title: 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.
abstract: 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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Australian National Health and Medical Research Council, Cancer Council New South Wales, Pfizer, Merck, Gilead Sciences.
authors: Infectious Diseases Unit, Alfred Health, and Department of Infectious Diseases, Central Clinical School, Monash University, Melbourne, VIC, Australia. o.morrissey@alfred.org.au
authors: C Orla
authors: CO
authors: Morrissey
authors: Sharon C-A
authors: SC
authors: Chen
authors: Tania C
authors: TC
authors: Sorrell
authors: Samuel
authors: S
authors: Milliken
authors: Peter G
authors: PG
authors: Bardy
authors: Kenneth F
authors: KF
authors: Bradstock
authors: Jeffrey
authors: J
authors: Szer
authors: Catriona L
authors: CL
authors: Halliday
authors: Nicole M
authors: NM
authors: Gilroy
authors: John
authors: J
authors: Moore
authors: Anthony P
authors: AP
authors: Schwarer
authors: Stephen
authors: S
authors: Guy
authors: Ashish
authors: A
authors: Bajel
authors: Adrian R
authors: AR
authors: Tramontana
authors: Timothy
authors: T
authors: Spelman
authors: Monica A
authors: MA
authors: Slavin
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000627:therapeutic use*; D001228:Aspergillosis / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D001230:Aspergillus / Q000302:isolation & purification* / Q000472:pathogenicity; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D005690:Galactose / Q000031:analogs & derivatives; D006801:Humans; D007945:Leukemia, Lymphoid / Q000188:drug therapy / Q000382:microbiology* / Q000601:surgery; D008297:Male; D008351:Mannans / Q000378:metabolism*; D008875:Middle Aged; D016133:Polymerase Chain Reaction / Q000379:methods*; D033581:Stem Cell Transplantation; D014184:Transplantation, Homologous
chemical_list: D000935:Antifungal Agents; D015415:Biomarkers; D008351:Mannans; C012990:galactomannan; D005690:Galactose