PREEMPTIVE VERSUS EMPIRICAL ANTIFUNGAL THERAPY FOR HIGH-RISK, FEBRILE, NEUTROPENIC SOLID TUMOR PATIENTS IN A LMIC SETTING

PREEMPTIVE VERSUS EMPIRICAL ANTIFUNGAL THERAPY FOR HIGH-RISK, FEBRILE, NEUTROPENIC SOLID TUMOR PATIENTS IN A LMIC SETTING | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Pediatric Blood & Cancer This is a preprint and has not been peer reviewed. Data may be preliminary. 8 July 2025 V1 Latest version Share on PREEMPTIVE VERSUS EMPIRICAL ANTIFUNGAL THERAPY FOR HIGH-RISK, FEBRILE, NEUTROPENIC SOLID TUMOR PATIENTS IN A LMIC SETTING Authors : Omnia Al Qadi 0009-0008-1089-1659 [email protected] , lobna shalaby , Mervat Elanany , Iman zaki , Maggie Naguib , Amr Kashef , Omneya Hassanain , Manal Zamzam , Leslie Lehmann , and Alaa Elhaddad Authors Info & Affiliations https://doi.org/10.22541/au.175198157.77006200/v1 420 views 238 downloads Contents Abstract Figure Legends Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background Pre-emptive antifungal therapy in neutropenic fever offers a rational alternative to the empiric strategy, potentially reducing drug toxicity, resistance, and treatment-related costs. However, its implementation in the Middle East and North Africa (MENA) region remains insufficiently addressed. Methods We prospectively observed episodes of neutropenia in Pediatric patients with solid tumors and prolonged neutropenia. This non-inferiority cohort study evaluated three primary endpoints: the cumulative incidence of invasive fungal infection (IFI), IFI-attributable mortality, and the rate of antifungal use. Outcomes from the prospective cohort managed with a pre-emptive strategy were compared with retrospective data from a historical cohort treated with the previously used empiric approach. Results A total of 422 pre-emptive episodes were prospectively recorded, and data from 338 historical empiric episodes were retrospectively reviewed. The incidence of IFI was comparable between the two groups (4·5% in the pre-emptive group vs 5·6% in the empiric group; p = 0·5). However, antifungal use was significantly lower in the pre-emptive group (5·0% vs 58·0%; p < 0·001). Overall survival was higher in the pre-emptive group (98·9% vs 94·6%). No IFI-attributable mortality was recorded in either group. Interpretation The combined EIA/HRCT-based pre-emptive strategy is feasible and associated with reduced antifungal use without compromising patient outcomes in Pediatric patients with solid tumors and prolonged neutropenia. PREEMPTIVE VERSUS EMPIRICAL ANTIFUNGAL THERAPY FOR HIGH-RISK, FEBRILE, NEUTROPENIC SOLID TUMOR PATIENTS IN A LMIC SETTING Omnia Al-Qadi 1 , Lobna Shalaby 1,2 , Mervat El Anany 3 , Iman Zaky 4 , Maggie Naguib 5 , Amr Kashef 6 , Omneya Hassanain 7 , Manal Zamzam 1,2 , Leslie Lehmann 8 , Alaa El Haddad 1,2 1 Pediatric Oncology Department and Pediatric Stem Cell Transplantation Unit, Children’s Cancer Hospital Egypt (CCHE 57357), Cairo, Egypt 2 Pediatric Oncology Department and Hematopoietic Stem Cell Transplantation, National Cancer Institute (NCI), Cairo University, Cairo, Egypt 3 Microbiology Department, Children’s Cancer Hospital Egypt (CCHE 57357), Cairo, Egypt 4 Radiology Department, Children’s Cancer Hospital Egypt (CCHE 57357), Cairo, Egypt 5 Pediatrics Department, Faculty of Medicine, Cairo University Children’s Hospital, Cairo, Egypt 6 Pharmacy Department, Children’s Cancer Hospital Egypt (CCHE 57357), Cairo, Egypt 7 Biostatistics and Epidemiology Unit, Research Department, Children’s Cancer Hospital Egypt (CCHE 57357), Cairo, Egypt 8 Pediatric Hematology Oncology and Stem Cell Transplantation Unit, Dana Farber/ Children’s Hospital Cancer Care Center, Boston, MA, USA Correspondence to: Omnia Al-Qadi Pediatric Oncology Department and Pediatric Stem Cell Transplantation Unit Children’s Cancer Hospital Egypt (CCHE 57357) Cairo 11712, Egypt Email: [email protected] Word Count: Abstract: 278 words (excluding the title ”Abstract” and the ”Keywords” section). Manuscript: 3,205 words (excluding title page, abstract, Conflicts of Interest, Acknowledgments, References, Tables, Figures, and Legends) Abstract Background Pre-emptive antifungal therapy in neutropenic fever offers a rational alternative to the empiric strategy, potentially reducing drug toxicity, resistance, and treatment-related costs. However, its implementation in the Middle East and North Africa (MENA) region remains insufficiently addressed. Methods We prospectively observed episodes of neutropenia in Pediatric patients with solid tumors and prolonged neutropenia. This non-inferiority cohort study evaluated three primary endpoints: the cumulative incidence of invasive fungal infection (IFI), IFI-attributable mortality, and the rate of antifungal use. Outcomes from the prospective cohort managed with a pre-emptive strategy were compared with retrospective data from a historical cohort treated with the previously used empiric approach. Results A total of 422 pre-emptive episodes were prospectively recorded, and data from 338 historical empiric episodes were retrospectively reviewed. The incidence of IFI was comparable between the two groups (4·5% in the pre-emptive group vs 5·6% in the empiric group; p = 0·5). However, antifungal use was