patients with a hematological malignancy are generally considered as being susceptible to fungal infections , which leads to development of invasive fungal disease ( ifd ) caused by filamentous fungi . many predisposing or risk factors has been described for the development of ifd , such as intensity and duration of neutropenia , diagnosis of acute leukemia , and severe impairment of lymphocytic activity . currently , empirical antifungal therapy is the classical and standard of the care method for ifd in hematological patients . generally , the use of antifungal drugs is initiated once clinical evidence of fungal infection is observed . empirical antifungal therapy is frequently recommended for patients with high or medium risk of ifd , such as those with fever for more than 3 days after broad - spectrum antimicrobial therapy . however , empirical antifungal therapy has a low specificity and certain limitations , such as over - treatment of the patients , drug resistance induction , and higher medical expenses . the concept of preemptive antifungal therapy was recently introduced for ifd therapy in hematological malignancy patients . briefly , preemptive antifungal therapy is a diagnosis - based therapy that uses antifungals based on the diagnosis of probable fungal infection by results from microbiological tests ( e.g. , gm testing ) or chest computed tomography ( ct ) . preemptive antifungal therapy is intended to provide antifungal therapy to early - stage patients to achieve anticipated effects and reduce the overuse of antifungal agents . a controlled trial systematically comparing empirical vs. preemptive antifungal therapy for high - risk , febrile , neutropenic patients concluded that although preemptive treatment increased the incidence of invasive fungal disease , it did not increase the overall mortality in patients and it reduced the expenses related to antifungal drugs used . however , because this strategy depends on galactomannan testing ( gm test ) and chest ct , preemptive antifungal therapy has certain disadvantages , such as the delayed initiation of antifungal treatment , and the low sensitivity of galactomannan testing for some aspergillus fumigatus - infected patients . in addition , the image markers from chest ct ( halo sign or reverse halo sign ) are not specific and may be observed in many infectious and non - infectious diseases rather than fungal infection . therefore , some researchers still view empirical antifungal therapy as a more validated treatment of ifd in patients with hematological malignancy . recently , the cdc of china issued a revised guideline of the diagnosis criteria and treatment regulation of hematological malignancy patients with invasive fungal disease ( the forth revised edition ) . in this guideline , we designed this study to evaluate the benefits of preemptive antifungal therapy for chinese patients . institutional ethics board approval was obtained from the medical ethics committee of the second hospital of hebei medical university . all participating patients were formally informed of the purpose of this study and written informed consent was obtained from all participants . we enrolled 268 patients with hematological malignancy admitted to the department of hematology in the second hospital of hebei medical university from october 2013 to december 2014 . all patients were subjected to cytomorphology , histological chemistry and biopsy of bone marrow , subtyping by flow cytometry , detection of fusion gene , and chromosome examination to confirm the occurrence of hematological malignancy . the ifd diagnosis criteria and standard of therapeutic effect were referenced to the diagnosis criteria and treatment regulation of hematological malignancy patients with invasive fungal disease ( forth revised edition ) . all patients were randomly assigned to either the empirical antifungal therapy group ( n=138 ) or the preemptive antifungal therapy group ( n=130 ) . all patients included in this study met the following criteria : older than 18 years , had hematological malignancy , had a plan of chemotherapy treatment , and had severe neutropenia ( less than 0.5 10 neutrophils / l for a minimum duration of 10 days ) . patients with any of the following situations were excluded : had received hematopoietic stem cell transplantation , had experience or symptoms of ifd , demonstrated low tolerance to triazoles , hiv - positive , and karnofsky performance status score less than 30 according to the accepted scale system . moreover , patients were excluded if they had no neutropenia or fever , were treated with antifungal therapy within 4 days of developing a fever , started antifungal therapy without proof of ifd at 414 days , or had no antifungal treatment but had proof of ifd at 414 days . briefly , 2 blood cultures , 1 urine culture , and related microbiological analysis were conducted for all patients . patients received broad - spectrum -lactam antibiotic with or without combination of aminoglycosides according to clinical manifestation . glycopeptides antibiotics were administrated immediately if the following symptoms occurred : infectious shock , stage iv mucositis according to who diagnostic criteria , colonization of infection caused by methicillin - resistant staphylococcus aureus or streptococcus pneumoniae , or catheter - related infections . glycopeptide antibiotics were added if the fever persisted for 48 h after administration of broad - spectrum -lactam antibiotic . for the empirical treatment group , antifungal therapy was started within 4 days of start of persistent fever and antibacterial treatment . if there was recurrent fever between day 4 and day 14 , antifungal therapy was initiated on the day of the recurrence . for the preemptive treatment group , antifungal therapy was initiated immediately if any of the flowing situations occurred : clinical or imaging examination suggested pneumonia , acute sinusitis , stage iii mucositis , or most importantly , infectious shock , ifd - related skin damage , central nerve system symptoms due to unknown reason , periorbital inflammation , abscess of liver or spleen , severely diarrhea , colonization by aspergilloma , or ( 1,3)--d - glucan test ( g test)-positive and galactomannan test ( gm test)-positive . the antifungal therapy was continued until patients recovered from febrile neutropenia . if a patients had fever after 14 days , the chief physician decided if additional treatment should be administered . the therapeutic effect was tested by g testing and gm testing twice a week until patients recovered from febrile neutropenia . voriconazole was used as the first - line treatment for patients in every 12 h via i.v . the initiating injection dose of voriconazole was 400 mg , then the dose was decreased to 200 mg for subsequent injections . the chief physician decided if the treatment was ineffective or if an adverse effect occurred . the end - point for the antifungal treatment was patient recovery from febrile neutropenia or when a patient quit treatment due to any reason . the survival rate of patients who recovered from neutropenia by day 14 was set as the primary end - point . patients with severe neutropenic within a maximum of 60 days after receiving treatment or who demonstrated severe adverse events were excluded from data analysis . the ratio of diagnosed ifd patients and duration of persistent fever were used as the secondary end - points . the safety of the treatment was demonstrated as the rate of patients quitting treatment due to ineffectiveness or adverse events during the treatment . the indicators of cost - effectiveness were the ratio of patients who received antifungal therapy , duration and expenses of antifungal therapy , and patient hospitalization . the data analysis was conducted by use of spss ( release 17.0 , spss , inc . , institutional ethics board approval was obtained from the medical ethics committee of the second hospital of hebei medical university . all participating patients were formally informed of the purpose of this study and written informed consent was obtained from all participants . we enrolled 268 patients with hematological malignancy admitted to the department of hematology in the second hospital of hebei medical university from october 2013 to december 2014 . all patients were subjected to cytomorphology , histological chemistry and biopsy of bone marrow , subtyping by flow cytometry , detection of fusion gene , and chromosome examination to confirm the occurrence of hematological malignancy . the ifd diagnosis criteria and standard of therapeutic effect were referenced to the diagnosis criteria and treatment regulation of hematological malignancy patients with invasive fungal disease ( forth revised edition ) . all patients were randomly assigned to either the empirical antifungal therapy group ( n=138 ) or the preemptive antifungal therapy group ( n=130 ) . all patients included in this study met the following criteria : older than 18 years , had hematological malignancy , had a plan of chemotherapy treatment , and had severe neutropenia ( less than 0.5 10 patients with any of the following situations were excluded : had received hematopoietic stem cell transplantation , had experience or symptoms of ifd , demonstrated low tolerance to triazoles , hiv - positive , and karnofsky performance status score less than 30 according to the accepted scale system . moreover , patients were excluded if they had no neutropenia or fever , were treated with antifungal therapy within 4 days of developing a fever , started antifungal therapy without proof of ifd at 414 days , or had no antifungal treatment but had proof of ifd at 414 days . briefly , 2 blood cultures , 1 urine culture , and related microbiological analysis were conducted for all patients . patients received broad - spectrum -lactam antibiotic with or without combination of aminoglycosides according to clinical manifestation . glycopeptides antibiotics were administrated immediately if the following symptoms occurred : infectious shock , stage iv mucositis according to who diagnostic criteria , colonization of infection caused by methicillin - resistant staphylococcus aureus or streptococcus pneumoniae , or catheter - related infections . glycopeptide antibiotics were added if the fever persisted for 48 h after administration of broad - spectrum -lactam antibiotic . for the empirical treatment group , antifungal therapy was started within 4 days of start of persistent fever and antibacterial treatment . if there was recurrent fever between day 4 and day 14 , antifungal therapy was initiated on the day of the recurrence . for the preemptive treatment group , antifungal therapy was initiated immediately if any of the flowing situations occurred : clinical or imaging examination suggested pneumonia , acute sinusitis , stage iii mucositis , or most importantly , infectious shock , ifd - related skin damage , central nerve system symptoms due to unknown reason , periorbital inflammation , abscess of liver or spleen , severely diarrhea , colonization by aspergilloma , or ( 1,3)--d - glucan test ( g test)-positive and galactomannan test ( gm test)-positive . the antifungal therapy was continued until patients recovered from febrile neutropenia . if a patients had fever after 14 days , the chief physician decided if additional treatment should be administered . the therapeutic effect was tested by g testing and gm testing twice a week until patients recovered from febrile neutropenia . voriconazole was used as the first - line treatment for patients in every 12 h via i.v . the initiating injection dose of voriconazole was 400 mg , then the dose was decreased to 200 mg for subsequent injections . the chief physician decided if the treatment was ineffective or if an adverse effect occurred . the end - point for the antifungal treatment was patient recovery from febrile neutropenia or when a patient quit treatment due to any reason . the survival rate of patients who recovered from neutropenia by day 14 was set as the primary end - point . patients with severe neutropenic within a maximum of 60 days after receiving treatment or who demonstrated severe adverse events were excluded from data analysis . the ratio of diagnosed ifd patients and duration of persistent fever were used as the secondary end - points . the safety of the treatment was demonstrated as the rate of patients quitting treatment due to ineffectiveness or adverse events during the treatment . the indicators of cost - effectiveness were the ratio of patients who received antifungal therapy , duration and expenses of antifungal therapy , and patient hospitalization . the data analysis was conducted by use of spss ( release 17.0 , spss , inc . , there were 138 patients ( 86 males and 52 females ) in the empirical group and 130 patients ( 75 males and 55 females ) in the preemptive group . the median duration of neutropenia for all patients from both groups was 13 days , with no significant difference observed between groups . the median age for patients in the empirical group was 38 years ( ranging from 18 to 77 years ) and the median age for the preemptive group was 38 years ( ranging from 18 to 81 years ) . table 1 shows the cases of acute myeloid leukemia ( aml ) , acute lymphoblastic leukemia ( all ) , mixed - lineage acute leukemia ( mal ) , and multiple myeloma ( mm ) among all patients . the phase of chemotherapy ( induction , relapse and consolidation ) , application of antifungal prophylaxis for patients , intensity and duration of neutropenia , and duration of fever are documented in table 1 . the overall survival rate for patients in the preemptive group was 94.6% compared with 97.1% in the empirical group ( p=0.305 ) , suggesting the survival rate was similar ( table 2 ) . there were 11 deaths recorded , including 4 ifd patients ( 1 in the empirical group and 3 in the preemptive group ) , 4 patients with bacterial septicemia , 2 with