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Efficacy of pre-emptive versus empirical antifungal therapy in children with cancer and high-risk febrile neutropenia: a randomized clinical trial

Efficacy of pre-emptive versus empirical antifungal therapy in children with cancer and high-risk... Abstract Objectives To compare the efficacy of pre-emptive versus empirical antifungal therapy in children with cancer, fever and neutropenia. Methods This was a prospective, multicentre, randomized clinical trial. Children presenting with persistent high-risk febrile neutropenia at five hospitals in Santiago, Chile, were randomized to empirical or pre-emptive antifungal therapy. The pre-emptive group received antifungal therapy only if the persistent high-risk febrile neutropenia was accompanied by clinical, laboratory, imaging or microbiological pre-defined criteria. The primary endpoint was overall mortality at day 30 of follow-up. Secondary endpoints included invasive fungal disease (IFD)-related mortality, number of days of fever, days of hospitalization and use of antifungal drugs, percentage of children developing IFD, requiring modification of initial treatment strategy and need for ICU. The trial was registered with Registro Brasileiro de Ensaios Clínicos (ReBEC) under trial number RBR-3m9d74. Results A total of 149 children were randomized, 73 to empirical therapy and 76 to pre-emptive therapy. Thirty-two out of 76 (42%) children in the pre-emptive group received antifungal therapy. The median duration of antifungal therapy was 11 days in the empirical arm and 6 days in the pre-emptive arm (P < 0.001), with similar overall mortality (8% in the empirical arm and 5% in the pre-emptive arm, P = 0.47). IFD-related mortality was the same in both groups (3%, P = 0.97), as were the percentage of children with IFD (12%, P = 0.92) and the number of days of fever (9, P = 0.76). The number of days of hospitalization was 19 in the empirical arm and 17 in the pre-emptive arm (P = 0.15) and the need for ICU was 25% in the empirical arm and 20% in the pre-emptive arm (P = 0.47). Conclusions Pre-emptive antifungal therapy was as effective as empirical antifungal therapy in children with cancer, fever and neutropenia, significantly reducing the use of antifungal drugs. Introduction Invasive fungal disease (IFD) causes significant morbidity and mortality in paediatric cancer patients with high-risk febrile neutropenia (HRFN), along with high utilization of resources for prevention, diagnosis and treatment.1–4 Early diagnosis of IFD and prompt implementation of aggressive antifungal treatment have proven to be critical for patient survival.5,6 Nevertheless, early identification of the causal pathogen of an IFD continues to be difficult. The classic approach is currently based on clinical, imaging, microbiological (cultures from sterile sites) and histological studies. Major advances for early diagnosis of IFD have been made by the development of non-culture assays such as detection of galactomannan (GM) antigen, (1-3)-β-d-glucan antigen detection and nucleic acid detection, by PCR techniques.7,8 Despite these advances, IFD diagnosis continues to be a challenge9,10 and current recommendations propose to initiate empirical antifungal therapy in IFD high-risk paediatric patients with persistent (≥96 h) fever and neutropenia that are unresponsive to broad-spectrum antibacterial agents.11 The downside of this approach is the overtreatment of patients meeting the above criteria but who do not have an IFD, leading to an increase in adverse events, prolonged hospitalizations and elevated costs associated with the use of antifungal drugs.12 A more reasonable approach in cancer subjects would be to consider early identification of patients at high risk of IFD, application of a complete screening diagnosis strategy followed by a rational approach to antifungal therapy based on results of this early and extensive diagnostic workup, adopting a more selective pre-emptive treatment strategy in patients with persistent fever and neutropenia.13 Studies aiming to reduce empirical antifungal overtreatment based on pre-emptive strategies have been published on adult patients with cancer and persistent fever and neutropenia.14–19 A meta-analysis published in 2015 reviewed nine studies, including randomized controlled trials, cohort studies and feasibility studies, and demonstrated that in adult populations a pre-emptive strategy was associated with significantly lower antifungal exposure (relative risk 0.48; 95% CI 0.27–0.85) without an increase in IFD-related mortality (relative risk 0.82; 95% CI 0.36–1.87) or overall mortality (relative risk 0.95; 95% CI 0.46–1.99).20 Similar studies in paediatric populations, to our knowledge, have not been performed. In this study we aim to determine the efficacy of pre-emptive treatment compared with current standard empirical antifungal treatment in children with cancer and HRFN. Methods Population From July 2013 to December 2016, a prospective, randomized, multicentre, government-sponsored study was conducted in five hospitals in Santiago, Chile, that belong to the National Child Programme of Antineoplastic Drugs network. Children and adolescents with cancer, ≤18 years of age, admitted because of a febrile neutropenic episode were invited to participate and enrolled after parental and child informed consent or assent (when older than 8 years of age). Children with HSCT or under prophylaxis with voriconazole or posaconazole were excluded. The study was approved by the Ethics Committee of each participating institution and registered with Registro Brasileiro de Ensaios Clínicos (ReBEC) under trial number RBR-3m9d74. Overall study design Each child with an episode of febrile neutropenia was classified at admission as having low-risk febrile neutropenia (LRFN) or HRFN based on the following parameters: type of cancer, type and date of last chemotherapy, blood pressure, haematological status [absolute neutrophil count (ANC) and platelet count] and quantitative C-reactive protein (CRP).21,22 The microbiological diagnosis protocol included central and peripheral automated blood cultures and other cultures if clinically indicated. After this initial evaluation, all children were treated according to the guidelines for the management of febrile neutropenia in children with cancer.23,24 Briefly, all children were hospitalized and those with LRFN were treated with a third-generation cephalosporin (ceftriaxone) whereas children with HRFN were treated with an anti-pseudomonal third-generation cephalosporin (ceftazidime) plus amikacin, with or without an anti-Gram-positive β-lactam or glycopeptide antimicrobial. Children with HRFN episodes who continued with fever and neutropenia at day 4 of antimicrobial treatment were subject to a 1:1 simple randomization by the blinded study coordinator using statistical software (GraphPad Prism, version 6.01; GraphPad, San Diego, CA, USA) into two groups. One group followed current recommendations receiving empirical antifungal treatment starting on day 4 and the second group followed a novel pre-emptive treatment protocol receiving antifungal therapy, at any time of the follow-up, only if persistent fever and ANC ≤500/mm3 were accompanied by any of the following findings suggesting IFD:20 (i) clinical/imaging documented pneumonia or sinusitis (characteristic chest or sinus CT scan); (ii) skin lesions suggesting IFD; (iii) clinical/imaging enterocolitis; (iv) unexplained CNS symptoms; (v) splenic or hepatic characteristic imaging; (vi) single positive GM; or (vii) positive mycological finding. All children, randomized to empirical or pre-emptive therapy, were evaluated with a standardized clinical, laboratory, imaging and microbiological panel for IFD. The evaluation included ANC, absolute monocyte count (AMC), CRP, repeat blood cultures, serum GM, chest and sinus CT scan, abdominal ultrasound and other imaging studies and diagnostic evaluations according to clinical presentation [fundoscopy, echocardiography, MRI, bronchoalveolar lavage (BAL), skin or other tissue biopsy]. Antifungal agents, in the empirical and pre-emptive groups, included liposomal amphotericin B, echinocandins or voriconazole, according to clinical and laboratory findings. Both groups were monitored until day 30 after enrolment for clinical, laboratory, imaging and microbiological resolution. Two investigators evaluated all cases at day 30, according to the primary and secondary endpoints, blind to information on randomization. Antifungal treatment was stopped or prolonged according to clinical, laboratory, imaging and microbiological findings in each individual case. Children who died were evaluated by a panel of experts including oncologists and infectious diseases specialists from all participating hospitals to determine if the death was or was not related to IFD. According to Ethics Committee requirements, it was possible to randomize each child in only one episode of febrile neutropenia that met study criteria; for this reason, one randomized episode of HRFN was equivalent to one randomized patient. Study endpoints The primary endpoint was overall mortality at day 30 of follow-up. Secondary endpoints included IFD-related mortality, number of days of fever, number of days of hospitalization, number of days of antifungal use, percentage of episodes that developed an IFD (proven, probable or possible), percentage of episodes requiring modification of initial treatment strategy (introduction of antifungal and antifungal modification) and percentage of episodes that needed ICU admission. Definitions Neutropenia: ANC ≤500/mm3. Fever: single axillary temperature ≥38.5°C or ≥38°C in two measurements separated by ≥1 h. HRFN: a febrile neutropenic episode with one or more of the following risk factors at the time of admission: (a) relapse of leukaemia as cancer type, (b) hypotension or (c) quantitative CRP ≥90 mg/L, or a febrile neutropenic episode with the following two factors at the time of admission: (d) ≤7 days between the end of the last chemotherapy and the beginning of the fever and (e) platelet count ≤50 000/mm3. LRFN: a febrile neutropenic episode without the above-mentioned factors at the time of admission. Persistent HRFN: fever and neutropenia ≥96 h in a child with HRFN. IFD status was