Introducing 1,3-beta-d-glucan for screening and diagnosis of invasive fungal diseases in Australian high-risk haematology patients: is there a clinical benefit?

BACKGROUND: Early, accurate diagnosis of invasive fungal disease (IFD) improves clinical outcomes. 1,3-beta-d-glucan (BDG) (Fungitell, Associates of Cape Cod, Inc., Falmouth, MA, USA) detection can improve IFD diagnosis but has been unavailable in Australia. AIMS: To assess performance of serum BDG for IFD diagnosis in a high-risk Australian haematology population. METHODS: We compared the diagnostic value of weekly screening of serum BDG with screening by Aspergillus polymerase chain reaction and Aspergillus galactomannan in 57 at-risk episodes for the diagnosis of IFD (proven, probable, possible IFD). RESULTS: IFD episodes were: proven (n = 4); probable (n = 4); possible (n = 18); and no IFD (n = 31). Using two consecutive BDG results of ≥80 pg/mL to call a result 'positive', the sensitivity, specificity, positive predictive value and negative predictive value was 37.5%, 64.5%, 23.1% and 80.7% respectively. For invasive aspergillosis, test performance increased to 50%, 90.3%, 57.1% and 87.5% respectively if any two of serum BDG/Aspergillus polymerase chain reaction/galactomannan yielded a 'positive' result. In proven/probable IFD, five of eight episodes returned a positive BDG result earlier (mean 6.6 days) than other diagnostic tests. False-negative BDG results occurred in three of eight episodes of proven/probable IFD, and false positive in 10 of 31 patients with no IFD. Erratic patterns of BDG values predicted false positive results (P = 0.03). Using serum BDG results, possible IFD were reassigned to either 'no' or 'probable' IFD in 44% cases. Empiric anti-fungal therapy use may have been optimised by BDG monitoring in 38.5% of courses. CONCLUSIONS: The BDG assay can add diagnostic speed and value but was hampered by low sensitivity and positive predictive value in Australian haematology patients.

Galactomannan and PCR versus culture and histology for directing use of antifungal treatment for invasive aspergillosis in high-risk haematology patients: a randomised controlled trial.

BACKGROUND: Empirical treatment with antifungal drugs is often used in haematology patients at high risk of invasive aspergillosis. We compared a standard diagnostic strategy (culture and histology) with a rapid biomarker-based diagnostic strategy (aspergillus galactomannan and PCR) for directing the use of antifungal treatment in this group of patients. METHODS: In this open-label, parallel-group, randomised controlled trial, eligible patients were adults undergoing allogeneic stem-cell transplantation or chemotherapy for acute leukaemia, with no history of invasive fungal disease. Enrolled patients were randomly assigned (1:1) by a computer-generated schedule to follow either a standard diagnostic strategy (based on culture and histology) or a biomarker-based diagnostic strategy (aspergillus galactomannan and PCR) to direct treatment with antifungal drugs. Patients, were followed up for 26 weeks or until death. Masking of the use of different diagnostic tests was not possible for patients, treating physicians, or investigators. The primary endpoint was empirical treatment with antifungal drugs in the 26 weeks after enrolment (for the biomarker-based diagnostic strategy, a single postive galactomannan or PCR result was deemed insufficient to confirm invasive aspergillosis, so treatment in this context was classified as empirical). This outcome was assessed by an independent data review committee from which the study allocations were masked. Analyses were by intention to treat and included all enrolled patients. This study is registered with ClinicalTrial.gov, number NCT00163722. FINDINGS: 240 eligible patients were recruited from six Australian centres between Sept 30, 2005, and Nov 19, 2009. 122 were assigned the standard diagnostic strategy and 118 the biomarker-based diagnostic strategy. 39 patients (32%) in the standard diagnosis group and 18 (15%) in the biomarker diagnosis group received empirical antifungal treatment (difference 17%, 95% CI 4-26; p=0·002). The numbers of patients who had hepatotoxic and nephrotoxic effects did not differ significantly between the standard diagnosis and biomarker diagnosis groups (hepatotoxic effects: 21 [17%] vs 12 [10%], p=0·11; nephrotoxic effects: 52 [43%] vs 60 [51%], p=0·20). INTERPRETATION: Use of aspergillus galactomannan and PCR to direct treatment reduced use of empirical antifungal treatment. This approach is an effective strategy for the management of invasive aspergillosis in high-risk haematology patients. FUNDING: Australian National Health and Medical Research Council, Cancer Council New South Wales, Pfizer, Merck, Gilead Sciences.

