title: Salvage combination antifungal therapy for acute invasive aspergillosis may improve outcomes: a systematic review and meta-analysis.
abstract: OBJECTIVE
  A meta-analysis was performed to compare mold-active triazoles or lipid amphotericin B plus an echinocandin to non-echinocandin monotherapy for acute invasive aspergillosis (IA).
  
  
  METHODS
  We searched PubMed, EMBASE, and other databases through May 2013 unrestricted by language. We included observational and experimental studies wherein patients with proven or probable IA by EORTC/MSG criteria underwent our comparative intervention. PRISMA and MOOSE guidelines were followed and quality was assessed using the Jadad and Newcastle-Ottawa criteria. Meta-regression with fixed and random effects and sensitivity analyses were performed. The primary study outcome measure was 12-week overall mortality. The secondary outcome assessed was complete and partial response.
  
  
  RESULTS
  Only observational studies of primary 12-week survival showed heterogeneity (I(2)=48.96%, p=0.05). For salvage IA therapy, fixed effects models demonstrated improved 12-week survival (Peto odds ratio (OR) 1.80, 95% confidence interval (CI) 1.08-3.01) and success (Peto OR 2.17, 95% CI 1.21-3.91) of combination therapy. Significance remained after applying random effects as a sensitivity analysis (12-week survival: Peto OR 1.90, 95% CI 1.04-3.46, and unchanged value for success). Restriction to high quality studies and including echinocandins as the comparator for refractory IA revealed an adjusted OR of 1.72 (95% CI 0.96-3.09; p=0.07) for global success, while the survival endpoint remained unaltered.
  
  
  CONCLUSIONS
  Combination antifungals for IA demonstrate improved outcomes over monotherapy in the salvage setting. Clinicians should consider this approach in certain situations.
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Clinical Research Center, Building 10, Room 11N222, 10 Center Drive, Bethesda, MD 20892, MSC 1888, USA; Division of Infectious Diseases, Department of Medicine, F. Hèbert School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USA. Electronic address: anil.panackal@nih.gov.
authors.forename: Anil A
authors.initials: AA
authors.lastname: Panackal
authors.affiliation: Center for Nano Science and Technology, Politecnico di Milano, Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Parisini
authors.affiliation: Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Proschan
mesh_terms: D000666:Amphotericin B / Q000627:therapeutic use; D000935:Antifungal Agents / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy* / Q000401:mortality; D004359:Drug Therapy, Combination; D054714:Echinocandins / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016879:Salvage Therapy; D016019:Survival Analysis; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D014230:Triazoles; D000666:Amphotericin B
keywords: Combination antifungal therapy; Invasive aspergillosis; Outcomes; Salvage therapy