defined according to the European Organization for Research and Treatment of Cancer (EORTC) as follows: proven if the child had microbiological or histological evidence of fungal tissue invasion or a positive fungal culture obtained from a sterile site, in addition to clinical or radiological findings consistent with fungal infection; probable, the presence of one or more host factors, a clinical criterion and one or more mycological criterion by a direct test (cytology, direct microscopy or culture) or an indirect test (detection of antigen); and possible, a case meeting host factor and clinical criteria but lacking any mycological documentation.25 Overall mortality at day 30 of follow-up: mortality due to any cause during the study period. IFD-related mortality: mortality attributable to IFD, according to a panel of experts, occurring during the study period, in a child with proven or probable IFD. Sample size The primary endpoint for this non-inferiority study was overall mortality at day 30 of follow-up. Sample size was calculated considering that overall mortality at day 30 of follow-up in children with persistent HRFN is 6%, as previously reported by our group.26,27 Considering the same frequency of overall mortality in both groups, a type I error of 0.05 and a potency of 90%, we calculated that 140 episodes of persistent HRFN were required. Based on our previous experience, we have determined our capacity to enrol 300 febrile neutropenic episodes per year for a total of 1000 episodes in 3.5 years. Statistical analysis Categorical variables were compared using the χ2 test or Fisher’s exact test depending on the number of episodes per comparison group. Continuous variables were compared according to distribution using Student’s t-test or the Mann–Whitney test. Overall mortality risk and the risk for secondary endpoints were evaluated for the exposed compared with the non-exposed groups, calculating the relative risk with the respective 95% CI. Statistical analyses were performed using GraphPad Prism version 6.01 and Stata IC version 14.0. Results Population characteristics A total of 1010/1180 febrile neutropenic episodes were evaluated between July 2013 and December 2016 in the five participating hospitals; 170 episodes were excluded: 97 rejected informed consent, 68 did not meet the inclusion criteria and 5 had incomplete data. Seven hundred and forty-one out of 1010 (73%) episodes were classified as HRFN episodes. At day 4 of follow-up, 153/741 (21%) had persistent HRFN and met the criteria for randomization, of which 149/153 (97%) were randomized, 73 into the empirical group and 76 into the pre-emptive group. Four episodes were not randomized owing to prophylactic use of voriconazole or posaconazole (Figure 1). Figure 1. View largeDownload slide Episodes of fever and neutropenia evaluated, enrolled and randomized during the study period. Figure 1. View largeDownload slide Episodes of fever and neutropenia evaluated, enrolled and randomized during the study period. Table 1 describes the main clinical characteristics of children with episodes of persistent HRFN randomized to empirical or pre-emptive antifungal therapy. No significant differences were observed in term of age, sex and type of cancer, with mainly haematological malignancy in both groups (85% and 88%, P = 0.56). Nearly 50% of the children had episodes of HRFN without clinical foci at admission; the other 50% of children had respiratory or intestinal foci. Table 1. Admission characteristics of 149 children with persistent fever and neutropenia, randomized into empirical versus pre-emptive antifungal therapy Characteristic Intervention P empirical, N = 73 pre-emptive, N = 76 Age (years), median (IQR) 6 (4–12) 7 (3–11) 0.84 Male, n (%) 39 (53) 43 (57) 0.69 Type of cancer, n (%)  leukaemia/lymphoma 46 (63) 49 (64) 0.85  leukaemia relapse 16 (22) 18 (24) 0.79  solid tumours 11 (15) 9 (12) 0.56 Use of granulocyte colony stimulating factor, n (%) 17 (23) 15 (20) 0.59 Use of central venous catheter, n (%) 62 (85) 64 (84) 0.90 Hours of fever prior to admission, median (IQR) 1 (1–3) 2 (1–4) 0.10 Admission clinical diagnosis, n (% )  fever without focus 35 (48) 37 (49) 0.92  respiratory infection 17 (23) 16 (21) 0.74  intestinal focus 18 (25) 19 (25) 0.96  othersa 3 (4) 4 (5) 0.73 Characteristic Intervention P empirical, N = 73 pre-emptive, N = 76 Age (years), median (IQR) 6 (4–12) 7 (3–11) 0.84 Male, n (%) 39 (53) 43 (57) 0.69 Type of cancer, n (%)  leukaemia/lymphoma 46 (63) 49 (64) 0.85  leukaemia relapse 16 (22) 18 (24) 0.79  solid tumours 11 (15) 9 (12) 0.56 Use of granulocyte colony stimulating factor, n (%) 17 (23) 15 (20) 0.59 Use of central venous catheter, n (%) 62 (85) 64 (84) 0.90 Hours of fever prior to admission, median (IQR) 1 (1–3) 2 (1–4) 0.10 Admission clinical diagnosis, n (% )  fever without focus 35 (48) 37 (49) 0.92  respiratory infection 17 (23) 16 (21) 0.74  intestinal focus 18 (25) 19 (25) 0.96  othersa 3 (4) 4 (5) 0.73 Categorical variables were compared using the χ2 test. Continuous variables were compared using the Mann–Whitney test. a Others: skin/soft-tissue infection. Table 1. Admission characteristics of 149 children with persistent fever and neutropenia, randomized into empirical versus pre-emptive antifungal therapy Characteristic Intervention P empirical, N = 73 pre-emptive, N = 76 Age (years), median (IQR) 6 (4–12) 7 (3–11) 0.84 Male, n (%) 39 (53) 43 (57) 0.69 Type of cancer, n (%)  leukaemia/lymphoma 46 (63) 49 (64) 0.85  leukaemia relapse 16 (22) 18 (24) 0.79  solid tumours 11 (15) 9 (12) 0.56 Use of granulocyte colony stimulating factor, n (%) 17 (23) 15 (20) 0.59 Use of central venous catheter, n (%) 62 (85) 64 (84) 0.90 Hours of fever prior to admission, median (IQR) 1 (1–3) 2 (1–4) 0.10 Admission clinical diagnosis, n (% )  fever without focus 35 (48) 37 (49) 0.92  respiratory infection 17 (23) 16 (21) 0.74  intestinal focus 18 (25) 19 (25) 0.96  othersa 3 (4) 4 (5) 0.73 Characteristic Intervention P empirical, N = 73 pre-emptive, N = 76 Age (years), median (IQR) 6 (4–12) 7 (3–11) 0.84 Male, n (%) 39 (53) 43 (57) 0.69 Type of cancer, n (%)  leukaemia/lymphoma 46 (63) 49 (64) 0.85  leukaemia relapse 16 (22) 18 (24) 0.79  solid tumours 11 (15) 9 (12) 0.56 Use of granulocyte colony stimulating factor, n (%) 17 (23) 15 (20) 0.59 Use of central venous catheter, n (%) 62 (85) 64 (84) 0.90 Hours of fever prior to admission, median (IQR) 1 (1–3) 2 (1–4) 0.10 Admission clinical diagnosis, n (% )  fever without focus 35 (48) 37 (49) 0.92  respiratory infection 17 (23) 16 (21) 0.74  intestinal focus 18 (25) 19 (25) 0.96  othersa 3 (4) 4 (5) 0.73 Categorical variables were compared using the χ2 test. Continuous variables were compared using the Mann–Whitney test. a Others: skin/soft-tissue infection. Outcome of children with persistent HRFN by study group Table 2 shows the clinical outcome of 149 randomized children, according to the intervention. Overall mortality at day 30 of follow-up was 8% (6/73) in the empirical arm and 5% (4/76) in the pre-emptive arm, with no difference in risks between groups (P = 0.47). In four of the ten children who died the expert panel concluded that mortality was related to an IFD, 2/73 (3%) in the group with empirical therapy and 2/76 (3%) in the group with pre-emptive therapy, with no difference in risk between groups (P = 0.97). The median number of days of antifungal therapy was 11 in the empirical arm and 6 in the pre-emptive arm (P < 0.001), the median number of days of fever was 9 in both groups (P = 0.76), the median number of days of hospitalization was 19 and 17, in the empirical and pre-emptive arms, respectively (P = 0.15), 12% of children developed IFD in each group (P = 0.92) and the need for ICU was 25% in the empirical arm and 20% in the pre-emptive arm (P = 0.47). Table 2. Clinical outcome of 149 children with persistent fever and neutropenia, randomized into empirical versus pre-emptive antifungal therapy Intervention P Relative risk (95% CI) empirical, N = 73 pre-emptive, N = 76 Primary endpoint  overall mortality at day 30, n (%) 6 (8) 4 (5) 0.47 0.64 (0.19–2.18) Secondary endpoints  IFD-related mortality at day 30, n (%) 2 (3) 2 (3) 0.97 0.96 (0.13–6.6)  days of fever, median (IQR) 9 (7–13) 9 (6–14) 0.76  days of hospitalization, median (IQR) 19 (14–23) 17 (13–22) 0.15  days of antifungal, median (IQR) 11 (7–16) 6 (3–13) <0.001  developing IFD, n (%) 9 (12) 9 (12) 0.92 0.96 (0.40–2.28)  antifungal start required, n (%) 32 (42)  antifungal modification required, n (%) 15 (21) 12 (16) 0.45 0.77 (0.39–1.53)  need for ICU, n (%) 18 (25) 15 (20) 0.47 0.80 (0.43–1.46) Intervention P Relative risk (95% CI) empirical, N = 73 pre-emptive, N = 76 Primary endpoint  overall mortality at day 30, n (%) 6 (8) 4 (5) 0.47 0.64 (0.19–2.18) Secondary endpoints  IFD-related mortality at day 30, n (%) 2 (3) 2 (3) 0.97 0.96 (0.13–6.6)  days of fever, median (IQR) 9 (7–13) 9 (6–14) 0.76  days of hospitalization, median (IQR) 19 (14–23) 17 (13–22) 0.15  days of antifungal, median (IQR) 11 (7–16) 6 (3–13) <0.001  developing IFD, n (%) 9 (12) 9 (12) 0.92 0.96 (0.40–2.28)  antifungal start required, n (%) 32 (42)  antifungal modification required, n (%) 15 (21) 12 (16) 0.45 0.77 (0.39–1.53)  need for ICU, n (%) 18 (25) 15 (20) 0.47 0.80 (0.43–1.46) Categorical variables were compared using the χ2 test. Continuous variables were compared using the Mann–Whitney test. Table 2. Clinical outcome of 149 children with persistent fever and neutropenia, randomized into empirical versus pre-emptive antifungal therapy Intervention P Relative risk (95% CI) empirical, N = 73 pre-emptive, N = 76 Primary endpoint  overall mortality at day 30, n (%) 6 (8) 4 (5) 0.47 0.64 (0.19–2.18) Secondary endpoints  IFD-related mortality at day 30, n (%) 2 (3) 2 (3) 0.97 0.96 (0.13–6.6)  days of fever, median (IQR) 9 (7–13) 9 (6–14) 0.76  days of hospitalization, median (IQR) 19 (14–23) 17 (13–22) 0.15  days of antifungal, median (IQR) 11 (7–16) 6 (3–13) <0.001  developing IFD, n (%) 9 (12) 9 (12) 0.92 0.96 (0.40–2.28)  antifungal start required, n (%) 32 (42)  antifungal modification required, n (%) 15 (21) 12 (16) 0.45 0.77 (0.39–1.53)  need for ICU, n (%) 18 (25) 15 (20) 0.47 0.80 (0.43–1.46) Intervention P Relative risk (95% CI) empirical, N = 73 pre-emptive, N = 76 Primary endpoint  overall mortality