unclear septicemia , and 1 with cardiogenic shock . the ifd - associated death rates were 0.7% and 2.3% for the empirical and preemptive group ( p=0.573 ) , receptively , but this difference was not significant ( table 2 ) . ifd was observed in 12 ( 9.2% ) patients in the preemptive group , which was significantly higher than the 3 ( 2.2% ) cases in the empirical group ( table 2 ) . moreover , out of these 12 ifd cases in the preemptive group , 8 were pulmonary aspergillosis ( including 6 cases of baseline ifd and 2 cases of breakthrough ifd ) and the rest were candidiasis ( including 2 cases of baseline ifd and 2 cases of breakthrough ifd ) . among these 4 cases of candidiasis , there were 2 cases of candida albicans , 1 case of candida tropicalis , and 1 case of candida glabrata . for ifd cases in the empirical group , only 2 cases of baseline ifd and 1 case of breakthrough ifd were observed ( table 2 ) . according our data , application of antifungal therapy ( 26 cases , 20% , p<0.001 ) in the preemptive group was significantly lower than in the empirical group ( 43 cases , 31.2% ) ( table 3 ) , which is consisted with previous observation . among 26 cases in the preemptive group , 2 had persistent or recurrent fever ; and the other 24 cases were clinical manifestations - positive or non - invasive diagnosis - positive , including 13 cases of pneumonia , 2 cases of severe mucositis , 3 cases of g test - positive , 3 cases of gm test - positive , 2 cases of sinusitis , and 1 case of diarrhea . in the empirical group , 25 cases had persistent or recurrent fever between day 4 and day 14 after antibacterial treatment initiation ( table 3 ) . the other cases were 13 cases of pneumonia , 2 cases of severely mucositis , 2 cases of g test - positive , and 1 case of gm test - positive ( table 3 ) . the average time of antifungal therapy for the empirical and preemptive groups were 20.04.7 days and 13.84.7 , respectively , which is statistically significant ( table 3 ) . the cost for each group was calculated and compared using the chinese currency , renminbi ( rmb ) . the average expense of antifungal therapy for empirical and preemptive groups was rmb 12 1043719 and rmb 83792253 , respectively . length of hospital stay was similar between the 2 groups of patients ( table 3 ) . moreover , 6 patients in the empirical group and 5 patients in the preemptive group demonstrated inefficacious voriconazole treatment . two patients in the empirical group and 1 patient in the preemptive group quit treatment due to adverse reactions to voriconazole . there were 138 patients ( 86 males and 52 females ) in the empirical group and 130 patients ( 75 males and 55 females ) in the preemptive group . the median duration of neutropenia for all patients from both groups was 13 days , with no significant difference observed between groups . the median age for patients in the empirical group was 38 years ( ranging from 18 to 77 years ) and the median age for the preemptive group was 38 years ( ranging from 18 to 81 years ) . table 1 shows the cases of acute myeloid leukemia ( aml ) , acute lymphoblastic leukemia ( all ) , mixed - lineage acute leukemia ( mal ) , and multiple myeloma ( mm ) among all patients . the phase of chemotherapy ( induction , relapse and consolidation ) , application of antifungal prophylaxis for patients , intensity and duration of neutropenia , and duration of fever are documented in table 1 . the overall survival rate for patients in the preemptive group was 94.6% compared with 97.1% in the empirical group ( p=0.305 ) , suggesting the survival rate was similar ( table 2 ) . there were 11 deaths recorded , including 4 ifd patients ( 1 in the empirical group and 3 in the preemptive group ) , 4 patients with bacterial septicemia , 2 with unclear septicemia , and 1 with cardiogenic shock . the ifd - associated death rates were 0.7% and 2.3% for the empirical and preemptive group ( p=0.573 ) , receptively , but this difference was not significant ( table 2 ) . ifd was observed in 12 ( 9.2% ) patients in the preemptive group , which was significantly higher than the 3 ( 2.2% ) cases in the empirical group ( table 2 ) . moreover , out of these 12 ifd cases in the preemptive group , 8 were pulmonary aspergillosis ( including 6 cases of baseline ifd and 2 cases of breakthrough ifd ) and the rest were candidiasis ( including 2 cases of baseline ifd and 2 cases of breakthrough ifd ) . among these 4 cases of candidiasis , there were 2 cases of candida albicans , 1 case of candida tropicalis , and 1 case of candida glabrata . for ifd cases in the empirical group , only 2 cases of baseline ifd and 1 case of breakthrough