Non-Culture Diagnostics for Invasive Candidiasis: Promise and Unintended Consequences

Abstract

Blood cultures are positive for Candida species in < 50% and < 20% of hematogenously disseminated and intra-abdominal candidiasis, respectively. Non-culture tests such as mannan, anti-mannan antibody, Candida albicans germ tube antibody (CAGTA), 1,3-β-d-glucan (BDG), the T2Candida nanodiagnostic panel, and polymerase chain reaction (PCR) are available for clinical use, but their roles in patient care are uncertain. Sensitivity/specificity of combined mannan/anti-mannan, BDG, T2Candida and PCR for candidemia are ~80%/80%, ~80%/80%, ~90%/98%, and ~90%/90%, respectively. Limited data for intra-abdominal candidiasis suggest CAGTA, BDG sensitivity/specificity of ~65%/75% and PCR sensitivity of ~85–90%. PCR specificity has varied widely for intra-abdominal candidiasis (33–97%), and T2Candida data are lacking. Tests will be useful if restricted to cases in which positive and negative predictive values (PPVs, NPVs) differ in a clinically meaningful way from the pre-test likelihood of invasive candidiasis. In some patients, PPVs are sufficient to justify antifungal treatment, even if blood cultures are negative. In most patients, NPVs of each test are excellent, which may support decisions to withhold antifungal therapy. If test results are not interpreted judiciously, non-culture diagnostics may have unintended consequences for stewardship and infection prevention programs. In particular, discrepant non-culture test-positive/culture-negative results may promote inappropriate antifungal treatment of patients who are unlikely to have candidiasis, and lead to spurious reporting of hospital-acquired infections. In conclusion, non-culture Candida diagnostics have potential to advance patient care, but this promise will be realized only if users understand tests’ strengths and limitations, and plan proactively for how best to employ them at their hospitals.

A New Age in Molecular Diagnostics for Invasive Fungal Disease: Are We Ready?

“…PCR performance data for forms of IC other than candidemia are relatively limited -for intra-abdominal candidiasis, PCR sensitivities of 86-91% have been reported for the species targeted, but specificity varies widely (33-97%) Fortún et al, 2014;León et al, 2016;Clancy and Nguyen, 2018b). Nguyen et al (2012) found a Candida real-time PCR assay to be more sensitive than the Fungitell R 1,3-β-D glucan (BDG) assay (Associates of Cape Cod, United States) for diagnosis of all IC (80 versus 56%) as well as deep seated (blood culture negative) candidiasis (89 versus 53%).…”

“…Many of these assays remain investigational as they have not been validated for diagnosing IC in multi-center studies, nor is there evidence that any one commercial test is superior. The choice of adopting an in house rather than commercial assay is dependent upon workflow and capacity in individual testing laboratories and cost (Clancy and Nguyen, 2018b), and results should be considered with caution. To date, the T2Candida panel and the T2Dx instrument (T2 Biosystems, United States) is the only platform approved by the US Food and Drug Administration (FDA) to detect Candida spp.…”

Advances in the Diagnosis and Management of Invasive Fungal Disease

“…[22][23][24] New diagnostic methods for the timely identification of IFD have emerged in recent years and are summarized in Table 3. [22][23][24][25][26][27][28] An ideal diagnostic test would be minimally invasive, have a rapid turnaround time to result, be both sensitive and specific for the diagnosis of IFD, differentiate between colonization and invasive disease, and yield speciation and susceptibility data. Clinical trials focused on new diagnostic methods or improvements of existing methods that are currently underway are described in Table 4.…”

“…23 The detection of C albicans, C parapsilosis, and C glabrata infections by C albicans germ tube antibody involves use of an indirect immunofluorescence assay against a protein expressed during tissue invasion and biofilm formation, thereby offering potentially useful information in differentiating between infection and colonization. 23,26 Although clinical studies of PCR have used a multitude of platforms and targets, it has generally performed well but is relatively high-cost and labor-intensive. 23,25 A recent development in the diagnosis of C albicans, C tropicalis, C glabrata, Candida krusei, and Candida parapsilosis infections is the T2Candida panel using T2MR technology, which enables the detection of specific molecular targets using magnetic resonance.…”

“…This test has a low limit of detection and does not require the use of purification or extraction techniques, resulting in a quick turnaround time. 25,26 Diagnostic tests for aspergillosis include the galactomannan enzyme immunoassay, BDG, PCR, and lateral flow device. Galactomannan, a cell wall component of Aspergillus species, is most sensitive in neutropenic patients with hematologic or oncologic disorders.…”