at day 30, n (%) 6 (8) 4 (5) 0.47 0.64 (0.19–2.18) Secondary endpoints  IFD-related mortality at day 30, n (%) 2 (3) 2 (3) 0.97 0.96 (0.13–6.6)  days of fever, median (IQR) 9 (7–13) 9 (6–14) 0.76  days of hospitalization, median (IQR) 19 (14–23) 17 (13–22) 0.15  days of antifungal, median (IQR) 11 (7–16) 6 (3–13) <0.001  developing IFD, n (%) 9 (12) 9 (12) 0.92 0.96 (0.40–2.28)  antifungal start required, n (%) 32 (42)  antifungal modification required, n (%) 15 (21) 12 (16) 0.45 0.77 (0.39–1.53)  need for ICU, n (%) 18 (25) 15 (20) 0.47 0.80 (0.43–1.46) Categorical variables were compared using the χ2 test. Continuous variables were compared using the Mann–Whitney test. After randomization, 32/76 (42%) children in the pre-emptive group received antifungal therapy within the 30 day follow-up period. The median number of days for the initiation of antifungal therapy in this group was 9 (IQR 7–11). The median number of days of neutropenia showed no difference between groups, with 9 days in the empirical arm (IQR 7–13) and 10 in the pre-emptive arm (IQR 7–15), P = 0.31. Diagnosis and outcome of children with proven or probable IFD by study group Eighteen children developed a proven or probable IFD during the study, nine in the empirical group and nine in the pre-emptive group. Possible cases were not considered for the analysis. The median age of children with IFD was similar in the two groups (9 and 8 years in the empirical and pre-emptive groups, respectively, P = 0.81). Most of the children were male (78% in each group, P = 1.00) and had a haematological malignancy (89% and 100% in the empirical and pre-emptive groups, respectively, P = 1.00). The outcome of children with proven and probable IFD was similar, irrespective of whether they were randomized into the empirical or pre-emptive group. The percentage of children with proven or probable IFD who died was 22% in each group (P = 1.00); the median number of days of fever was 13 and 17 (P = 0.18), the median number of days of hospitalization was 21 and 26 (P = 0.50) and the median number of days of antifungal use was 21 and 17 in the empirical and pre-emptive groups, respectively (P = 0.35); 33% in each group required antifungal modification (P = 1.00); and 56% and 44% in the empirical and pre-emptive groups, respectively, needed ICU admission (P = 1.00) (Table 3). Table 3. Demographic characteristics and clinical outcomes of 18 children with final diagnosis of proven or probable IFD, randomized into empirical versus pre-emptive antifungal therapy Intervention P empirical, N = 9 pre-emptive, N = 9 Characteristic  age (years), mean (SD) 9 (5) 8 (6) 0.81  male, n (%) 7 (78) 7 (78) 1.00  type of cancer, n (%)   leukaemia/lymphoma/leukaemia  relapse 8 (89) 9 (100) 1.00   solid tumours 1 (11) Clinical outcome  mortality, n (%) 2 (22) 2 (22) 1.00  days of fever, mean (SD) 13 (5) 17 (6) 0.18  days of hospitalization, median (IQR) 21 (20–38) 26 (23–32) 0.50  days of antifungal, median (IQR) 21 (18–33) 17 (14–26) 0.35  antifungal modification required, n (%) 3 (33) 3 (33) 1.00  need for ICU, n (%) 5 (56) 4 (44) 1.00 Intervention P empirical, N = 9 pre-emptive, N = 9 Characteristic  age (years), mean (SD) 9 (5) 8 (6) 0.81  male, n (%) 7 (78) 7 (78) 1.00  type of cancer, n (%)   leukaemia/lymphoma/leukaemia  relapse 8 (89) 9 (100) 1.00   solid tumours 1 (11) Clinical outcome  mortality, n (%) 2 (22) 2 (22) 1.00  days of fever, mean (SD) 13 (5) 17 (6) 0.18  days of hospitalization, median (IQR) 21 (20–38) 26 (23–32) 0.50  days of antifungal, median (IQR) 21 (18–33) 17 (14–26) 0.35  antifungal modification required, n (%) 3 (33) 3 (33) 1.00  need for ICU, n (%) 5 (56) 4 (44) 1.00 Categorical variables were compared using Fisher’s exact test. Continuous variables were compared using Student’s t-test or the Mann–Whitney test according to data distribution. Table 3. Demographic characteristics and clinical outcomes of 18 children with final diagnosis of proven or probable IFD, randomized into empirical versus pre-emptive antifungal therapy Intervention P empirical, N = 9 pre-emptive, N = 9 Characteristic  age (years), mean (SD) 9 (5) 8 (6) 0.81  male, n (%) 7 (78) 7 (78) 1.00  type of cancer, n (%)   leukaemia/lymphoma/leukaemia  relapse 8 (89) 9 (100) 1.00   solid tumours 1 (11) Clinical outcome  mortality, n (%) 2 (22) 2 (22) 1.00  days of fever, mean (SD) 13 (5) 17 (6) 0.18  days of hospitalization, median (IQR) 21 (20–38) 26 (23–32) 0.50  days of antifungal, median (IQR) 21 (18–33) 17 (14–26) 0.35  antifungal modification required, n (%) 3 (33) 3 (33) 1.00  need for ICU, n (%) 5 (56) 4 (44) 1.00 Intervention P empirical, N = 9 pre-emptive, N = 9 Characteristic  age (years), mean (SD) 9 (5) 8 (6) 0.81  male, n (%) 7 (78) 7 (78) 1.00  type of cancer, n (%)   leukaemia/lymphoma/leukaemia  relapse 8 (89) 9 (100) 1.00   solid tumours 1 (11) Clinical outcome  mortality, n (%) 2 (22) 2 (22) 1.00  days of fever, mean (SD) 13 (5) 17 (6) 0.18  days of hospitalization, median (IQR) 21 (20–38) 26 (23–32) 0.50  days of antifungal, median (IQR) 21 (18–33) 17 (14–26) 0.35  antifungal modification required, n (%) 3 (33) 3 (33) 1.00  need for ICU, n (%) 5 (56) 4 (44) 1.00 Categorical variables were compared using Fisher’s exact test. Continuous variables were compared using Student’s t-test or the Mann–Whitney test according to data distribution. The demographic, clinical, imaging and microbiological characteristics of the eighteen children with proven and probable IFD are described in Table 4. The most common species was Candida spp., causing seven cases of candidaemia. We also had seven cases of invasive aspergillosis, one proven and six probable, all with pneumonia (by clinical and imaging findings) and positive GM detection in serum and/or in BAL. Other diagnoses included Fusarium solani infection, Scedosporium apiospermum brain abscess, Sarocladium kiliense fungaemia and mucormycosis. Table 4. Demographic, clinical, imaging and microbiological characteristics of 18 children with proven or probable IFD Age [years (y) or months (m)]/sex Type of cancer Clinical focus and imaging Maximum GM Microbiological findings Outcome Randomization group Proven IFD  14 y/male ALL relapse sepsis/enterocolitis 0.2 BC(+) Candida albicans, BC(+) Klebsiella pneumoniae died empirical  17 y/male ALL relapse enterocolitis 0.4 BC(+) Candida glabrata favourable empirical  4 y/male ALL none 0.1 BC(+) C. albicans favourable empirical  4 y/male ALL relapse central venous catheter infection 0.3 BC(+) Candida parapsilosis, BC(+) Escherichia coli favourable pre-emptive  1 y/female AML enterocolitis 0.1 BC(+) Candida tropicalis, BC(+) Pseudomonas sp. favourable pre-emptive  17 y/male ALL relapse central venous catheter infection 0.2 BC(+) Candida lusitaniae, BC(+) CoNS favourable pre-emptive  4 m/male AML enterocolitis 0.3 BC(+) C. albicans favourable pre-emptive  12 y/female ALL relapse pneumonia 0.7 Aspergillus fumigatus in lung biopsy favourable pre-emptive  3 y/male AML pneumonia 0.7 BC(+) Fusarium solani favourable empirical  3 y/female ALL brain abscess 0.4 S. apiospermum in brain biopsy favourable empirical  13 y/male lymphoma none 0.2 BC(+) S. kiliense favourable empirical  11 y/male AML sinusitis/pneumonia 0.5 Rhizopus sp. in sinus biopsy favourable empirical Probable IFD  14 y/female ALL pneumonia 4.6 BC(+) E. coli favourable empirical  3 y/male AML pneumonia 6.4 (BAL) BC(+) CoNS died empirical  9 y/male solid tumour pneumonia 0.8 (BAL) none favourable empirical  11 y/male ALL relapse enterocolitis/pneumonia 4.6 BC(+) E. coli died pre-emptive  5 y/male ALL pneumonia 1.5 none favourable pre-emptive  10 y/male AML relapse pneumonia 7.7 (BAL) BC(+) CoNS died pre-emptive Age [years (y) or months (m)]/sex Type of cancer Clinical focus and imaging Maximum GM Microbiological findings Outcome Randomization group Proven IFD  14 y/male ALL relapse sepsis/enterocolitis 0.2 BC(+) Candida albicans, BC(+) Klebsiella pneumoniae died empirical  17 y/male ALL relapse enterocolitis 0.4 BC(+) Candida glabrata favourable empirical  4 y/male ALL none 0.1 BC(+) C. albicans favourable empirical  4 y/male ALL relapse central venous catheter infection 0.3 BC(+) Candida parapsilosis, BC(+) Escherichia coli favourable pre-emptive  1 y/female AML enterocolitis 0.1 BC(+) Candida tropicalis, BC(+) Pseudomonas sp. favourable pre-emptive  17 y/male ALL relapse central venous catheter infection 0.2 BC(+) Candida lusitaniae, BC(+) CoNS favourable pre-emptive  4 m/male AML enterocolitis 0.3 BC(+) C. albicans favourable pre-emptive  12 y/female ALL relapse pneumonia 0.7 Aspergillus fumigatus in lung biopsy favourable pre-emptive  3 y/male AML pneumonia 0.7 BC(+) Fusarium solani favourable empirical  3 y/female ALL brain abscess 0.4 S. apiospermum in brain biopsy favourable empirical  13 y/male lymphoma none 0.2 BC(+) S. kiliense favourable empirical  11 y/male AML sinusitis/pneumonia 0.5 Rhizopus sp. in sinus biopsy favourable empirical Probable IFD  14 y/female ALL pneumonia 4.6 BC(+) E. coli favourable empirical  3 y/male AML pneumonia 6.4 (BAL) BC(+) CoNS died empirical  9 y/male solid tumour pneumonia 0.8 (BAL) none favourable empirical  11 y/male ALL relapse enterocolitis/pneumonia 4.6 BC(+) E. coli died pre-emptive  5 y/male ALL pneumonia 1.5 none favourable pre-emptive  10 y/male AML relapse pneumonia 7.7 (BAL) BC(+) CoNS died pre-emptive BC, blood culture. Table 4. Demographic, clinical, imaging and microbiological characteristics of 18 children with proven or probable IFD Age [years (y) or months (m)]/sex Type of cancer Clinical focus and imaging Maximum GM Microbiological findings Outcome Randomization group Proven IFD  14 y/male ALL relapse sepsis/enterocolitis 0.2 BC(+) Candida albicans, BC(+) Klebsiella pneumoniae died empirical  17 y/male ALL relapse enterocolitis 0.4 BC(+) Candida glabrata favourable empirical  4 y/male ALL none 0.1 BC(+) C. albicans favourable empirical  4 y/male ALL relapse central venous catheter infection 0.3 BC(+) Candida parapsilosis, BC(+) Escherichia coli favourable pre-emptive  1 y/female AML enterocolitis 0.1 BC(+) Candida tropicalis, BC(+) Pseudomonas sp. favourable pre-emptive  17 y/male ALL relapse central venous catheter infection 0.2 BC(+) Candida lusitaniae, BC(+) CoNS favourable pre-emptive  4 m/male AML enterocolitis 0.3 BC(+) C. albicans favourable pre-emptive  12 y/female