significantly lower in the pre-emptive group (5·0% vs 58·0%; p < 0·001). Overall survival was higher in the pre-emptive group (98·9% vs 94·6%). No IFI-attributable mortality was recorded in either group. Interpretation The combined EIA/HRCT-based pre-emptive strategy is feasible and associated with reduced antifungal use without compromising patient outcomes in Pediatric patients with solid tumors and prolonged neutropenia. Keywords : Pre-emptive antifungal therapy; neutropenic fever; Pediatric oncology; invasive fungal infection; MENA region; EIA/HRCT strategy Introduction Fungal infections are a major cause of morbidity and mortality in high risk neutropenic population. Proper management can significantly reduce up to 80% of Invasive Fungal Infection (IFI) deaths. (Hahn-Ast et al. 2010) Empiric antifungal therapy, typically initiated based on clinical suspicion alone, was the standard approach for treating immunocompromised patients at risk for IFI, aiming to prevent delays in treatment. (J. Maertens et al. 2005) Several studies have demonstrated that, although empiric therapy effectively prevented the consequences of delayed treatment, it led to substantial antifungal misuse, with 40%-50% of neutropenic patients receiving antifungals despite a true incidence of only 10%-15%. This contributed to drug toxicity, antifungal resistance, and increased healthcare costs. (Anaissie, McGinnis, and Pfaller 2009) With advancements in diagnostic methods, the paradigm of antifungal introduction has shifted to more targeted, evidence-based preemptive approaches using non culture based diagnostic tools like the galactomannan enzyme immunoassay (EIA) and high resolution computed tomography (HRCT) scans. This strategy has proven to be a viable alternative for certain neutropenic patients, without adversely impacting mortality from IFI. Multiple studies support that this approach can reduce unnecessary antifungal use and its associated risks, while still effectively managing infections when diagnosed. (Freifeld et al. 2011; Johan Maertens et al. 2023) Thus far the preemptive strategy has not yet fully replaced the empiric approach, particularly in regions with limited evidence, such as the Middle East and North Africa (MENA). Investigating this within the MENA context is crucial to assess the potential benefits and limitations in light of the region’s unique environment, demographic, healthcare challenges, and resource constraints. Therefore, we aimed to evaluate the feasibility of a combined EIA/HRCT-based preemptive strategy in Pediatric patients with solid tumors and prolonged neutropenia in our institution, hypothesizing that this approach would reduce antifungal use without compromising patient outcomes. Patients and methods: Study design and participants This observational cohort study compared a pre-emptive antifungal strategy currently implemented at the Children’s Cancer Hospital Egypt (CCHE) with the previously used empiric approach for the management of immunocompromised Pediatric patients with solid tumors and persistent neutropenic fever. Eligible participants were aged ≤18 years, had a diagnosis of a solid tumor, and were admitted for supportive care during the nadir of immunosuppressive therapy. Neutropenic episodes were included if the duration of neutropenia exceeded 5 days. Exclusion criteria included a recent history (within 8 weeks) of proven or probable IFI, the presence of serious comorbidities likely to affect antifungal management, hereditary immunodeficiencies requiring antifungal prophylaxis, and previous hematopoietic stem cell transplantation (HSCT). More than one neutropenic episode per patient was included, provided no IFI was diagnosed during the episode. Once an IFI was diagnosed, the patient was excluded from further inclusion until complete resolution of the infection. The study was approved by the Institutional Review Board of CCHE, and written informed consent was obtained from parents or legal guardians, in accordance with institutional and ethical guidelines. Data Collection Details of febrile neutropenic treatment episodes were prospectively collected from February 17, 2020, to February 17, 2021. These were analyzed alongside retrospectively collected data from episodes of empiric antifungal therapy in patients admitted between Jan 1, 2018, and Jan 1, 2019. Definition of Febrile Neutropenia Febrile neutropenia was defined as a temperature of ≥38.3°C once or ≥38.0°C twice consecutively, accompanied by an absolute neutrophil count (ANC) <500 neutrophils/mm³ or expected to fall below the threshold within 48 hours. Diagnostic and Monitoring Protocol For the preemptive group, serial serum galactomannan levels were measured twice weekly from admission until recovery. Blood cultures were obtained every 72 hours in the presence of fever. Fungal screening, including CT of the paranasal sinuses, chest, and upper abdomen, was conducted on day 7 of persistent or relapsing fever with neutropenia, or earlier if clinically warranted. Weekly screening was continued once weekly for patients who remained febrile. Additional investigations, including cultures from other clinical sources, virological testing, broncho alveolar lavage, fungal panel PCR, and