Chronic Disseminated Candidiasis During Hematological Malignancies: An Immune Reconstitution Inflammatory Syndrome With Expansion of Pathogen-Specific T Helper Type 1 Cells

Abstract

Background Chronic disseminated candidiasis (CDC) is a rare disease that mostly occurs after chemotherapy-induced prolonged neutropenia in patients with hematological malignancies. It is believed to ensue from Candida colonization, breach of the intestinal epithelial barrier, and venous translocation to organs. Fungal blood or liver biopsy cultures are generally negative, suggesting the absence of an ongoing invasive fungal disease. Methods To unravel the contribution of the immune system to CDC pathogenesis, we undertook a prospective multicentric exploratory study in 44 CDC patients at diagnosis and 44 matched controls. Results Analysis of Candida-specific T-cell responses using enzyme-linked immunospot assays revealed higher numbers of interferon (IFN)γ-producing T cells reactive to mp65 or candidin in 27 CDC cases compared with 33 controls. Increased plasma levels of soluble CD25, interleukin (IL)-6, IL-1β, tumor necrosis factor-α, and IL-10 and lower levels of IL-2 were observed in CDC patients versus controls. Neutrophilia and higher levels of CD4 and CD8 T-cell activation were found in CDC patients as well as increased proportions of CXCR3-expressing TCRγδ +Vδ2+ cells. Conclusions The expansion of Candida-specific IFNγ-producing T cells together with features of T-cell activation and systemic inflammation identified here support the view that CDC belongs to the broad spectrum of fungal-associated immune reconstitution inflammatory syndromes.

Pathogenesis and virulence of Candida albicans

“…Thus, although neutrophils play a critical role in defense against systemic candidiasis, their prolonged and/or excessive recruitment and activation may exert damaging effects. Additional studies are needed to delineate the complex tissue-specific regulatory networks that control the spatial and temporal regulation of neutrophil accumulation and function and to define the relevance of these pathways in humans with systemic candidiasis, in whom neutrophil-associated immunopathology has been observed in the settings of hepatosplenic candidiasis during neutrophil recovery and of renal candidiasis [ 333–335 ].…”

Hepatosplenic Candidiasis in Patients With Hematological Malignancies: A 13-Year Retrospective Cohort Study

“…The physiopathology might be different for cases occurring after lymphoid diseases. The CANHPARI study (Hepatosplenic Candidiasis: PET Scan and Immune Response Analysis), which is an ongoing multicenter prospective pilot study investigating the pathogenesis, diagnosis, and therapeutic strategies of hepatosplenic candidiasis ( https://research.pasteur.fr/fr/project/canhpari/ ), should soon deliver interesting results and might give new insights on the pathogenesis of HSC [ 36 ].…”

Does 18F-FDG PET/CT add value to conventional imaging in clinical assessment of chronic disseminated candidiasis?

“…Hence, prolonged treatments up to 3–6 months are frequent, leading to antifungal toxicity and cost increase ( 2 , 6 , 7 ). Finally, our group advocated that CDC belonged to the spectrum of fungal immune reconstitution inflammatory syndrome (IRIS), thereby raising questions on the tools most appropriate to evaluate the CDC-induced inflammatory reaction over time ( 8 – 10 ).…”

“…Indeed, a preliminary study by our team has assessed PET/CT as a diagnostic tool for invasive fungal diseases (IFD), including CDC ( 16 ), its appropriateness being further documented by descriptive case reports or small case series uptake ( 17 – 21 ). PET/CT might therefore help to assess lesions at baseline and monitor antifungal treatment duration of CDC ( 9 , 10 ). Through the largest prospective study on CDC ever performed ( 10 ), the aim was to determine whether the addition of PET/CT to conventional radiology added clinical value both at diagnosis and after 3 months of antifungal therapy.…”

“…PET/CT might therefore help to assess lesions at baseline and monitor antifungal treatment duration of CDC ( 9 , 10 ). Through the largest prospective study on CDC ever performed ( 10 ), the aim was to determine whether the addition of PET/CT to conventional radiology added clinical value both at diagnosis and after 3 months of antifungal therapy.…”