ALL relapse pneumonia 0.7 Aspergillus fumigatus in lung biopsy favourable pre-emptive  3 y/male AML pneumonia 0.7 BC(+) Fusarium solani favourable empirical  3 y/female ALL brain abscess 0.4 S. apiospermum in brain biopsy favourable empirical  13 y/male lymphoma none 0.2 BC(+) S. kiliense favourable empirical  11 y/male AML sinusitis/pneumonia 0.5 Rhizopus sp. in sinus biopsy favourable empirical Probable IFD  14 y/female ALL pneumonia 4.6 BC(+) E. coli favourable empirical  3 y/male AML pneumonia 6.4 (BAL) BC(+) CoNS died empirical  9 y/male solid tumour pneumonia 0.8 (BAL) none favourable empirical  11 y/male ALL relapse enterocolitis/pneumonia 4.6 BC(+) E. coli died pre-emptive  5 y/male ALL pneumonia 1.5 none favourable pre-emptive  10 y/male AML relapse pneumonia 7.7 (BAL) BC(+) CoNS died pre-emptive Age [years (y) or months (m)]/sex Type of cancer Clinical focus and imaging Maximum GM Microbiological findings Outcome Randomization group Proven IFD  14 y/male ALL relapse sepsis/enterocolitis 0.2 BC(+) Candida albicans, BC(+) Klebsiella pneumoniae died empirical  17 y/male ALL relapse enterocolitis 0.4 BC(+) Candida glabrata favourable empirical  4 y/male ALL none 0.1 BC(+) C. albicans favourable empirical  4 y/male ALL relapse central venous catheter infection 0.3 BC(+) Candida parapsilosis, BC(+) Escherichia coli favourable pre-emptive  1 y/female AML enterocolitis 0.1 BC(+) Candida tropicalis, BC(+) Pseudomonas sp. favourable pre-emptive  17 y/male ALL relapse central venous catheter infection 0.2 BC(+) Candida lusitaniae, BC(+) CoNS favourable pre-emptive  4 m/male AML enterocolitis 0.3 BC(+) C. albicans favourable pre-emptive  12 y/female ALL relapse pneumonia 0.7 Aspergillus fumigatus in lung biopsy favourable pre-emptive  3 y/male AML pneumonia 0.7 BC(+) Fusarium solani favourable empirical  3 y/female ALL brain abscess 0.4 S. apiospermum in brain biopsy favourable empirical  13 y/male lymphoma none 0.2 BC(+) S. kiliense favourable empirical  11 y/male AML sinusitis/pneumonia 0.5 Rhizopus sp. in sinus biopsy favourable empirical Probable IFD  14 y/female ALL pneumonia 4.6 BC(+) E. coli favourable empirical  3 y/male AML pneumonia 6.4 (BAL) BC(+) CoNS died empirical  9 y/male solid tumour pneumonia 0.8 (BAL) none favourable empirical  11 y/male ALL relapse enterocolitis/pneumonia 4.6 BC(+) E. coli died pre-emptive  5 y/male ALL pneumonia 1.5 none favourable pre-emptive  10 y/male AML relapse pneumonia 7.7 (BAL) BC(+) CoNS died pre-emptive BC, blood culture. Discussion In our study, pre-emptive antifungal therapy was as effective as empirical antifungal therapy in children with cancer and HRFN, with a significant reduction in antifungal use. A reduction of antifungal use, based on stringent diagnostic criteria, could favour the adoption of evidence-based management strategies in this population. This approach requires optimal laboratory support with rapid turnaround response. Introduction of non-culture-based diagnostic techniques into clinical practice could contribute to better management of these patients, favouring the possibility of patient-based individualized therapy. Active monitoring and early diagnostic workup is a necessary step prior to proposing an evidence-based management strategy.28–30 Studies comparing empirical versus pre-emptive antifungal therapy in adult populations have evaluated different endpoints: overall mortality, IFD-related mortality, percentage of patients with final diagnosis of IFD, percentage of patients receiving antifungal therapy and number of days of antifungal treatment.20 Overall mortality was our primary endpoint in accordance with studies in adult populations and because it represents the most relevant outcome in children. To our knowledge, this is the first prospective, multicentre, randomized study that compares standard versus pre-emptive antifungal therapy in HRFN children with prolonged fever and neutropenia. The comparative analysis between our study and studies in adult populations must be performed cautiously as populations and outcomes are different.28 The pending question of which is the best approach to antifungal therapy in children with cancer cannot be definitely answered until other groups replicate these findings. This study had limitations, including the lack of double-blinding, which was decided on because the majority of these children received antifungal therapy through their central venous catheter. We decided not to use the central venous catheter for a possible placebo in order to avoid potentially deleterious manipulation. Another limitation is that we did not evaluate the toxicity of antifungal therapy. Results in adult populations concluded that pre-emptive antifungal therapy has been related to reduction of antifungal drug use and associated toxicity, without increasing mortality.20 In our experience, 58% of patients of the pre-emptive group did not receive antifungal therapy, with similar clinical outcome to the empirical group, with the aim of reserving antifungal therapy for the subset of patients who have early evidence of IFD by careful clinical, laboratory, imaging and microbiological assessment. The main findings of our study lead us to propose a step forward in the rational approach to treating children with cancer focusing on one yet-unresolved issue in the management of the patients: adoption of a more selective pre-emptive antifungal treatment strategy in children with prolonged fever and neutropenia. Acknowledgements We thank the research nurses of the participant hospitals for their invaluable support in enrolling patients. We appreciate the support provided by Magdalena Bastías, RN, in the statistical analysis. We thank the FONDECYT programme for their support. Funding This study was supported by the National Fund for Scientific and Technological Development (FONDECYT), Chile (grant numbers 1120800 and 1161662). Transparency declarations None to declare. Author contributions Conception and design: María E. Santolaya, Milena Villarroel, Mauricio Farfán, Verónica de la Maza and Juan P. Torres. Collection and assembly of data: Ana M. Alvarez, Mirta Acuña, Carmen L. Avilés, Carmen Salgado, Juan Tordecilla, Monica Varas, Marcela Venegas and Marcela Zubieta. Data analysis and intrepretation: María E. Santolaya, Alejandra Vergara, Romina Valenzuela and Juan P. Torres. Manuscript writing and final approval of manuscript: all authors. References 1 Mor M , Gilad G , Kornreich L et al. Invasive fungal infections in pediatric oncology . Pediatr Blood Cancer 2011 ; 56 : 1092. Google Scholar Crossref Search ADS PubMed 2 Drgona L , Khachatryan A , Stephens J et al. Clinical and economic burden of invasive fungal diseases in Europe: focus on pre-emptive and empirical treatment of Aspergillus and Candida species . Eur J Clin Microbiol Infect Dis 2014 ; 33 : 7 – 21 . Google Scholar Crossref Search ADS PubMed 3 Villarroel M , Avilés CL , Silva P et al. Risk factors associated with invasive fungal disease in children with cancer and febrile neutropenia: a prospective, multicenter evaluation . Pediatr Infect Dis J 2010 ; 29 : 816 – 21 . Google Scholar Crossref Search ADS PubMed 4 Fisher BT , Robinson PD , Lehrnbecher T et al. Risk factors for invasive fungal disease in pediatric cancer and hematopoietic stem cell transplantation: a systematic review . J Pediatric Infect Dis Soc 2017 ; doi:10.1093/jpids/pix030. 5 Hahn-Ast C , Glasmacher A , Mückter S et al. Overall survival and fungal infection-related mortality in patients with invasive fungal infection and neutropenia after myelosuppressive chemotherapy in a tertiary care centre from 1995 to 2006 . J Antimicrob Chemother 2010 ; 65 : 761 – 8 . Google Scholar Crossref Search ADS PubMed 6 Maschmeyer G. Invasive fungal disease: better survival through early diagnosis and therapeutic intervention . Expert Review Anti Infect Ther 2011 ; 9 : 279 – 81 . Google Scholar Crossref Search ADS 7 Colombo AL , Cortes JA , Zurita J et al. Recommendations for the diagnosis of candidemia in Latin America . Rev Iberoam Micol 2013 ; 30 : 150 – 7 . 8 Lehrnbecher T , Robinson P , Fisher B et al. Galactomannan, β-D-glucan, and polymerase chain reaction-based assays for the diagnosis of invasive fungal disease in pediatric cancer and hematopoietic stem cell transplantation: a systematic review and meta-analysis . Clin Infect Dis 2016 ; 63 : 1340 – 8 . Google Scholar Crossref Search ADS PubMed 9 Groll AH , Castagnola E , Cesaro S et al. Fourth European Conference on Infections in Leukaemia (ECIL-4): guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation . Lancet Oncol 2014 ; 15 : 327 – 40 . Google Scholar Crossref Search ADS 10 Santolaya ME , Alvarado T , Queiroz-Telles F et al. Active surveillance of candidemia in children from Latin America: a key requirement for improving disease outcome . Pediatr Infect Dis J 2014 ; 33 : 40 – 4 . Google Scholar Crossref Search ADS 11 Lehrnbecher T , Robinson P , Fisher B et al. Guideline for the management of fever and neutropenia in children with cancer and hematopoietic stem-cell transplantation recipients: 2017 update . J Clin Oncol 2017 ; 35 : 2082 – 94 . Google Scholar Crossref Search ADS PubMed 12 Tissot F , Agrawal S , Pagano L et al. ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients . Haematologica 2017 ; 102 : 433 – 44 . Google Scholar Crossref Search ADS PubMed 13 Morgan J , Hassan H , Cockle J et al. Critical review of current clinical practice guidelines for antifungal therapy in paediatric haematology and oncology . Support Care Cancer 2017 ; 25 : 221 – 8 . Google Scholar Crossref Search ADS PubMed 14 Cordonnier C , Pautas C , Maury S et al. Empirical versus preemptive antifungal therapy for high-risk, febrile, neutropenic patients: a randomized, controlled trial . Clin Infect Dis 2009 ; 48 : 1042 – 51 . Google Scholar Crossref Search ADS PubMed 15 Girmenia C , Micozzi A , Gentile G et al. Clinically driven diagnostic antifungal approach in neutropenic patients: a prospective feasibility study . J Clin Oncol 2010 ; 28 : 667 – 74 . Google Scholar Crossref Search ADS PubMed 16 Pagano L , Caira M , Nosari A et al. The use and efficacy of empirical versus pre-emptive therapy in the management of fungal infections: the HEMA e-Chart project . Haematologica 2011 ; 96 : 1366 – 70 . Google Scholar Crossref Search ADS PubMed 17 Freemantle N , Tharmanathan P , Herbrecht R. Systematic review and mixed treatment comparison of randomized evidence for empirical, pre-emptive and directed treatment strategies for invasive mould disease . J Antimicrob Chemother 2011 ; 66 : i25 – 35 . Google Scholar Crossref Search ADS PubMed 18 Martín-Peña A , Gil-Navarro MV , Aguilar-Guisado M et al. Cost effectiveness analysis comparing two approaches for empirical antifungal therapy in hematological patients with persistent febrile neutropenia . Antimicrob Agents Chemother 2013 ; 57 : 4664 – 72 . Google Scholar Crossref Search ADS PubMed 19 Barnes R , Earnshaw S , Herbrecht R et al. Economic comparison of an empirical versus diagnostic-driven strategy for treating invasive fungal disease in immunocompromised patients . Clin Ther 2015 ; 37 : 1317 – 28 . Google Scholar Crossref Search ADS PubMed 20 Fung M , Kim J , Marty F et al. Meta-analysis and cost comparison of empirical versus pre-emptive antifungal strategies in hematologic malignancy patients with high-risk febrile neutropenia . PLoS One 2015 ; 10 : e0140930. Google Scholar Crossref Search ADS PubMed 21 Santolaya ME , Alvarez AM , Becker A et al. Prospective, multicenter evaluation of risk factors associated with invasive bacterial infection in children with cancer, neutropenia and fever . J Clin Oncol 2001 ; 19 : 3415 – 21 . Google Scholar Crossref Search ADS PubMed 22 Santolaya ME , Alvarez A , Avilés CL et al. Prospective evaluation of a model of prediction of invasive bacterial infection risk among children with cancer, fever and neutropenia . Clin Infect Dis 2002 ; 35 : 678 – 83 . Google Scholar Crossref Search ADS PubMed 23 Paganini H , Santolaya ME , Álvarez M et al. Diagnóstico y tratamiento de la neutropenia febril en niños con cáncer. Consenso de la Sociedad Latinoamericana de infectología pediátrica . Rev Chil Infect 2011 ; 28 : 10 – 38 . Google Scholar Crossref Search ADS 24 Lehrnbecher T , Phillips R , Alexander S et al. Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation . J Clin Oncol 2012 ; 30 : 4427 – 38 . Google Scholar Crossref Search ADS PubMed 25 De Pauw B , Walsh T , Donnelly J et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infection Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORT/MSG) Consensus Group . Clin Infect Dis 2008 ; 46 : 1813 – 21 . Google Scholar Crossref Search ADS PubMed 26 Santolaya ME , Alvarez AM , Avilés CL et al. Admission clinical and laboratory factors associated with death in children with cancer during a febrile neutropenic episode . Pediatr Infect Dis J 2007 ; 26 : 794 – 8 . Google Scholar Crossref Search ADS PubMed 27 Santolaya ME , Alvarez AM , Avilés CL et al. Prospective validation of a risk prediction model for severe sepsis in children with cancer and high-risk febrile neutropenia . Pediatr Infect Dis J 2013 ; 32 : 1318–23 . Google Scholar Crossref Search ADS PubMed 28 Cordonnier C , Robin C , Alanio A et al. Antifungal pre-emptive strategy for high-risk neutropenic patients: why the story is still ongoing . Clin Microbiol Infect 2014 ; 20 : 27 – 35 . Google Scholar Crossref Search ADS PubMed 29 Donnelly JP , Maertens J. The end of the road for empirical antifungal treatment? Lancet Infect Dis 2013 ; 13 : 470 – 2 . Google Scholar Crossref Search ADS PubMed 30 Klastersky J. Antifungal therapy in patients with fever and neutropenia—more rational and less empirical? N Engl J Med 2004 ; 351 : 1445 – 7 . Google Scholar Crossref Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Efficacy of pre-emptive versus empirical antifungal therapy in children with cancer and high-risk febrile neutropenia: a randomized clinical trial

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Abstract

Abstract Objectives To compare the efficacy of pre-emptive versus empirical antifungal therapy in children with cancer, fever and neutropenia. Methods This was a prospective, multicentre, randomized clinical trial. Children presenting with persistent high-risk febrile neutropenia at five hospitals in Santiago, Chile, were randomized to empirical or pre-emptive antifungal therapy. The pre-emptive group received antifungal therapy only if the persistent high-risk febrile neutropenia was accompanied by clinical, laboratory, imaging or microbiological pre-defined criteria. The primary endpoint was overall mortality at day 30 of follow-up. Secondary endpoints included invasive fungal disease (IFD)-related mortality, number of days of fever, days of hospitalization and use of antifungal drugs, percentage of children developing IFD, requiring modification of initial treatment strategy and need for ICU. The trial was registered with Registro Brasileiro de Ensaios Clínicos (ReBEC) under trial number RBR-3m9d74. Results A total of 149 children were randomized, 73 to empirical therapy and 76 to pre-emptive therapy. Thirty-two out of 76 (42%) children in the pre-emptive group received antifungal therapy. The median duration of antifungal therapy was 11 days in the empirical arm and 6 days in the pre-emptive arm (P < 0.001), with similar overall mortality (8% in the empirical arm and 5% in the pre-emptive arm, P = 0.47). IFD-related mortality was the same in both groups (3%, P = 0.97), as were the percentage of children with IFD (12%, P = 0.92) and the number of days of fever (9, P = 0.76). The number of days of hospitalization was 19 in the empirical arm and 17 in the pre-emptive arm (P = 0.15) and the need for ICU was 25% in the empirical arm and 20% in the pre-emptive arm (P = 0.47). Conclusions Pre-emptive antifungal therapy was as effective as empirical antifungal therapy in children with cancer, fever and neutropenia, significantly reducing the use of antifungal drugs. Introduction Invasive fungal disease (IFD) causes significant morbidity and mortality in paediatric cancer patients with high-risk febrile neutropenia (HRFN), along with high utilization of resources for prevention, diagnosis and treatment.1–4 Early diagnosis of IFD and prompt implementation of aggressive antifungal treatment have proven to be critical for patient survival.5,6 Nevertheless, early identification of the causal pathogen of an IFD continues to be difficult. The classic approach is currently based on clinical, imaging, microbiological (cultures from sterile sites) and histological studies. Major advances for early diagnosis of IFD have been made by the development of non-culture assays such as detection of galactomannan (GM) antigen, (1-3)-β-d-glucan antigen detection and nucleic acid detection, by PCR techniques.7,8 Despite these advances, IFD diagnosis continues to be a challenge9,10 and current recommendations propose to initiate empirical antifungal therapy in IFD high-risk paediatric patients with persistent (≥96 h) fever and neutropenia that are unresponsive to broad-spectrum antibacterial agents.11 The downside of this approach is the overtreatment of patients meeting the above criteria but who do not have an IFD, leading to an increase in adverse events, prolonged hospitalizations and elevated costs associated with the use of antifungal drugs.12 A more reasonable approach in cancer subjects would be to consider early identification of patients at high risk of IFD, application of a complete screening diagnosis strategy followed by a rational approach to antifungal therapy based on results of this early and extensive diagnostic workup, adopting a more selective pre-emptive treatment strategy in patients with persistent fever and neutropenia.13 Studies aiming to reduce empirical antifungal overtreatment based on pre-emptive strategies have been published on adult patients with cancer and persistent fever and neutropenia.14–19 A meta-analysis published in 2015 reviewed nine studies, including randomized controlled trials, cohort studies and feasibility studies, and demonstrated that in adult populations a pre-emptive strategy was associated with significantly lower antifungal exposure (relative risk 0.48; 95% CI 0.27–0.85) without an increase in IFD-related mortality (relative risk 0.82; 95% CI 0.36–1.87) or overall mortality (relative risk 0.95; 95% CI 0.46–1.99).20 Similar studies in paediatric populations, to our knowledge, have not been performed. In this study we aim to determine the efficacy of pre-emptive treatment compared with current standard empirical antifungal treatment in children with cancer and HRFN. Methods Population From July 2013 to December 2016, a prospective, randomized, multicentre, government-sponsored study was conducted in five hospitals in Santiago, Chile, that belong to the National Child Programme of Antineoplastic Drugs network. Children and adolescents with cancer, ≤18 years of age, admitted because of a febrile neutropenic episode were invited to participate and enrolled after parental and child informed consent or assent (when older than 8 years of age). Children with HSCT or under prophylaxis with voriconazole or posaconazole were excluded. The study was approved by the Ethics Committee of each participating institution and registered with Registro Brasileiro de Ensaios Clínicos (ReBEC) under trial number RBR-3m9d74. Overall study design Each child with an episode of febrile neutropenia was classified at admission as having low-risk febrile neutropenia (LRFN) or HRFN based on the following parameters: type of cancer, type and date of last chemotherapy, blood pressure, haematological status [absolute neutrophil count (ANC) and platelet count] and quantitative C-reactive protein (CRP).21,22 The microbiological diagnosis protocol included central and peripheral automated blood cultures and other cultures if clinically indicated. After this initial evaluation, all children were treated according to the guidelines for the management of febrile neutropenia in children with cancer.23,24 Briefly, all children were hospitalized and those with LRFN were treated with a third-generation cephalosporin (ceftriaxone) whereas children with HRFN were treated with an anti-pseudomonal third-generation cephalosporin (ceftazidime) plus amikacin, with or without an anti-Gram-positive β-lactam or glycopeptide antimicrobial. Children with HRFN episodes who continued with fever and neutropenia at day 4 of antimicrobial treatment were subject to a 1:1 simple randomization by the blinded study coordinator using statistical software (GraphPad Prism, version 6.01; GraphPad, San