ifd were observed ( table 2 ) . according our data , application of antifungal therapy ( 26 cases , 20% , p<0.001 ) in the preemptive group was significantly lower than in the empirical group ( 43 cases , 31.2% ) ( table 3 ) , which is consisted with previous observation . among 26 cases in the preemptive group , 2 had persistent or recurrent fever ; and the other 24 cases were clinical manifestations - positive or non - invasive diagnosis - positive , including 13 cases of pneumonia , 2 cases of severe mucositis , 3 cases of g test - positive , 3 cases of gm test - positive , 2 cases of sinusitis , and 1 case of diarrhea . in the empirical group , 25 cases had persistent or recurrent fever between day 4 and day 14 after antibacterial treatment initiation ( table 3 ) . the other cases were 13 cases of pneumonia , 2 cases of severely mucositis , 2 cases of g test - positive , and 1 case of gm test - positive ( table 3 ) . the average time of antifungal therapy for the empirical and preemptive groups were 20.04.7 days and 13.84.7 , respectively , which is statistically significant ( table 3 ) . the cost for each group was calculated and compared using the chinese currency , renminbi ( rmb ) . the average expense of antifungal therapy for empirical and preemptive groups was rmb 12 1043719 and rmb 83792253 , respectively . length of hospital stay was similar between the 2 groups of patients ( table 3 ) . moreover , 6 patients in the empirical group and 5 patients in the preemptive group demonstrated inefficacious voriconazole treatment . two patients in the empirical group and 1 patient in the preemptive group quit treatment due to adverse reactions to voriconazole . empirical antifungal therapy is a commonly used strategy to treat hematological disease for reducing mortality of ifd patients . however , the effectiveness of this strategy is still controversial due to lack of reliable data . generally , empirical antifungal therapy is initiated if persistent fever or recurrent fever is observed in patients and is terminated at disappearance of fever [ 8,1922 ] . however , it is questionable to set the appearance and disappearance of fever as the initiation and termination point of antifungal therapy , since fever is not a specific symptom of ifd [ 18,2325 ] . moreover , application of empirical antifungal therapy may result certain disadvantages , such as over - treatment or higher expense . however , since more diagnostic technologies , such as g test , gm test , chest ct , and polymerase chain reaction ( pcr ) , are now used for early detection of ifd , it is possible to determine more precise initiating points for antifungal treatment . therefore , diagnosis - based preemptive antifungal therapy has become an alternative strategy which allows patients receiving antifungal treatment as early as possible to achieve a better outcome and decrease overuse of antifungal drugs . however , preemptive therapy is not recommended as standard care due to the insensitivity and un - specificity of diagnostic tools , and the initiating point of treatment is not yet well defined . segal et al . suggested that the initiation of antifungal therapy in febrile neutropenic patients could be determined by chest ct and experimental examinations . in our study , antifungal therapy was recommended only to those patients who had clinical manifestations , even with normal results of g testing , gm testing , and chest ct . according to previously reports , analysis conducted by pooling the results of published randomized trials of empirical treatment with polyenes demonstrated the expected survival rate of empirical therapy was 1677 of 1846 ( 90.8% ; 95% ci , 89.592.2% ) . the same reports also suggested that a noninferiority margin of 8% was chosen on the basis of guidelines issued by the center for drug evaluation and research and the committee for proprietary medicinal products , and the use of a 10% non - inferiority margin for evaluation of new antibacterials whose expected success rate is 90% . in the preemptive group of our study , only 26 ( 18.6% ) of the intent - to - treat cases received antifungal therapy , and the overall survival rate was 94.6% , which is similar to previous reports of the survival rate in empirical therapy . therefore , application of preemptive therapy did not increase the mortality of the intent - to - treat group in a chinese population , and is consistent with previous reports from western countries . the survival rates of the preemptive and empirical groups were similar in our study , and we also noticed that the incidence of ifd cases was significantly higher ( 12 cases , 9.2% ) in the preemptive