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Title: Molecular diagnosis of invasive fungal disease
Author: Gorton, Rebecca Louise
ISNI:       0000 0004 7231 9117
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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BACKGROUND: Invasive fungal infections (IFI) are opportunistic infections caused by yeast or filamentous fungi, typically presenting in immunocompromised patients (haemato-oncology, intensive care, HIV, solid organ transplant settings). This research aims to comprehensively evaluate molecular diagnostics to address the current shortfall in IFI diagnosis and, where appropriate, embed molecular methods into routine clinical service. METHODS: Molecular methodologies, including PCR, MALDI-TOF MS and PNA-FISH, were evaluated on clinical sample cohorts from the Royal Free Hospital NHS Foundation Trust. Each method was critically appraised for: statistical performance, clinical utility and suitability for service adoption. RESULTS: MALDI-TOF MS improved yeast agar culture identification, demonstrating 97.4% (185/190) concordance with ITS rRNA sequencing, and time to identification was significantly reduced (p < 0.01, 24 hrs. v’s 15 mins). Lower identification rates of 66% (33/50) were observed when applying MALDI-TOF MS directly to blood culture for yeast identification. In contrast PNA-FISH identified 98.5% (93/96, CI: 91.2, 98.9) of yeasts direct from blood culture within 30 minutes. Using PCP PCR a 60% (3/5) increase in the detection of PCP from BAL in non-HIV patients was demonstrated compared with GMS staining. Overall sensitivity was 100% (95% CI: 56.6, 100) and specificity was 97.9% (95% CI: 88.9, 99.6) for the diagnosis of PCP. Aspergillus PCR demonstrated a sensitivity of 100% (95% CI: 34.2, 100) and specificity of 93.8% (95% CI: 86.4, 97.3) for the diagnosis of IA but a low PPV of 28.6% (95% CI: 8.2, 64.1). CONCLUSIONS: Molecular diagnostic assays can improve the diagnosis of IFI through improved accuracy of identification and increased detection of fungal pathogens from specimens. Results must be interpreted alongside clinical presentation, as false positivity occurs utilising highly sensitive molecular assays. Dual biomarker strategies may improve the performance of molecular diagnostics but the associated impact on healthcare economics must also be considered.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available