title: Meta-Analysis and Cost Comparison of Empirical versus Pre-Emptive Antifungal Strategies in Hematologic Malignancy Patients with High-Risk Febrile Neutropenia.
abstract: BACKGROUND
  Invasive fungal disease (IFD) causes significant morbidity and mortality in hematologic malignancy patients with high-risk febrile neutropenia (FN). These patients therefore often receive empirical antifungal therapy. Diagnostic test-guided pre-emptive antifungal therapy has been evaluated as an alternative treatment strategy in these patients.
  
  
  METHODS
  We conducted an electronic search for literature comparing empirical versus pre-emptive antifungal strategies in FN among adult hematologic malignancy patients. We systematically reviewed 9 studies, including randomized-controlled trials, cohort studies, and feasibility studies. Random and fixed-effect models were used to generate pooled relative risk estimates of IFD detection, IFD-related mortality, overall mortality, and rates and duration of antifungal therapy. Heterogeneity was measured via Cochran's Q test, I2 statistic, and between study τ2. Incorporating these parameters and direct costs of drugs and diagnostic testing, we constructed a comparative costing model for the two strategies. We conducted probabilistic sensitivity analysis on pooled estimates and one-way sensitivity analyses on other key parameters with uncertain estimates.
  
  
  RESULTS
  Nine published studies met inclusion criteria. Compared to empirical antifungal therapy, pre-emptive strategies were associated with significantly lower antifungal exposure (RR 0.48, 95% CI 0.27-0.85) and duration without an increase in IFD-related mortality (RR 0.82, 95% CI 0.36-1.87) or overall mortality (RR 0.95, 95% CI 0.46-1.99). The pre-emptive strategy cost $324 less (95% credible interval -$291.88 to $418.65 pre-emptive compared to empirical) than the empirical approach per FN episode. However, the cost difference was influenced by relatively small changes in costs of antifungal therapy and diagnostic testing.
  
  
  CONCLUSIONS
  Compared to empirical antifungal therapy, pre-emptive antifungal therapy in patients with high-risk FN may decrease antifungal use without increasing mortality. We demonstrate a state of economic equipoise between empirical and diagnostic-directed pre-emptive antifungal treatment strategies, influenced by small changes in cost of antifungal therapy and diagnostic testing, in the current literature. This work emphasizes the need for optimization of existing fungal diagnostic strategies, development of more efficient diagnostic strategies, and less toxic and more cost-effective antifungals.
authors.affiliation: Beth Israel Deaconess Medical Center, Department of Internal Medicine, Boston, Massachusetts, United States of America.|Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Monica
authors.initials: M
authors.lastname: Fung
authors.affiliation: Harvard T.H. Chan School of Public Health, Department of Health Policy and Management, Boston, Massachusetts, United States of America.
authors.forename: Jane
authors.initials: J
authors.lastname: Kim
authors.affiliation: Harvard Medical School, Boston, Massachusetts, United States of America.|Brigham and Women's Hospital, Division of Infectious Diseases, Boston, Massachusetts, United States of America.|Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Marty
authors.affiliation: Translational Health Economics Network, Paris, France.|Decision Sciences in Infectious Disease: Prevention, Control, and Care, INSERM, IAME, Paris, France.|Université Paris Diderot, IAME, Paris, France.
authors.forename: Michaël
authors.initials: M
authors.lastname: Schwarzinger
authors.affiliation: Harvard Medical School, Boston, Massachusetts, United States of America.|Brigham and Women's Hospital, Division of Infectious Diseases, Boston, Massachusetts, United States of America.|Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Sophia
authors.initials: S
authors.lastname: Koo
mesh_terms: D000935:Antifungal Agents / Q000008:administration & dosage / Q000191:economics / Q000627:therapeutic use*; D064146:Chemotherapy-Induced Febrile Neutropenia / Q000150:complications* / Q000276:immunology; D003362:Cost-Benefit Analysis; D003365:Costs and Cost Analysis; D003663:Decision Trees; D003955:Diagnostic Tests, Routine / Q000191:economics; D004334:Drug Administration Schedule; D016527:Drug Costs; D042241:Early Diagnosis; D016021:Epidemiologic Studies; D005240:Feasibility Studies; D005690:Galactose / Q000031:analogs & derivatives; D017048:Health Care Costs; D019337:Hematologic Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000276:immunology; D006801:Humans; D016867:Immunocompromised Host; D008172:Lung Diseases, Fungal / Q000175:diagnosis / Q000188:drug therapy / Q000191:economics / Q000209:etiology; D008351:Mannans / Q000097:blood*; D009181:Mycoses / Q000175:diagnosis / Q000188:drug therapy / Q000191:economics / Q000209:etiology / Q000517:prevention & control*; D009894:Opportunistic Infections / Q000175:diagnosis / Q000188:drug therapy / Q000191:economics / Q000209:etiology / Q000517:prevention & control*; D016032:Randomized Controlled Trials as Topic
chemical_list: D000935:Antifungal Agents; D008351:Mannans; C012990:galactomannan; D005690:Galactose