group than in the empirical group ( 3 cases , 2.3% ) . a previous report evaluated the feasibility of preemptive therapy based on clinical symptoms , galactomannan antigenemia ( cut - off for antigen level , 0.5 ng / ml ) , lung ct , and bronchoalveolar lavage . the data indicated that fewer patients meet criteria for preemptive treatment than empirical treatment , which is consistent with our observations . however , due to it open design , this report could not determine whether preemptive treatment was non - inferior to empirical treatment . in another trial , the incident rate of ifd cases was also higher in the preemptive group than in the empirical group ( 9.1% vs. 2.7%)4 . taken together , these findings may suggest that the low ifd incidence rate may reflect the lower positive predictive value of diagnostic investigations when the incidence of ifd is low . therefore , the fact that more patients in the empirical group received antifungal treatment may have decreased the incidence rate of ifd but conferred little benefit to overall survival rate . we also noticed that the ifd - related deaths in the preemptive mainly occurred in elderly patients or patients whose performance score ( ps ) was higher than 2 ( data not shown ) . this observation suggests that empirical therapy may be preferable for elderly or high ps patients to avoid ifd - related death , while preemptive treatment is recommended for younger or low ps patients . the average durations of antifungal therapy for empirical and preemptive groups were 20.04.7 days and 13.84.7 days , respectively . moreover , the average expense for preemptive antifungal treatment was 8379.002253.00 cny in this study . although this result was not concluded by a completely randomized analysis , the duration and expense for antifungal therapy was significantly lower in the preemptive group . in china , due to the large population and relatively scarce hospitals , treatments with lower costs and shorter regimens we found voriconazole was well tolerated , and only 2 patients in the empirical group and 1 in the preemptive groups quit treatment . our data demonstrate that the preemptive antifungal therapy did not increase the ifd mortality compared to empirical therapy in patients with febrile neutropenic hematological malignancy , but preemptive antifungal therapy is an economically preferable medical practice in china . however , the increased incidence of ifd in the preemptive antifungal therapy group also suggest that the age and ps score of patients were factors for selecting the strategy . moreover , to apply the preemptive strategy more accurately , clinical manifestations , physical signs , and more diagnostic methods ( e.g. , different imaging technics , biological markers , or pcr ) have to be carefully assessed to achieve more effective preventive antifungal therapy .
backgroundthe aim of this study was to evaluate the efficiency , adverse effects , and pharmacoeconomic impact of empirical and preemptive antifungal therapy for febrile neutropenic hematological malignancy patients in china.material/methodspatients with febrile neutropenia during hematological malignancy were randomly divided into an empirical group and a preemptive group . 
 the preemptive antifungal treatment was initiated if patient status was confirmed by clinical manifestation , imaging diagnosis , 1 - 3--d glucan(g ) testing , and galactomannan ( gm ) test . 
 the treatment was ended 2 weeks later if the patient was recovered from neutropenia . 
 voriconazole was used as the first - line medicine . 
 all patients received intravenous administration of voriconazole every 12 h , with an initiating dose of 400 mg , then the dose was reduced to 200 mg.resultsthe overall survival rate was 97.1% and 94.6% in the empirical group and preemptive group , respectively , with no significant difference observed ( 2=1.051 , p=0.305 ) . 
 however , the occurrence rate of invasive fungal disease ( ifd ) in the preemptive group was 9.2% vs. 2.2% in the empirical group . 
 moreover , the mortality rate due to ifd was 0.7% and 2.3% for the empirical group and preemptive group , respectively . 
 the average duration and cost of preemptive antifungal therapy were 13.84.7 days and 8379.002253.00 rmb , respectively , which were lower than for empirical therapy . 
 however , no significant differences were observed for incidence of adverse effects and hospital stay between the 2 groups.conclusionspreemptive antifungal therapy for patients with febrile neutropenic hematological malignancy demonstrated a similar survival rate as with empirical therapy but is economically favorable in a chinese population .