized by widespread erythema, epidermal necrosis, and detachment of skin and mucosa. Efforts to grow and develop functional international collaborations and a multidisciplinary interactive network focusing on SJS/TEN as an uncommon but high burden disease will be necessary to improve efforts in prevention, early diagnosis and improved acute and long-term management. SJS/TEN 2019: From Science to Translation was a 1.5-day scientific program held April 26-27, 2019, in Vancouver, Canada. The meeting successfully engaged clinicians, researchers, and patients and conducted many productive discussions on research and patient care needs.

Cost of managing severe cutaneous adverse drug reactions to first-line tuberculosis therapy in South Africa.

OBJECTIVE: To compare the cost of managing treatment-limiting cutaneous adverse drug reactions (CADRs) to first-line anti-tuberculosis drugs to an alternative strategy of immediate treatment initiation using second-line drugs in a South African setting. METHODS: Clinical and cost data were retrospectively collected from patients presenting with a first-line anti-tuberculosis therapy-associated CADR. Costs (2016 US$) were estimated using an ingredient's approach from a healthcare provider perspective. The per-patient and total cost of drug rechallenge, the current management strategy for severe CADR, was calculated. Alternative strategies involving second-line treatment were derived from literature and expert clinical advice. RESULTS: Drug rechallenge costs US $5831 (95% CI: 5134-6527) per patient. Hospitalisation accounted for 62% of this cost. Alternative CADR management strategies using regimens containing rifabutin, bedaquiline and/or delamanid cost 44%-55% less than drug rechallenge (US $2651-US $3276/patient). In univariate sensitivity analyses, drug rechallenge and alternative strategies were most sensitive to hospitalisation and tuberculosis drug costs, respectively. CONCLUSION: Cutaneous adverse drug reactions to anti-tuberculosis treatment represent a significant economic burden. An alternate strategy of outpatient-initiated second-line therapy is economically feasible but requires clinical validation to assess effectiveness.

OBJECTIF: Comparer le coût de la prise ne charge des effets indésirables cutanés (EIC) limitant le traitement aux antituberculeux de première ligne à celui d'une stratégie alternative d'initiation immédiate du traitement par des médicaments de deuxième ligne dans un contexte sud-africain. MÉTHODES: Les données cliniques et les coûts ont été collectés rétrospectivement chez des patients présentant un EIC associé au traitement antituberculeux de première ligne. Les coûts (USD, 2016) ont été estimés en utilisant une approche d'ingrédient du point de vue d'un prestataire de soins de santé. Le coût par patient et le coût total du nouveau traitement, de la stratégie actuelle de prise en charge des cas d'EIC sévère, ont été calculés. Des stratégies alternatives impliquant un traitement de deuxième ligne ont été dérivées de la littérature et de conseils cliniques d'experts. RÉSULTATS: Le coût du nouveau traitement était de 5.831 USD (IC95%: 5.134 - 6.527) par patient. L'hospitalisation représentait 62% de ce coût. Les stratégies alternatives de prise en charge des EIC utilisant des schémas thérapeutiques contenant de la rifabutine, de la bédaquiline et/ou du delamanide coûtent de 44 % à 55 % moins cher que le nouveau traitement (2.651 USD - 3.276 USD/patient). Dans les analyses de sensibilité univariées, les stratégies de re-traitement et les stratégies alternatives étaient plus sensibles aux coûts d'hospitalisation et de médicaments antituberculeux, respectivement. CONCLUSION: Les EIC des antituberculeux représentent une charge économique importante. Une stratégie alternative de traitement de deuxième ligne mise en place chez des patients ambulatoires est économiquement réalisable mais nécessite une validation clinique pour évaluer l'efficacité.

Drug hypersensitivity in HIV infection.

PURPOSE OF REVIEW: Immune-mediated adverse drug reactions (IM-ADRs) are many times more common in HIV-infected patients. Usual offending drugs include antiretroviral and antiinfectives, but the burden of specific drug IM-ADRs is population-specific; changing as new and fixed dose combinations enter the market, and drug-resistance patterns demand. This review considers recent literature on epidemiology, mechanisms, clinical management and prevention of IM-ADRs amongst persons living with HIV/AIDS. RECENT FINDINGS: Epidemiological studies continue to describe high rates of delayed hypersensitivity to known offenders, as well as similar reactions in preexposure prophylaxis. IM-ADRs to oral and injectable integrase strand transfer inhibitors are reported with expanding use. The clinical spectrum and management of IM-ADRs occurring in HIV-infected populations is similar to uninfected; with exceptions such as a recently described severe delayed efavirenz DILI with high mortality. Furthermore, the context can be unique, such as the lower than expected mortality in a Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) cohort from a HIV/TB high burden setting. Programmatic data showing the near complete elimination of Abacavir drug hypersensitivity syndrome following implementation of HLA-B57:01 screening is a stellar example of how prevention is possible with mechanistic insight. SUMMARY: IM-ADRs remain a challenge in persons living with HIV. The complexities posed by polypharmacy, overlapping drug toxicities, drug interactions, overlap of IM-ADRs with other diseases, limited alternative drugs, and vulnerable patients with advanced immunosuppression with high mortality, necessitate increased use of drug provocation testing, treat-through and desensitization strategies. There is an urgent need for improved diagnostics and predictive biomarkers for prevention, or to guide treat-through, rechallenge and desensitization approaches.

Applications of Immunopharmacogenomics: Predicting, Preventing, and Understanding Immune-Mediated Adverse Drug Reactions.

Adverse drug reactions (ADRs) are a significant health care burden. Immune-mediated adverse drug reactions (IM-ADRs) are responsible for one-fifth of ADRs but contribute a disproportionately high amount of that burden due to their severity. Variation in human leukocyte antigen ( HLA) genes has emerged as a potential preprescription screening strategy for the prevention of previously unpredictable IM-ADRs. Immunopharmacogenomics combines the disciplines of immunogenomics and pharmacogenomics and focuses on the effects of immune-specific variation on drug disposition and IM-ADRs. In this review, we present the latest evidence for HLA associations with IM-ADRs, ongoing research into biological mechanisms of IM-ADRs, and the translation of clinical actionable biomarkers for IM-ADRs, with a focus on T cell-mediated ADRs.