Diagnosis of Invasive Candidiasis: From Gold Standard Methods to Promising Leading-edge Technologies

Abstract

Invasive candidiasis (IC) poses a major public health problem worldwide. Despite the introduction of new antifungal agents and changes in clinical practices, its morbidity and mortality rates and healthcare costs remain persistently high. This is mainly because of the serious underlying conditions of infected patients (critically ill or severely immunocompromised patients) and the difficulties encountered in early diagnosing this opportunistic mycosis and initiating prompt and appropriate antifungal therapy. In the light of this great clinical challenge, the past decades have witnessed the development of diverse early detection and therapeutic intervention strategies aimed at minimizing the clinical impact and economic burden of this healthcare-associated infection caused by Candida species. Here, we review the currently available methods for IC diagnosis. These encompass (i) gold standard methods (fungal culture and tissue histopathology), (ii) pathogen-derived biomarker detection tests (PCR, protein antigens, mannan, ß-D-glucan and D-arabinitol-based assays), (iii) host-derived biomarker detection tests (Candida albicans germ tube antibodies or CAGTA, anti-mannan antibodies, other infection-specific antibodies, procalcitonin, serum amyloid A, interleukin 17, interleukin 23 and transforming growth factor ß-based assays), (iv) clinical prediction algorithms (Candida score, colonization index and other prediction rules), and (v) leading-edge molecular, proteomic and immunomic technologies (such as peptide nucleic acid-fluorescent in situ hybridization or PNA-FISH, T2 magnetic resonance or T2Candida assay, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or MALDI-TOF MS, among others). Their strengths, utility, limitations as well as combined use to assist in the diagnosis of this lifethreatening and costly fungal infection (including candidemia and deep-seated candidiasis) are also discussed.

Diagnosis and Treatment of Candidemia in the Intensive Care Unit

“…119 Some tests for detecting Candida protein antigens have been hypothesized or developed, but their applicability in clinical practice remains low because of low sensitivity, possibly linked to rapid clearance, formation of immune complexes, and low serum concentrations. [127][128][129][130][131][132][133][134][135] Suboptimal performances and lack of standardization are also important limitations of tests based on the detection of the Candida sugar alcohol D-arabinitol in serum. 128,133,136,137 Combinations of Available Antigen/Antibody Tests Some authors have tried to combine the use of available tests, to improve their usefulness in guiding pre-emptive therapeutic decisions.…”

“…[127][128][129][130][131][132][133][134][135] Suboptimal performances and lack of standardization are also important limitations of tests based on the detection of the Candida sugar alcohol D-arabinitol in serum. 128,133,136,137 Combinations of Available Antigen/Antibody Tests Some authors have tried to combine the use of available tests, to improve their usefulness in guiding pre-emptive therapeutic decisions. Martínez-Jiménez and colleagues evaluated the combined use of different, possible combinations of antigen/antibody markers (BDG, Mn, A-Mn, CAGTA) for differentiating candidemia (31 patients) from bacteremia (50 patients).…”

The Evolving Landscape of Fungal Diagnostics, Current and Emerging Microbiological Approaches

“…Furthermore, positive BDG assays in patients without IC can be seen with Candida or mold colonization, damage to the intestinal wall, hemodialysis, cellulose dressings, enteral nutrition, or mucositis, and should be only used with caution for screening or to guide pre-emptive antifungal therapy in high-risk immunocompromised patients [7]. [24,29] Antibody testing for Candida has been employed to detect infection and has the theoretical potential to monitor disease response with titers. Commercially available antibody testing including the combined mannan (a polysaccharide target of the Candida cell wall [24]) and antimannan IgG tests (Platelia Candida Ag-Plus and Ab-Plus, Bio-Rad; Serion Mannan Kit, Serio GmbH, Bio-Rad, Marnes-la-Coquette, France) are used clinically in Europe but are not FDA cleared in the US.…”

“…[24,29] Antibody testing for Candida has been employed to detect infection and has the theoretical potential to monitor disease response with titers. Commercially available antibody testing including the combined mannan (a polysaccharide target of the Candida cell wall [24]) and antimannan IgG tests (Platelia Candida Ag-Plus and Ab-Plus, Bio-Rad; Serion Mannan Kit, Serio GmbH, Bio-Rad, Marnes-la-Coquette, France) are used clinically in Europe but are not FDA cleared in the US. Though insensitive alone, their combined sensitivity and specificity is 83% and 86%, respectively, for candidemia and 40% and 25% for intra-abdominal infection [25].…”

PCR-detectable Candida DNA exists a short period in the blood of systemic candidiasis murine model

“…However, the BDG is not a speciesspecific test and cannot discriminate infections caused by different fungal pathogens, resulting in difficulties in designing specific management protocol in clinic. Furthermore, false-positive results due to contamination are not rare in using BDG assays [12,13].…”