Human rhinovirus C in adult haematopoietic stem cell transplant recipients with respiratory illness.

BACKGROUND: A previously unidentified species of human rhinovirus, HRV-C, was described in 2006 in association with lower respiratory tract infection (LRTI). Features of infection in immunosuppressed adults are poorly characterised. OBJECTIVES: This study aims to determine the epidemiology of HRV-C in haematopoietic stem cell transplant (HSCT) recipients in a single centre. STUDY DESIGN: A prospective cohort study of all HSCT recipients admitted to Westmead Hospital, Westmead, Australia from 1 July 2005 to 30 September 2007 was undertaken. Nose/throat samples were collected from all patients at the time of admission and patients developing pre-defined symptoms and/or signs of respiratory infection during the admission. Samples were processed and tested for rhinoviruses and 14 other respiratory viruses using nucleic acid-based methods, immunofluorescence and culture. HRV genotyping was performed by sequencing a region of the rhinovirus 5' untranslated region (UTR). Clinical data on each episode were collected prospectively. RESULTS: HRVs were identified in 24 episodes: 8% of 299 episodes of clinically- defined respiratory infections and 39% of 61 episodes in which respiratory viruses were detected. HRV-C was most frequent (HRV-C: nine, HRV-A: eight and HRV-B: two). Seven episodes of HRV-C, five with pneumonia, occurred within 100 days of HSCT. Co-pathogens were frequent. CONCLUSIONS: The newly described HRV-C was the most common rhinovirus group detected in HSCT recipients with respiratory infection, with co-pathogens being frequent. Further research is required to understand the activity and pathogenicity of this virus in HSCT recipients.

Design issues in a randomized controlled trial of a pre-emptive versus empiric antifungal strategy for invasive aspergillosis in patients with high-risk hematologic malignancies.

Invasive aspergillosis (IA) is a major cause of mortality in patients with hematological malignancies, due largely to the inability of traditional culture and biopsy methods to make an early or accurate diagnosis. Diagnostic accuracy studies suggest that Aspergillus galactomannan (GM) enzyme immunoassay (ELISA) and Aspergillus PCR-based methods may overcome these limitations, but their impact on patient outcomes should be evaluated in a diagnostic randomized controlled trial (D-RCT). This article describes the methodology of a D-RCT which compares a new pre-emptive strategy (GM-ELISA- and Aspergillus PCR-driven antifungal therapy) with the standard fever-driven empiric antifungal treatment strategy. Issues including primary end-point and patient selection, duration of screening, choice of tests for the pre-emptive strategy, antifungal prophylaxis and bias control, which were considered in the design of the trial, are discussed. We suggest that the template presented herein is considered by researchers when evaluating the utility of new diagnostic tests (ClinicalTrials.gov number, NCT00163722).

Whole-genome characterization and genotyping of global WU polyomavirus strains.

Exploration of the genetic diversity of WU polyomavirus (WUV) has been limited in terms of the specimen numbers and particularly the sizes of the genomic fragments analyzed. Using whole-genome sequencing of 48 WUV strains collected in four continents over a 5-year period and 16 publicly available whole-genome sequences, we identified three main WUV clades and five subtypes, provisionally termed Ia, Ib, Ic, II, IIIa, and IIIb. Overall nucleotide variation was low (0 to 1.2%). The discriminatory power of the previous VP2 fragment typing method was found to be limited, and a new, larger genotyping region within the VP2/1 interface was proposed.

Parainfluenza virus type 3 pneumonia in bone marrow transplant recipients: multiple small nodules in high- resolution lung computed tomography scans provide a radiological clue to diagnosis.

We report the findings of high-resolution chest computed tomography of 6 hematopoietic stem cell transplant recipients with parainfluenza virus type 3 pneumonia who were not infected with any other pathogens. All patients had multiple small nodules (diameter, !5 mm) without cavitation ina peribronchial distribution. Changes preceded microbiological diagnosis in 4 of 6 cases.