ABSTRACT Background Haemophagocytic lymphohistiocytosis (HLH) is a life‐threatening hyperinflammatory syndrome that may occur in people living with HIV/AIDS (PLWHA), often triggered by opportunistic infections such as disseminated histoplasmosis (DH). The substantial overlap in clinical and laboratory features between HLH and DH complicates timely diagnosis. Objectives To describe HLH among PLWHA with DH and compare clinical, laboratory and outcome characteristics between patients with and without HLH . Patients/Methods A retrospective observational study was conducted at São José Hospital of Infectious Diseases, Fortaleza, Brazil, between March 2023 and June 2024. Hospitalised PLWHA with DH were evaluated for HLH based on the presence of ≥ 3 HLH‐2004 criteria and an H‐Score ≥ 169. Baseline clinical, laboratory and outcome parameters were compared between patients with and without HLH. Results Among 61 patients diagnosed with DH, 11 (18.0%) met the study criteria for HLH. Patients with HLH were more likely to present with hepatomegaly ( p = 0.036), haemoptysis ( p = 0.030) and lower platelet counts ( p = 0.029). In‐hospital mortality was significantly higher among patients with HLH (54.5% versus 18.0%; p = 0.019). These patients more frequently required renal replacement therapy ( p = 0.028) and intensive care unit admission ( p = 0.048). Kaplan–Meier analysis with log‐rank testing demonstrated significantly reduced in‐hospital survival among patients with HLH ( p = 0.015). Conclusions HLH represents a severe complication in PLWHA with DH and is associated with increased mortality and greater need for intensive care. Early recognition and use of adjunctive diagnostic tools may facilitate timely management and improve clinical outcomes.
ABSTRACT Background Black yeast‐like species of the order Chaetothyriales cause superficial to life‐threatening systemic infections. Comprehensive global epidemiology data remain limited. Objectives This study aimed to analyze the global epidemiology, spectrum of pathogens, clinical manifestations and outcomes of Chaetothyriales infections. Methods We systematically reviewed 712 cases reported between 1976 and 2025. Results The analysis revealed a steady increase in diagnosed cases, with Cladophialophora bantiana (21%), Exophiala dermatitidis (19%), and E. jeanselmei (15%) being the predominant causative agents; notably, the proportion of E. jeanselmei declined from 18%–28% in 1976–2015 to 7% in 2016–2025. Published cases were more frequent in tropical/subtropical regions; however, cases were reported from Africa. Although 42% of infections occurred in immunocompetent individuals, transplant recipients, diabetics, and those with CARD9 deficiency showed higher risk. Deep infections exhibited substantially greater mortality than cutaneous forms (47% vs. 7%; p < 0.001); particularly, central nervous system infections (58%) and disseminated disease (53%) were involved. Conclusions This study highlights a seemingly growing burden of Chaetothyriales infections, possibly partly due to better recognition, emphasizing the need for improved surveillance, diagnostics, and targeted prevention in high‐risk populations.
ABSTRACT Background Aspergillus infections can pose significant treatment challenges, due in part to increasing triazole resistance. Clinical insight is needed to understand the potential for rezafungin, a next‐generation echinocandin with once‐weekly dosing, to address some limitations of current treatments for Aspergillus infections. Methods This retrospective case series collected anonymized real‐world data from eight adults who received once‐weekly rezafungin for difficult‐to‐treat Aspergillus infections. The cases were provided by clinicians in Spain, the UK, and Italy with considerable experience in treating challenging fungal infections. Results Most patients had pulmonary aspergillosis, nearly all had failed or were intolerant to triazole‐based regimens, and half had prior echinocandin or amphotericin B exposure. Rezafungin was used primarily to enable outpatient parenteral antimicrobial therapy (OPAT), avoiding the need for daily IV echinocandin in settings of azole resistance or intolerance. About half received rezafungin as monotherapy; others had combination regimens. Clinical and/or radiological improvement or disease stabilization was observed in most cases, including in patients with azole‐resistant infections. Notably, one patient achieved resolution of chronic otitis media, and others had negative cultures or sustained clinical benefit. Rezafungin was well tolerated, including in patients with renal impairment. One patient with chronic aspergilloma did not achieve adequate symptomatic control with rezafungin and required surgery. Conclusions This report provides initial clinical insights on rezafungin as a potential option for difficult‐to‐treat Aspergillus infections. In this limited group of patients, rezafungin enabled OPAT, facilitated hospital discharge, and provided clinically meaningful improvements, including prolonged disease stabilization and resolution, which merit further investigation in clinical trials.
Psoriasis is a chronic inflammatory skin disease involving intricate neuroimmune crosstalk. However, the specific mechanisms and therapeutic targets remain elusive. In this study, a pilot clinical trial demonstrated that intravenous scopolamine, a muscarinic receptor antagonist, significantly ameliorated skin lesions in psoriasis patients. Consistently, scopolamine reduced inflammation in an imiquimod-induced mouse model. Metabolomic profiling identified acetylcholine (ACh) as a significantly upregulated neurotransmitter in psoriatic skin, and exogenous ACh exacerbated inflammatory phenotypes. To pinpoint the cellular target, single-cell RNA sequencing revealed that dendritic cells (DCs), unlike T cells or macrophages, uniquely coexpressed neurointeraction receptors and the pathogenic cytokine Il23a. Mechanistically, scopolamine competitively inhibited ACh binding to M1 muscarinic receptors (M1Rs) on DCs, suppressing interleukin (IL)-23 secretion. This therapeutic efficacy was recapitulated in mice with DC-specific M1R deletion. Crucially, the protective effect of M1R deficiency was abolished by recombinant IL-23 administration, whereas scopolamine failed to inhibit inflammation induced by direct IL-23 injection, confirming its action upstream of cytokine release. Collectively, our findings provide compelling evidence that scopolamine treats psoriasis by antagonizing elevated ACh and blocking M1 receptor-mediated IL-23 release in DCs.
Clonal hematopoiesis of indeterminate potential (CHIP) arises from age-related somatic mutations in hematopoietic stem cells in the bone marrow (BM), driving clonal expansion and altered phenotypes. Loss-of-function mutations in the epigenetic regulator TET2 are among the most frequent in CHIP and increase the risk of hematologic malignancies and chronic inflammatory disorders. Here, we investigated the impact of TET2-driven CHIP on inflammatory bone loss. Partial BM reconstitution with TET2-deficient (Tet2-/-) cells promoted clonal expansion and spontaneous periodontitis, characterized by gingival inflammation and alveolar bone loss. Furthermore, mice with TET2-driven CHIP exhibited heightened susceptibility to experimentally induced bone loss, including ligature-induced periodontitis and collagen antibody-induced arthritis. This inflammatory bone loss phenotype was associated with increased tissue infiltration of hyperinflammatory Tet2-/- neutrophils and monocytes, elevated IL-17-producing CD4(+) T cells (Th17), and enhanced osteoclastogenesis driven by paracrine signals from Tet2-/- myeloid cells acting on wild-type osteoclast precursors. Although T cell-intrinsic TET2 deficiency minimally affected Th17 differentiation in vitro, Tet2-/- dendritic cells exhibited enhanced capacity to drive Th17 differentiation from wild-type CD4(+) T cells. These findings reveal mechanistic links between TET2-driven CHIP and the pathogenesis of inflammatory bone loss disorders.