surgical biopsy, were conducted based on clinical assessment and in consultation with the infectious diseases team. All specimens were processed for direct microscopy and culture, fungal PCR, and histopathological evaluation. Definition, classification and treatment of Invasive Fungal Infections IFIs were diagnosed and classified according to the revised criteria of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSG) (Donnelly et al. 2020; Otto and Green 2020). A probable IFD required the presence of at least one host factor (e.g., immunocompromised), clinical features suggestive of fungal infection, and mycological evidence (e.g., fungal culture or molecular detection). This category is typically used for immunocompromised patients. In contrast. A proven IFD required definitive mycological evidence, such as histopathological or cultural identification of fungi in clinical specimens or biopsy tissue, regardless of immune status. Antifungal treatment was initiated preemptively if imaging features or mycological evidence of IFI were present, or if two consecutive and rising Galactomannan levels, with both levels ≥ 0.7, reference for cut off was based on the modified EORTC and the MSG revised criteria. (Donnelly et al. 2020) Antifungal agents included voriconazole (9 mg/kg per dose every 12 h with therapeutic drug monitoring), liposomal amphotericin B (3 mg/kg per day), and caspofungin (loading dose of 70 mg on day 1, followed by 50 mg daily). All included episodes were followed for 42 days from onset. The diagnostic and therapeutic workflow is illustrated in figure 1. Retrospective Comparison Group In the retrospective group, antifungal therapy was initiated empirically after 5 days of persistent, unexplained fever, despite broad-spectrum antibiotic coverage, or in cases of breakthrough fever following resolution of a prior episode during the neutropenic nadir. Liposomal amphotericin B (3 mg/kg per day) was the principal antifungal agent used in this group; however, other antifungal agents were administered as clinically indicated, in accordance with the EORTC/MSG criteria for the diagnosis of invasive fungal infections. (De Pauw et al. 2008) <> End Points The primary end points of this study were to assess the cumulative incidence of IFIs within 42 days from the onset of neutropenia, and IFI-attributable mortality. Secondary end points included the duration of neutropenia, length of hospital stay, and the rate of antifungal therapy use. Statistical analysis Descriptive analyses were conducted to report the demographic, clinical, and mycological characteristics of the study population. IFI-attributable mortality was defined as death directly linked to invasive fungal infections within six weeks from the onset of neutropenia, excluding other causes. The statistical analysis aimed to demonstrate the non-inferiority of the pre-emptive antifungal strategy compared with the empiric strategy in terms of the cumulative incidence of IFI. Non-inferiority was established if the upper bound of the 95% confidence interval (CI) for the difference in cumulative IFI incidence between the pre-emptive and empiric arms did not exceed a prespecified non-inferiority margin of 3%. Survival probabilities were estimated using the Kaplan–Meier method, and differences between treatment arms were evaluated using the log-rank test. For survival analysis, non-inferiority was established if the lower bound of the 95% CI for the difference in survival probability between the pre-emptive and empiric arms did not exceed the same non-inferiority margin of 3%. Continuous variables were summarized as means with standard deviations or medians with ranges and compared using Student’s t-test or the Mann–Whitney U test, as appropriate. Categorical variables were compared using the χ² test or Fisher’s exact test. A p value of less than 0.05 was considered statistically significant. Study population A total of 895 pre-emptive episodes were prospectively observed between February 17, 2020, and February 17, 2021. Of these, 455 episodes lasted more than five days, and 33 episodes were excluded due to initiation of antifungal therapy on an empirical basis, leaving 422 episodes eligible for inclusion. In addition, 809 empiric episodes from patients admitted between January 1, 2018, and January 1, 2019, were retrospectively reviewed. Of these, 421 episodes lasted fewer than five days, resulting in 338 episodes eligible for comparison. Therefore, a total of 422 pre-emptive episodes and 338 empiric episodes were included in the final analysis. A CONSORT-style flow diagram is presented in Figure 2. <> The median duration of neutropenia was 7 days in the pre-emptive group and 9 days in the empiric group. The median length of hospital stay was 7 days in the pre-emptive group and 10 days in the empiric group. Further characteristics of the study population are summarized in Table 1. <> Invasive fungal infections By day 42, there was no significant difference in the incidence of IFIs between the pre-emptive and empiric groups (4.5% vs 5.6%, p = 0.506). A total of 19 IFI cases were reported in each group. In the pre-emptive group, three cases were classified as probable and three as proven, whereas the empiric