Improving Efficacy of Antifungal Therapy by Polymerase Chain Reaction–Based Strategy among Febrile Patients with Neutropenia and Cancer

Lin∥, Ming–Tsan; Lu, Hsi-Chi; Chen, Woan-Ling

doi:10.1086/322631

Cited by 59 publications

(44 citation statements)

References 30 publications

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“…The net clinical benefit afforded by PCR testing for IC could not be assessed. Although PCR results were available to clinicians attending the patient in the several studies performing PCR in real time, only one study directed patients' treatment by PCR results, showing that PCR-directed treatment was initiated 3 days (median; range, 0 to 8 days) before the diagnosis of candidemia by blood culture (44). None of the studies reported the effects of PCR on clinical outcomes.…”

Section: Resultsmentioning

confidence: 99%

PCR Diagnosis of Invasive Candidiasis: Systematic Review and Meta-Analysis

2011

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Invasive candidiasis (IC) is a significant cause of morbidity and mortality. Diagnosis relies on culture-based methods, which lack sensitivity and delay diagnosis. We conducted a systematic review assessing the diagnostic accuracy of PCR-based methods to detect Candida spp. directly in blood samples. We searched electronic databases for prospective or retrospective cohort and case-control studies. Two reviewers abstracted data independently. Meta-analysis was performed using a hierarchical logistic regression model. Random-effects metaregression was performed to assess the effects of study methods and infection characteristics on sensitivity or specificity values. We included 54 studies with 4,694 patients, 963 of whom had proven/probable or possible IC. Perfect (100%) sensitivity and specificity for PCR in whole-blood samples was observed when patients with cases had candidemia and controls were healthy people. When PCR was performed to evaluate patients with suspected invasive candidiasis, the pooled sensitivity for the diagnosis of candidemia was 0.95 (confidence interval, 0.88 to 0.98) and the pooled specificity was 0.92 (0.88 to 0.95). A specificity of >90% was maintained in several analyses considering different control groups. The use of whole-blood samples, rRNA, or P450 gene targets and a PCR detection limit of <10 CFU/ml were associated with improved test performance. PCR positivity rates among patients with proven or probable IC were 85% (78 to 91%), while blood cultures were positive for 38% (29 to 46%). We conclude that direct PCR using blood samples had good sensitivity and specificity for the diagnosis of IC and offers an attractive method for early diagnosis of specific Candida spp. Its effects on clinical outcomes should be investigated.Invasive candidiasis (IC) is a serious cause of morbidity and mortality. In hospitals, Candida spp. represent 8 to 9% of all nosocomial bloodstream infections, and the risk is higher among patients in the intensive care unit (ICU) and cancer patients (19, 81). As many as half of the cases are not diagnosed antemortem (12,21). In North America, non-Candida albicans spp. are currently more prevalent than C. albicans; Candida glabrata and Candida krusei, which are less susceptible to fluconazole, account for 28% of all candidemias (30). Crude mortality rates are uniformly high, ranging from 40 to 54% (3, 59).The current gold standard for the diagnosis of IC is blood culture, which takes 24 to 48 h to become positive (16). Identification of the specific Candida sp. might take even longer, delaying appropriate antifungal treatment. Studies consistently show that a delay of 12 to 48 h in appropriate antifungal therapy is associated with significantly increased all-cause mortality that is independent of other risk factors for mortality; adjusted odds ratios range from 2.17 to 4.75 (8,24,40,58,60,72). Conversely, the use of empirical antifungal treatment for high-risk patients is highly prevalent, leading to increased costs and adverse ecological effects (25). Non-cultur...

