galactomannan and Chemotherapy-Induced-Febrile-Neutropenia

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.. 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.. 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.. 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.

Topics: Antifungal Agents; Chemotherapy-Induced Febrile Neutropenia; Cost-Benefit Analysis; Costs and Cost Analysis; Decision Trees; Diagnostic Tests, Routine; Drug Administration Schedule; Drug Costs; Early Diagnosis; Epidemiologic Studies; Feasibility Studies; Galactose; Health Care Costs; Hematologic Neoplasms; Humans; Immunocompromised Host; Lung Diseases, Fungal; Mannans; Mycoses; Opportunistic Infections; Randomized Controlled Trials as Topic

Invasive fungal disease is a major cause of morbidity and mortality in children with cancer and high-risk febrile neutropenia (HRFN). Repeated serum galactomannan (sGM) measurements have been described as an effective tool to guide therapy in adults under suspicion of invasive aspergillosis. However, the utility of this approach has not been reported in paediatric population.. To evaluate the usefulness of sGM measurements in initiating and modifying antifungal therapy (AFT) in children with cancer and persistent HRFN.. Nested case-control study in children with cancer and persistent HRFN episodes, between July 2013 and January 2019. Patients were classified as cases and controls depending on if they received AFT or not, respectively. Through odds ratio analysis, we assessed the role of sGM positivity in the AFT initiation decision. Then, we analysed the group of patients that initiated AFT, and compared those who had AFT modifications and those who did not, analysing different sGM kinetics thresholds.. A total of 191 episodes from children with persistent HRFN were enrolled, of which 107 received AFT and 84 did not. The median age was 7 years (IQR 4-12), 52% were male and 89% had a haematologic malignancy as underlying disease. Positive sGM was not associated with AFT initiation (OR 0.99, 95% CI 0.43-2.33, P = .99). A difference threshold in sGM Δ ≥ 0.3 sGM was significantly associated with AFT modification (OR 5.07, 95% CI 1.02- 25.70, P = .04).. Our results suggest the utility of serial sGM sampling during AFT in children with persistent HRFN.

Topics: Antifungal Agents; Aspergillosis; Case-Control Studies; Chemotherapy-Induced Febrile Neutropenia; Child; Female; Galactose; Hematologic Neoplasms; Humans; Invasive Fungal Infections; Invasive Pulmonary Aspergillosis; Male; Mannans; Neoplasms

Invasive aspergillosis is a major concern in neutropenic patients. We studied the utility of Galactomannan antigen detection test in serum using ELISA technique for early detection of invasive aspergillosis. Diagnostic accuracy of Galactomannan index (GMI) test was maximum at a cut-off of > 1.5 with a negative predictive value of more than 95%.

Topics: Aspergillosis; Chemotherapy-Induced Febrile Neutropenia; Child; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Galactose; Humans; Immunocompromised Host; Mannans; ROC Curve

The performance of serum biomarkers for the early detection of invasive aspergillosis expectedly depends on the timing of test results relative to the empirical administration of antifungal therapy during neutropenia, although a dynamic evaluation framework is lacking.. We developed a multi-state model describing simultaneously the likelihood of empirical antifungal therapy and the risk of invasive aspergillosis during neutropenia. We evaluated whether the first positive test result with a biomarker is an independent predictor of invasive aspergillosis when both diagnostic information used to treat and risk factors of developing invasive aspergillosis are taken into account over time. We applied the multi-state model to a homogeneous cohort of 185 high-risk patients with acute myeloid leukemia. Patients were prospectively screened for galactomannan antigenemia twice a week for immediate treatment decision; 2,214 serum samples were collected on the same days and blindly assessed for (1->3)- β-D-glucan antigenemia and a quantitative PCR assay targeting a mitochondrial locus.. The usual evaluation framework of biomarker performance was unable to distinguish clinical benefits of β-glucan or PCR assays. The multi-state model evidenced that the risk of invasive aspergillosis is a complex time function of neutropenia duration and risk management. The quantitative PCR assay accelerated the early detection of invasive aspergillosis (P = .010), independently of other diagnostic information used to treat, while β-glucan assay did not (P = .53).. The performance of serum biomarkers for the early detection of invasive aspergillosis is better apprehended by the evaluation of time-varying predictors in a multi-state model. Our results provide strong rationale for prospective studies testing a preemptive antifungal therapy, guided by clinical, radiological, and bi-weekly blood screening with galactomannan antigenemia and a standardized quantitative PCR assay.

Topics: Adult; Aged; Antifungal Agents; Antigens, Fungal; Antineoplastic Agents; beta-Glucans; Biomarkers; Chemotherapy-Induced Febrile Neutropenia; DNA, Fungal; Early Diagnosis; Female; Fungal Polysaccharides; Galactose; Genes, Fungal; Humans; Invasive Pulmonary Aspergillosis; Leukemia, Myeloid, Acute; Male; Mannans; Markov Chains; Middle Aged; Models, Biological; Prospective Studies; Randomized Controlled Trials as Topic; Real-Time Polymerase Chain Reaction