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.

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.

Advances in the Pathomechanisms of Delayed Drug Hypersensitivity.

Delayed drug hypersensitivity continues to contribute to major clinical problems worldwide. The clinical presentations of delayed drug hypersensitivity are diverse, ranging from mild skin rashes to life-threatening systemic reactions. The pathomechanism of delayed drug hypersensitivity involves human leukocyte antigens (HLA) presentation of drugs/metabolites to T cell receptors (TCR), resulting in T-cell activation. The pathogenesis of delayed drug hypersensitivity also has reactivation of the virus, and activation of many immune mediators. In this review, we discuss the immune pathogenesis, molecular interactions of HLA/drugs/TCR, and downstream signaling of cytotoxic proteins/cytokines/chemokines, as well as disease prevention and management for delayed drug hypersensitivity.

Updates and Insights in the Diagnosis and Management of DRESS Syndrome.

PURPOSE OF REVIEW: To provide updates on recent advances in the diagnosis and management of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. RECENT FINDINGS: The number of identified HLA allele associations with DRESS continues to grow. There is increasing evidence indicating viral infection, reactivation, and cross-reactivity may play key roles in disease. Translational work illuminated JAK/STAT activation in recalcitrant disease. There is expanding recognition of rapid-onset DRESS resulting from specific drugs. SUMMARY: DRESS is a severe form of adverse drug reaction with potential for significant morbidity and mortality. Recent research advances may improve clinical care. HLA screening can now be performed to prevent disease in susceptible patients and may help identify culprit drugs in the near future. Viral testing should be performed on every patient, and if positive, patients potentially treated with antiviral therapy. JAK inhibitors may be an effective treatment option for DRESS. Early onset of disease relative to drug exposure should not exclude the diagnosis of DRESS.

Skin Resident Memory T Cells May Play Critical Role in Delayed-Type Drug Hypersensitivity Reactions.

Delayed-type drug hypersensitivity reactions (dtDHR) are immune-mediated reactions with skin and visceral manifestations ranging from mild to severe. Clinical care is negatively impacted by a limited understanding of disease pathogenesis. Though T cells are believed to orchestrate disease, the type of T cell and the location and mechanism of T cell activation remain unknown. Resident memory T cells (TRM) are a unique T cell population potentially well situated to act as key mediators in disease pathogenesis, but significant obstacles to defining, identifying, and testing TRM in dtDHR preclude definitive conclusions at this time. Deeper mechanistic interrogation to address these unanswered questions is necessary, as involvement of TRM in disease has significant implications for prediction, diagnosis, and treatment of disease.