Diego, CA, USA) into two groups. One group followed current recommendations receiving empirical antifungal treatment starting on day 4 and the second group followed a novel pre-emptive treatment protocol receiving antifungal therapy, at any time of the follow-up, only if persistent fever and ANC ≤500/mm3 were accompanied by any of the following findings suggesting IFD:20 (i) clinical/imaging documented pneumonia or sinusitis (characteristic chest or sinus CT scan); (ii) skin lesions suggesting IFD; (iii) clinical/imaging enterocolitis; (iv) unexplained CNS symptoms; (v) splenic or hepatic characteristic imaging; (vi) single positive GM; or (vii) positive mycological finding. All children, randomized to empirical or pre-emptive therapy, were evaluated with a standardized clinical, laboratory, imaging and microbiological panel for IFD. The evaluation included ANC, absolute monocyte count (AMC), CRP, repeat blood cultures, serum GM, chest and sinus CT scan, abdominal ultrasound and other imaging studies and diagnostic evaluations according to clinical presentation [fundoscopy, echocardiography, MRI, bronchoalveolar lavage (BAL), skin or other tissue biopsy]. Antifungal agents, in the empirical and pre-emptive groups, included liposomal amphotericin B, echinocandins or voriconazole, according to clinical and laboratory findings. Both groups were monitored until day 30 after enrolment for clinical, laboratory, imaging and microbiological resolution. Two investigators evaluated all cases at day 30, according to the primary and secondary endpoints, blind to information on randomization. Antifungal treatment was stopped or prolonged according to clinical, laboratory, imaging and microbiological findings in each individual case. Children who died were evaluated by a panel of experts including oncologists and infectious diseases specialists from all participating hospitals to determine if the death was or was not related to IFD. According to Ethics Committee requirements, it was possible to randomize each child in only one episode of febrile neutropenia that met study criteria; for this reason, one randomized episode of HRFN was equivalent to one randomized patient. Study endpoints The primary endpoint was overall mortality at day 30 of follow-up. Secondary endpoints included IFD-related mortality, number of days of fever, number of days of hospitalization, number of days of antifungal use, percentage of episodes that developed an IFD (proven, probable or possible), percentage of episodes requiring modification of initial treatment strategy (introduction of antifungal and antifungal modification) and percentage of episodes that needed ICU admission. Definitions Neutropenia: ANC ≤500/mm3. Fever: single axillary temperature ≥38.5°C or ≥38°C in two measurements separated by ≥1 h. HRFN: a febrile neutropenic episode with one or more of the following risk factors at the time of admission: (a) relapse of leukaemia as cancer type, (b) hypotension or (c) quantitative CRP ≥90 mg/L, or a febrile neutropenic episode with the following two factors at the time of admission: (d) ≤7 days between the end of the last chemotherapy and the beginning of the fever and (e) platelet count ≤50 000/mm3. LRFN: a febrile neutropenic episode without the above-mentioned factors at the time of admission. Persistent HRFN: fever and neutropenia ≥96 h in a child with HRFN. IFD status was defined according to the European Organization for Research and Treatment of Cancer (EORTC) as follows: proven if the child had microbiological or histological evidence of fungal tissue invasion or a positive fungal culture obtained from a sterile site, in addition to clinical or radiological findings consistent with fungal infection; probable, the presence of one or more host factors, a clinical criterion and one or more mycological criterion by a direct test (cytology, direct microscopy or culture) or an indirect test (detection of antigen); and possible, a case meeting host factor and clinical criteria but lacking any mycological documentation.25 Overall mortality at day 30 of follow-up: mortality due to any cause during the study period. IFD-related mortality: mortality attributable to IFD, according to a panel of experts, occurring during the study period, in a child with proven or probable IFD. Sample size The primary endpoint for this non-inferiority study was overall mortality at day 30 of follow-up. Sample size was calculated considering that overall mortality at day 30 of follow-up in children with persistent HRFN is 6%, as previously reported by our group.26,27 Considering the same frequency of overall mortality in both groups, a type I error of 0.05 and a potency of 90%, we calculated that 140 episodes of persistent HRFN were required. Based on our previous experience, we have determined our capacity to enrol 300 febrile neutropenic episodes per year for a total of 1000 episodes in 3.5 years. Statistical analysis Categorical variables were compared using the χ2 test or Fisher’s exact test depending on the number of episodes per comparison group. Continuous variables were compared according to distribution using Student’s t-test or the Mann–Whitney test. Overall mortality risk and the risk for secondary endpoints were evaluated for the exposed compared with the non-exposed groups, calculating the relative risk with the respective 95% CI. Statistical analyses were performed using GraphPad Prism version 6.01 and Stata IC version 14.0. Results Population characteristics A total of 1010/1180 febrile neutropenic episodes were evaluated between July 2013 and December 2016 in the five participating hospitals; 170 episodes were excluded: 97 rejected informed consent, 68 did not meet the inclusion criteria and 5 had incomplete data. Seven hundred and forty-one out of 1010 (73%) episodes were classified as HRFN episodes. At day 4 of follow-up, 153/741 (21%) had persistent HRFN and met the criteria for randomization, of which 149/153 (97%) were randomized, 73 into the empirical group and 76 into the pre-emptive group. Four episodes were not randomized owing to prophylactic use of voriconazole or posaconazole (Figure 1). Figure 1. View largeDownload slide Episodes of fever and neutropenia evaluated, enrolled and randomized during the study period. Figure 1. View largeDownload slide Episodes of fever and neutropenia evaluated, enrolled and randomized during the study period. Table 1 describes the main clinical characteristics of children with episodes of persistent HRFN randomized to empirical or pre-emptive antifungal therapy. No significant differences were observed in term of age, sex and type of cancer, with mainly haematological malignancy in both groups (85% and 88%, P = 0.56). Nearly 50% of the children had episodes of HRFN without clinical foci at admission; the other 50% of children had respiratory or intestinal foci. Table 1. Admission characteristics of 149 children with persistent fever and neutropenia, randomized into empirical versus pre-emptive antifungal therapy Characteristic Intervention P empirical, N = 73 pre-emptive, N = 76 Age (years), median (IQR) 6 (4–12) 7 (3–11) 0.84 Male, n (%) 39 (53) 43 (57) 0.69 Type of cancer, n (%)  leukaemia/lymphoma 46 (63) 49 (64) 0.85  leukaemia relapse 16 (22) 18 (24) 0.79  solid tumours 11 (15) 9 (12) 0.56 Use of granulocyte colony stimulating factor, n (%) 17 (23) 15 (20) 0.59 Use of central venous catheter, n (%) 62 (85) 64 (84) 0.90 Hours of fever prior to admission, median (IQR) 1 (1–3) 2 (1–4) 0.10 Admission clinical diagnosis, n (% )  fever without focus 35 (48) 37 (49) 0.92  respiratory infection 17 (23) 16 (21) 0.74  intestinal focus 18 (25) 19 (25) 0.96  othersa 3 (4) 4 (5) 0.73 Characteristic Intervention P empirical, N = 73 pre-emptive, N = 76 Age (years), median (IQR) 6 (4–12) 7 (3–11) 0.84 Male, n (%) 39 (53) 43 (57) 0.69 Type of cancer, n (%)  leukaemia/lymphoma 46 (63) 49 (64) 0.85  leukaemia relapse 16 (22) 18 (24) 0.79  solid tumours 11 (15) 9 (12) 0.56 Use of granulocyte colony stimulating factor, n (%) 17 (23) 15 (20) 0.59 Use of central venous catheter, n (%) 62 (85) 64 (84) 0.90 Hours of fever prior to admission, median (IQR) 1 (1–3) 2 (1–4) 0.10 Admission clinical diagnosis, n (% )  fever without focus 35 (48) 37 (49) 0.92  respiratory infection 17 (23) 16 (21) 0.74  intestinal focus 18 (25) 19 (25) 0.96  othersa 3 (4) 4 (5) 0.73 Categorical variables were compared using the χ2 test. Continuous variables were compared using the Mann–Whitney test. a Others: skin/soft-tissue infection. Table 1. Admission characteristics of 149 children with persistent fever and neutropenia, randomized into empirical versus pre-emptive antifungal therapy Characteristic Intervention P empirical, N = 73 pre-emptive, N = 76 Age (years), median (IQR) 6 (4–12) 7 (3–11) 0.84 Male, n (%) 39 (53) 43 (57) 0.69 Type of cancer, n (%)  leukaemia/lymphoma 46 (63) 49 (64) 0.85  leukaemia relapse 16 (22) 18 (24) 0.79  solid tumours 11 (15) 9 (12) 0.56 Use of granulocyte colony stimulating factor, n (%) 17 (23) 15 (20) 0.59 Use of central venous catheter, n (%) 62 (85) 64 (84) 0.90 Hours of fever prior to admission, median (IQR) 1 (1–3) 2 (1–4) 0.10 Admission clinical diagnosis, n (% )  fever without focus 35 (48) 37 (49) 0.92  respiratory infection 17 (23) 16 (21) 0.74  intestinal focus 18 (25) 19 (25) 0.96  othersa 3 (4) 4 (5) 0.73 Characteristic Intervention P empirical, N = 73 pre-emptive, N = 76 Age (years), median (IQR) 6 (4–12) 7 (3–11) 0.84 Male, n (%) 39 (53) 43 (57) 0.69 Type of cancer, n (%)  leukaemia/lymphoma 46 (63) 49 (64) 0.85  leukaemia relapse 16 (22) 18 (24) 0.79  solid tumours 11 (15) 9 (12) 0.56 Use of granulocyte colony stimulating factor, n (%) 17 (23) 15 (20) 0.59 Use of central venous catheter, n (%) 62 (85) 64 (84) 0.90 Hours of fever prior to admission, median (IQR) 1 (1–3) 2 (1–4) 0.10 Admission clinical diagnosis, n (% )  fever without focus 35 (48) 37 (49) 0.92  respiratory infection 17 (23) 16 (21) 0.74  intestinal focus 18 (25) 19 (25) 0.96  othersa 3 (4) 4 (5) 0.73 Categorical variables were compared using the χ2 test. Continuous variables were compared using the Mann–Whitney test. a Others: skin/soft-tissue infection. Outcome of children with persistent HRFN by study group Table 2 shows the clinical outcome of 149 randomized children, according to the intervention. Overall