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Section: Resultsmentioning

confidence: 99%

PCR Diagnosis of Invasive Candidiasis: Systematic Review and Meta-Analysis

2011

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“…In a study of PCR-guided therapy in paediatric cancer patients, a reduced mortality was observed for febrile neutropenic patients with IFI and no fungal deaths were recorded in patients with PCR-negative febrile neutropenia. 35 Current management of IFI in haemato-oncology patients relies on empirical antifungal therapy. However, despite significant financial expenditure on antifungal therapy (around 33% of our SCT unit's total drug budget), this strategy is failing with mortality from IA remaining around 80-90%.…”

Section: Discussionmentioning

confidence: 99%

A prospective study of real-time panfungal PCR for the early diagnosis of invasive fungal infection in haemato-oncology patients

Jordanides

Allan

McLintock

et al. 2005

Bone Marrow Transplant

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Summary:A blinded prospective study was performed to determine whether screening of whole blood using a real-time, panfungal polymerase chain reaction (PCR) technique could predict the development of invasive fungal infection (IFI) in immunocompromised haemato-oncology patients. In all, 78 patients (125 treatment episodes) were screened twice weekly by real-time panfungal PCR using LightCyclert technology. IFI was documented in 19 treatment episodes (five proven, three probable and 11 possible), and in 12, PCR was sequentially positive. PCR positivity occurred in: 4/5 proven; 2/3 probable; 6/11 possible; and 29/106 with no IFI. In 8/12 with IFI and sequentially positive PCR results, PCR positivity occurred before (median 19.5 days) and in 4/12 (median 10.5 days) after the initiation of empirical antifungal therapy. Based on sequential positive results for proven/probable IFI sensitivity, specificity, positive predictive value and negative predictive value were 75, 70, 15 and 98%, respectively. Real-time panfungal PCR is a sensitive tool for the early diagnosis of IFI in immunocompromised haemato-oncology patients. It may be most useful as a screening method in high-risk patients, either to direct early pre-emptive antifungal therapy or to determine when empirical antifungal therapy can be withheld in patients with antibiotic-resistant neutropenic fever. However, these strategies require further assessment in comparative clinical trials.

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“…Sensitivity has been highly variable, ranging from 50 to 100%, primarily because of differences in assay characteristics, types of patients evaluated, and certainty of IPA diagnosis (6, 8-10, 15, 19, 23). More recent studies have evaluated the use of real-time PCR assays applied to blood and BAL fluid (6,15,22); results suggest utility, although no standard assay platform has been used and no large study has been performed.…”

mentioning

confidence: 99%

AspergillusGalactomannan Enzyme Immunoassay and Quantitative PCR for Diagnosis of Invasive Aspergillosis with Bronchoalveolar Lavage Fluid

et al. 2004

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Invasive pulmonary aspergillosis (IPA) is frequent and often fatal in hematopoietic stem cell transplant patients. Diagnosis requires microbiological or histopathologic demonstration of the organism in tissues; however, cultivation of Aspergillus species from respiratory secretions has low diagnostic sensitivity. Assays to detect Aspergillus antigen or DNA in bronchoalveolar lavage (BAL) fluid could facilitate earlier diagnosis, thereby guiding optimal therapy and obviating the need for additional costly and potentially morbid diagnostic evaluation. We evaluated the performance of a galactomannan enzyme immunoassay (GM EIA; Bio-Rad) by using a range of index cutoffs to define positivity and a quantitative PCR (qPCR) assay for the detection of Aspergillus species from BAL samples of patients with proven and probable IPA (case patients; n ‫؍‬ 49) and without IPA (control patients; n ‫؍‬ 50). The sensitivity of the GM EIA was 61% with an index cutoff of 1.0 and 76% with an index cutoff of 0.5; the corresponding specificities were 98 and 94%, respectively. The sensitivity and specificity of qPCR assay were 67 and 100%, respectively.

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Improving Efficacy of Antifungal Therapy by Polymerase Chain Reaction–Based Strategy among Febrile Patients with Neutropenia and Cancer

Cited by 59 publications

References 30 publications

PCR Diagnosis of Invasive Candidiasis: Systematic Review and Meta-Analysis

PCR Diagnosis of Invasive Candidiasis: Systematic Review and Meta-Analysis

A prospective study of real-time panfungal PCR for the early diagnosis of invasive fungal infection in haemato-oncology patients

AspergillusGalactomannan Enzyme Immunoassay and Quantitative PCR for Diagnosis of Invasive Aspergillosis with Bronchoalveolar Lavage Fluid

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