mortality at day 30 of follow-up was 8% (6/73) in the empirical arm and 5% (4/76) in the pre-emptive arm, with no difference in risks between groups (P = 0.47). In four of the ten children who died the expert panel concluded that mortality was related to an IFD, 2/73 (3%) in the group with empirical therapy and 2/76 (3%) in the group with pre-emptive therapy, with no difference in risk between groups (P = 0.97). The median number of days of antifungal therapy was 11 in the empirical arm and 6 in the pre-emptive arm (P < 0.001), the median number of days of fever was 9 in both groups (P = 0.76), the median number of days of hospitalization was 19 and 17, in the empirical and pre-emptive arms, respectively (P = 0.15), 12% of children developed IFD in each group (P = 0.92) and the need for ICU was 25% in the empirical arm and 20% in the pre-emptive arm (P = 0.47). Table 2. Clinical outcome of 149 children with persistent fever and neutropenia, randomized into empirical versus pre-emptive antifungal therapy Intervention P Relative risk (95% CI) empirical, N = 73 pre-emptive, N = 76 Primary endpoint  overall mortality at day 30, n (%) 6 (8) 4 (5) 0.47 0.64 (0.19–2.18) Secondary endpoints  IFD-related mortality at day 30, n (%) 2 (3) 2 (3) 0.97 0.96 (0.13–6.6)  days of fever, median (IQR) 9 (7–13) 9 (6–14) 0.76  days of hospitalization, median (IQR) 19 (14–23) 17 (13–22) 0.15  days of antifungal, median (IQR) 11 (7–16) 6 (3–13) <0.001  developing IFD, n (%) 9 (12) 9 (12) 0.92 0.96 (0.40–2.28)  antifungal start required, n (%) 32 (42)  antifungal modification required, n (%) 15 (21) 12 (16) 0.45 0.77 (0.39–1.53)  need for ICU, n (%) 18 (25) 15 (20) 0.47 0.80 (0.43–1.46) Intervention P Relative risk (95% CI) empirical, N = 73 pre-emptive, N = 76 Primary endpoint  overall mortality at day 30, n (%) 6 (8) 4 (5) 0.47 0.64 (0.19–2.18) Secondary endpoints  IFD-related mortality at day 30, n (%) 2 (3) 2 (3) 0.97 0.96 (0.13–6.6)  days of fever, median (IQR) 9 (7–13) 9 (6–14) 0.76  days of hospitalization, median (IQR) 19 (14–23) 17 (13–22) 0.15  days of antifungal, median (IQR) 11 (7–16) 6 (3–13) <0.001  developing IFD, n (%) 9 (12) 9 (12) 0.92 0.96 (0.40–2.28)  antifungal start required, n (%) 32 (42)  antifungal modification required, n (%) 15 (21) 12 (16) 0.45 0.77 (0.39–1.53)  need for ICU, n (%) 18 (25) 15 (20) 0.47 0.80 (0.43–1.46) Categorical variables were compared using the χ2 test. Continuous variables were compared using the Mann–Whitney test. Table 2. Clinical outcome of 149 children with persistent fever and neutropenia, randomized into empirical versus pre-emptive antifungal therapy Intervention P Relative risk (95% CI) empirical, N = 73 pre-emptive, N = 76 Primary endpoint  overall mortality at day 30, n (%) 6 (8) 4 (5) 0.47 0.64 (0.19–2.18) Secondary endpoints  IFD-related mortality at day 30, n (%) 2 (3) 2 (3) 0.97 0.96 (0.13–6.6)  days of fever, median (IQR) 9 (7–13) 9 (6–14) 0.76  days of hospitalization, median (IQR) 19 (14–23) 17 (13–22) 0.15  days of antifungal, median (IQR) 11 (7–16) 6 (3–13) <0.001  developing IFD, n (%) 9 (12) 9 (12) 0.92 0.96 (0.40–2.28)  antifungal start required, n (%) 32 (42)  antifungal modification required, n (%) 15 (21) 12 (16) 0.45 0.77 (0.39–1.53)  need for ICU, n (%) 18 (25) 15 (20) 0.47 0.80 (0.43–1.46) Intervention P Relative risk (95% CI) empirical, N = 73 pre-emptive, N = 76 Primary endpoint  overall mortality at day 30, n (%) 6 (8) 4 (5) 0.47 0.64 (0.19–2.18) Secondary endpoints  IFD-related mortality at day 30, n (%) 2 (3) 2 (3) 0.97 0.96 (0.13–6.6)  days of fever, median (IQR) 9 (7–13) 9 (6–14) 0.76  days of hospitalization, median (IQR) 19 (14–23) 17 (13–22) 0.15  days of antifungal, median (IQR) 11 (7–16) 6 (3–13) <0.001  developing IFD, n (%) 9 (12) 9 (12) 0.92 0.96 (0.40–2.28)  antifungal start required, n (%) 32 (42)  antifungal modification required, n (%) 15 (21) 12 (16) 0.45 0.77 (0.39–1.53)  need for ICU, n (%) 18 (25) 15 (20) 0.47 0.80 (0.43–1.46) Categorical variables were compared using the χ2 test. Continuous variables were compared using the Mann–Whitney test. After randomization, 32/76 (42%) children in the pre-emptive group received antifungal therapy within the 30 day follow-up period. The median number of days for the initiation of antifungal therapy in this group was 9 (IQR 7–11). The median number of days of neutropenia showed no difference between groups, with 9 days in the empirical arm (IQR 7–13) and 10 in the pre-emptive arm (IQR 7–15), P = 0.31. Diagnosis and outcome of children with proven or probable IFD by study group Eighteen children developed a proven or probable IFD during the study, nine in the empirical group and nine in the pre-emptive group. Possible cases were not considered for the analysis. The median age of children with IFD was similar in the two groups (9 and 8 years in the empirical and pre-emptive groups, respectively, P = 0.81). Most of the children were male (78% in each group, P = 1.00) and had a haematological malignancy (89% and 100% in the empirical and pre-emptive groups, respectively, P = 1.00). The outcome of children with proven and probable IFD was similar, irrespective of whether they were randomized into the empirical or pre-emptive group. The percentage of children with proven or probable IFD who died was 22% in each group (P = 1.00); the median number of days of fever was 13 and 17 (P = 0.18), the median number of days of hospitalization was 21 and 26 (P = 0.50) and the median number of days of antifungal use was 21 and 17 in the empirical and pre-emptive groups, respectively (P = 0.35); 33% in each group required antifungal modification (P = 1.00); and 56% and 44% in the empirical and pre-emptive groups, respectively, needed ICU admission (P = 1.00) (Table 3). Table 3. Demographic characteristics and clinical outcomes of 18 children with final diagnosis of proven or probable IFD, randomized into empirical versus pre-emptive antifungal therapy Intervention P empirical, N = 9 pre-emptive, N = 9 Characteristic  age (years), mean (SD) 9 (5) 8 (6) 0.81  male, n (%) 7 (78) 7 (78) 1.00  type of cancer, n (%)   leukaemia/lymphoma/leukaemia  relapse 8 (89) 9 (100) 1.00   solid tumours 1 (11) Clinical outcome  mortality, n (%) 2 (22) 2 (22) 1.00  days of fever, mean (SD) 13 (5) 17 (6) 0.18  days of hospitalization, median (IQR) 21 (20–38) 26 (23–32) 0.50  days of antifungal, median (IQR) 21 (18–33) 17 (14–26) 0.35  antifungal modification required, n (%) 3 (33) 3 (33) 1.00  need for ICU, n (%) 5 (56) 4 (44) 1.00 Intervention P empirical, N = 9 pre-emptive, N = 9 Characteristic  age (years), mean (SD) 9 (5) 8 (6) 0.81  male, n (%) 7 (78) 7 (78) 1.00  type of cancer, n (%)   leukaemia/lymphoma/leukaemia  relapse 8 (89) 9 (100) 1.00   solid tumours 1 (11) Clinical outcome  mortality, n (%) 2 (22) 2 (22) 1.00  days of fever, mean (SD) 13 (5) 17 (6) 0.18  days of hospitalization, median (IQR) 21 (20–38) 26 (23–32) 0.50  days of antifungal, median (IQR) 21 (18–33) 17 (14–26) 0.35  antifungal modification required, n (%) 3 (33) 3 (33) 1.00  need for ICU, n (%) 5 (56) 4 (44) 1.00 Categorical variables were compared using Fisher’s exact test. Continuous variables were compared using Student’s t-test or the Mann–Whitney test according to data distribution. Table 3. Demographic characteristics and clinical outcomes of 18 children with final diagnosis of proven or probable IFD, randomized into empirical versus pre-emptive antifungal therapy Intervention P empirical, N = 9 pre-emptive, N = 9 Characteristic  age (years), mean (SD) 9 (5) 8 (6) 0.81  male, n (%) 7 (78) 7 (78) 1.00  type of cancer, n (%)   leukaemia/lymphoma/leukaemia  relapse 8 (89) 9 (100) 1.00   solid tumours 1 (11) Clinical outcome  mortality, n (%) 2 (22) 2 (22) 1.00  days of fever, mean (SD) 13 (5) 17 (6) 0.18  days of hospitalization, median (IQR) 21 (20–38) 26 (23–32) 0.50  days of antifungal, median (IQR) 21 (18–33) 17 (14–26) 0.35  antifungal modification required, n (%) 3 (33) 3 (33) 1.00  need for ICU, n (%) 5 (56) 4 (44) 1.00 Intervention P empirical, N = 9 pre-emptive, N = 9 Characteristic  age (years), mean (SD) 9 (5) 8 (6) 0.81  male, n (%) 7 (78) 7 (78) 1.00  type of cancer, n (%)   leukaemia/lymphoma/leukaemia  relapse 8 (89) 9 (100) 1.00   solid tumours 1 (11) Clinical outcome  mortality, n (%) 2 (22) 2 (22) 1.00  days of fever, mean (SD) 13 (5) 17 (6) 0.18  days of hospitalization, median (IQR) 21 (20–38) 26 (23–32) 0.50  days of antifungal, median (IQR) 21 (18–33) 17 (14–26) 0.35  antifungal modification required, n (%) 3 (33) 3 (33) 1.00  need for ICU, n (%) 5 (56) 4 (44) 1.00 Categorical variables were compared using Fisher’s exact test. Continuous variables were compared using Student’s t-test or the Mann–Whitney test according to data distribution. The demographic, clinical, imaging and microbiological characteristics of the eighteen children with proven and probable IFD are described in Table 4. The most common species was Candida spp., causing seven cases of candidaemia. We also had seven cases of invasive aspergillosis, one proven and six probable, all with pneumonia (by clinical and imaging findings) and positive GM detection in serum and/or in BAL. Other diagnoses included Fusarium solani infection, Scedosporium apiospermum brain abscess, Sarocladium kiliense fungaemia and mucormycosis. Table 4. Demographic, clinical, imaging and microbiological characteristics of 18 children with proven or probable IFD Age [years (y) or months (m)]/sex Type of cancer Clinical focus and imaging Maximum GM Microbiological findings Outcome Randomization group Proven IFD  14 y/male ALL relapse sepsis/enterocolitis 0.2 BC(+) Candida albicans, BC(+) Klebsiella pneumoniae died empirical  17 y/male ALL relapse enterocolitis 0.4 BC(+) Candida glabrata favourable empirical  4 y/male ALL none 0.1 BC(+) C. albicans favourable empirical  4 y/male ALL relapse central venous catheter infection 0.3 BC(+) Candida parapsilosis, BC(+) Escherichia coli favourable pre-emptive  1 y/female AML enterocolitis 0.1 BC(+) Candida tropicalis, BC(+) Pseudomonas sp. favourable pre-emptive  17 y/male ALL relapse central venous catheter infection 0.2 BC(+) Candida lusitaniae, BC(+) CoNS favourable pre-emptive  4 m/male AML enterocolitis 0.3 BC(+) C. albicans favourable pre-emptive  12 y/female ALL relapse pneumonia 0.7 Aspergillus fumigatus in lung biopsy favourable pre-emptive  3 y/male AML pneumonia 0.7 BC(+) Fusarium solani favourable empirical  3 y/female ALL brain abscess 0.4 S. apiospermum in brain biopsy favourable empirical  13 y/male lymphoma none 0.2 BC(+) S. kiliense favourable empirical  11 y/male AML sinusitis/pneumonia 0.5 Rhizopus sp. in sinus biopsy favourable empirical Probable IFD  14 y/female ALL pneumonia 4.6 BC(+) E. coli favourable empirical  3 y/male AML pneumonia 6.4 (BAL) BC(+) CoNS died empirical  9 y/male solid tumour pneumonia 0.8 (BAL) none favourable empirical  11 y/male ALL relapse enterocolitis/pneumonia 4.6 BC(+) E. coli died pre-emptive  5 y/male ALL pneumonia 1.5 none favourable pre-emptive  10 y/male AML relapse pneumonia 7.7 (BAL) BC(+) CoNS died pre-emptive Age [years (y) or months (m)]/sex Type of cancer Clinical focus and imaging Maximum GM Microbiological findings Outcome Randomization group Proven IFD  14 y/male ALL relapse sepsis/enterocolitis 0.2 BC(+) Candida albicans, BC(+) Klebsiella pneumoniae died empirical  17 y/male ALL relapse enterocolitis 0.4 BC(+) Candida glabrata favourable empirical  4 y/male ALL none 0.1 BC(+) C. albicans favourable empirical  4 y/male ALL relapse central venous catheter infection 0.3 BC(+) Candida parapsilosis, BC(+) Escherichia coli favourable pre-emptive  1 y/female AML enterocolitis 0.1 BC(+) Candida tropicalis, BC(+) Pseudomonas sp. favourable pre-emptive  17 y/male ALL relapse central venous catheter infection 0.2 BC(+) Candida lusitaniae, BC(+) CoNS favourable pre-emptive  4 m/male AML enterocolitis 0.3 BC(+) C. albicans favourable pre-emptive  12 y/female ALL relapse pneumonia 0.7 Aspergillus fumigatus in lung biopsy favourable pre-emptive  3 y/male AML pneumonia 0.7 BC(+) Fusarium solani favourable empirical  3 y/female ALL brain abscess 0.4 S. apiospermum in brain biopsy favourable empirical  13 y/male lymphoma none 0.2 BC(+) S. kiliense favourable empirical  11 y/male AML sinusitis/pneumonia 0.5 Rhizopus sp. in sinus biopsy favourable empirical Probable IFD  14 y/female ALL pneumonia 4.6 BC(+) E. coli favourable empirical  3 y/male AML pneumonia 6.4 (BAL) BC(+) CoNS died empirical  9 y/male solid tumour pneumonia 0.8 (BAL) none favourable empirical  11 y/male ALL relapse enterocolitis/pneumonia 4.6 BC(+) E. coli died pre-emptive  5 y/male ALL pneumonia 1.5 none favourable pre-emptive  10 y/male AML relapse pneumonia 7.7 (BAL) BC(+) CoNS died pre-emptive BC, blood culture. Table 4. Demographic, clinical, imaging and microbiological characteristics of 18 children with proven or probable IFD Age [years (y) or months (m)]/sex Type of cancer Clinical focus and imaging Maximum GM Microbiological findings Outcome Randomization group Proven IFD  14 y/male ALL relapse sepsis/enterocolitis 0.2 BC(+) Candida albicans, BC(+) Klebsiella pneumoniae died empirical  17 y/male ALL relapse enterocolitis 0.4 BC(+) Candida glabrata favourable empirical  4 y/male ALL none 0.1 BC(+) C. albicans favourable empirical  4 y/male ALL relapse central venous catheter infection 0.3 BC(+) Candida parapsilosis, BC(+) Escherichia coli favourable pre-emptive  1 y/female AML enterocolitis 0.1 BC(+) Candida tropicalis, BC(+) Pseudomonas sp. favourable pre-emptive  17 y/male ALL relapse central venous catheter infection 0.2 BC(+) Candida lusitaniae, BC(+) CoNS favourable pre-emptive  4 m/male AML enterocolitis 0.3 BC(+) C. albicans favourable pre-emptive  12 y/female ALL relapse pneumonia 0.7 Aspergillus fumigatus in lung biopsy favourable pre-emptive  3 y/male AML pneumonia 0.7 BC(+) Fusarium solani favourable empirical  3 y/female ALL brain abscess 0.4 S. apiospermum in brain biopsy favourable empirical  13 y/male lymphoma none 0.2 BC(+) S. kiliense favourable empirical  11 y/male AML sinusitis/pneumonia 0.5 Rhizopus sp. in sinus biopsy favourable empirical Probable IFD  14 y/female ALL pneumonia 4.6 BC(+) E. coli favourable empirical  3 y/male AML pneumonia 6.4 (BAL) BC(+) CoNS died empirical  9 y/male solid tumour pneumonia 0.8 (BAL) none favourable empirical  11 y/male ALL relapse enterocolitis/pneumonia 4.6 BC(+) E. coli died pre-emptive  5 y/male ALL pneumonia 1.5 none favourable pre-emptive  10 y/male AML relapse pneumonia 7.7 (BAL) BC(+) CoNS died pre-emptive Age [years (y) or months (m)]/sex Type of cancer Clinical focus and imaging Maximum GM Microbiological findings Outcome Randomization group Proven IFD  14 y/male ALL relapse sepsis/enterocolitis 0.2 BC(+) Candida albicans, BC(+) Klebsiella pneumoniae died empirical  17 y/male ALL relapse enterocolitis 0.4 BC(+) Candida glabrata favourable empirical  4 y/male ALL none 0.1 BC(+) C. albicans favourable empirical  4 y/male ALL relapse central venous catheter infection 0.3 BC(+) Candida parapsilosis, BC(+) Escherichia coli favourable pre-emptive  1 y/female AML enterocolitis 0.1 BC(+) Candida tropicalis, BC(+) Pseudomonas sp. favourable pre-emptive  17 y/male ALL relapse central venous catheter infection 0.2 BC(+) Candida lusitaniae, BC(+) CoNS favourable pre-emptive  4 m/male AML enterocolitis 0.3 BC(+) C. albicans favourable pre-emptive  12 y/female ALL relapse pneumonia 0.7 Aspergillus fumigatus in lung biopsy favourable pre-emptive  3 y/male AML pneumonia 0.7 BC(+) Fusarium solani favourable empirical  3 y/female ALL brain abscess 0.4 S. apiospermum in brain biopsy favourable empirical  13 y/male lymphoma none 0.2 BC(+) S. kiliense favourable empirical  11 y/male AML sinusitis/pneumonia 0.5 Rhizopus sp. in sinus biopsy favourable empirical Probable IFD  14 y/female ALL pneumonia 4.6 BC(+) E. coli favourable empirical  3 y/male AML pneumonia 6.4 (BAL) BC(+) CoNS died empirical  9 y/male solid tumour pneumonia 0.8 (BAL) none favourable empirical  11 y/male ALL relapse enterocolitis/pneumonia 4.6 BC(+) E. coli died pre-emptive  5 y/male ALL pneumonia 1.5 none favourable pre-emptive  10 y/male AML relapse pneumonia 7.7 (BAL) BC(+) CoNS died pre-emptive BC, blood culture. Discussion In our study, pre-emptive antifungal therapy was as effective as empirical antifungal therapy in children with cancer and HRFN, with a significant reduction in antifungal use. A reduction of antifungal use, based on stringent diagnostic criteria, could favour the adoption of evidence-based management strategies in this population. This approach requires optimal laboratory support with rapid turnaround response. Introduction of non-culture-based diagnostic techniques into clinical practice could contribute to better management of these patients, favouring the possibility of patient-based individualized therapy. Active monitoring and early diagnostic workup is a necessary step prior to proposing an evidence-based management strategy.28–30 Studies comparing empirical versus pre-emptive antifungal therapy in adult populations have evaluated different endpoints: overall mortality, IFD-related mortality, percentage of patients with final diagnosis of IFD, percentage of patients receiving antifungal therapy and number of days of antifungal treatment.20 Overall mortality was our primary endpoint in accordance with studies in adult populations and because it represents the most relevant outcome in children. To our knowledge, this is the first prospective, multicentre, randomized study that compares standard versus pre-emptive antifungal therapy in HRFN children with prolonged fever and neutropenia. The comparative analysis between our study and studies in adult populations must be performed cautiously as populations and outcomes are different.28 The pending question of which is the best approach to antifungal therapy in children with cancer cannot be definitely answered until other groups replicate these findings. This study had limitations, including the lack of double-blinding, which was decided on because the majority of these children received antifungal therapy through their central venous catheter. We decided not to use the central venous catheter for a possible placebo in order to avoid potentially deleterious manipulation. Another limitation is that we did not evaluate the toxicity of antifungal therapy. Results in adult populations concluded that pre-emptive antifungal therapy has been related to reduction of antifungal drug use and associated toxicity, without increasing mortality.20 In our experience, 58% of patients of the pre-emptive group did not receive antifungal therapy, with similar clinical outcome to the empirical group, with the aim of reserving antifungal therapy for the subset of patients who have early evidence of IFD by careful clinical, laboratory, imaging and microbiological assessment. The main findings of our study lead us to propose a step forward in the rational approach to treating children with cancer focusing on one yet-unresolved issue in the management of the patients: adoption of a more selective pre-emptive antifungal treatment strategy in children with prolonged fever and neutropenia. Acknowledgements We thank the research nurses of the participant hospitals for their invaluable support in enrolling patients. We appreciate the support provided by Magdalena Bastías, RN, in the statistical analysis. We thank the FONDECYT programme for their support. Funding This study was supported by the National Fund for Scientific and Technological Development (FONDECYT), Chile (grant numbers 1120800 and 1161662). Transparency declarations None to declare. Author contributions Conception and design: María E. Santolaya, Milena Villarroel, Mauricio Farfán, Verónica de la Maza and Juan P. Torres. Collection and assembly of data: Ana M. Alvarez, Mirta Acuña, Carmen L. Avilés, Carmen Salgado, Juan Tordecilla, Monica Varas, Marcela Venegas and Marcela Zubieta. Data analysis and intrepretation: María E. Santolaya, Alejandra Vergara, Romina Valenzuela and Juan P. Torres. Manuscript writing and final approval of manuscript: all authors. References 1 Mor M , Gilad G , Kornreich L et al. Invasive fungal infections in pediatric oncology . Pediatr Blood Cancer 2011 ; 56 : 1092. 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Antifungal therapy in patients with fever and neutropenia—more rational and less empirical? N Engl J Med 2004 ; 351 : 1445 – 7 . Google Scholar Crossref Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

Journal of Antimicrobial Chemotherapy – Oxford University Press

Published: Oct 1, 2018

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