group reported seven proven cases. Further details are presented in Table 2. <> Overall survival The survival outcome in the pre-emptive group was non-inferior to that in the empiric group, with 420 patients surviving compared with 320 in the empiric group (98.9% vs 94.6%). The lower bound of the 95% confidence interval for the 42-day survival probability in the pre-emptive group remained above the pre-specified non-inferiority margin of 93.05%. These findings demonstrate that the pre-emptive strategy is non-inferior to the empiric approach with respect to overall survival, where death was the event of interest. <> Mortality By day 42 of the neutropenic episode, no deaths were attributed to invasive fungal infection in either group. Overall, 20 patients died: 2 in the pre-emptive group and 18 in the empiric group. Details of causes of death are presented in Table 3. <> Antifungal use The use of antifungal therapy was significantly lower in the pre-emptive group, with antifungal agents administered in only 5% of episodes, compared with 58% in the empiric group ( p <0.001). <> Details of antifungal class and duration are presented in Table 5. All patients who received pre-emptive antifungal therapy recovered, except for one patient who was non-compliant with treatment and lost to follow-up for 8 weeks. The patient later presented with severe chest infection and subsequently died. Cultures grew Candida dubliniensis , and PCR was positive for Pneumocystis jirovecii . <> Discussion: Our findings demonstrate that a combined galactomannan EIA and HRCT-based pre-emptive antifungal strategy is clinically effective and safe in pediatric patients with solid tumors admitted for fever and neutropenia. This approach significantly reduced antifungal use when compared to our previous approach, empiric antifungal therapy after 5 days of fever, without compromising survival or increasing the incidence of IFIs. There is limited definitive data comparing the efficacy of pre-emptive therapy and empiric therapy in oncology populations. Our findings are consistent with those of a previous modeling study conducted in a similar geographical region, which demonstrated that a diagnostic-driven approach in immunocompromised patients from Egypt and Algeria yielded comparable survival outcomes and was more cost-effective than empiric treatment. (Kaci et al. 2019) However, clinical studies in adult patients with hematological malignancies have reported mixed results. For instance, the PREVERT trial reported a higher incidence of IFIs in the pre-emptive group (16.4%) compared to the empiric group (3.8%) among patients receiving AML induction therapy, though overall survival remained comparable (95.1% vs 97.3%), demonstrating non-inferiority. Similarly, the Italian HEMA-e Chart study found a higher incidence of proven or probable Invasive Fungal Diseases (IFDs) in the pre-emptive group (23.7% vs 7·4%; p <0.001) and a higher IFD-related mortality rate (22.5% vs 7.1%; p =0·002). (Cordonnier et al. 2009; Pagano et al. 2011) Conversely, a study involving 549 patients with AML or myelodysplastic syndromes (MDS) receiving fluconazole prophylaxis demonstrated that a pre-emptive strategy was associated with comparable incidence of IFD by day 84 (7.7% vs 6.6%) and overall survival (96.7% vs 93.1%) compared to empiric therapy. Notably, the pre-emptive approach was associated with a significantly reduced use of caspofungin (27% vs 63%). (Johan Maertens et al. 2023) There are few pediatric studies directly comparing empirical and pre-emptive antifungal therapy in febrile neutropenia. However, a notable randomized trial by Santolaya involving 149 children with persistent high-risk febrile neutropenia in Chile demonstrated that only 42% of patients in the pre-emptive group required antifungal treatment. There were no significant differences between the empirical and pre-emptive groups in overall mortality (8% vs 5%; p =0·47), IFD-related mortality (3% in both groups; p =0·97), incidence of invasive fungal disease (12% in both groups; p =0·92), duration of fever, length of hospital stay, or intensive care unit admissions. (Santolaya et al. 2018) A recent analysis of major studies in pediatric patients was recently published and identified the above trial as the only one that allowed for robust analysis. (Sachdeva et al. 2024) Differences across studies may be attributable to variations in patient populations, diagnostic algorithms, and definitions of IFI. Given the limited data on IFI rates in North Africa, the inclusion of pediatric patients with solid tumors in our study was a deliberate and pragmatic choice. This population constitutes a substantial proportion of patients at our center, typically experiences shorter durations of neutropenia, and carries a lower baseline risk of IFIs, making it a suitable group for evaluating pre-emptive antifungal strategies. While our study provides valuable insights, several limitations must be acknowledged. One limitation of our study is the retrospective nature of the comparator group. Furthermore, the findings may not be generalizable to patients with hematological malignancies or SCT, who are at higher risk of IFIs due to prolonged neutropenia and immune dysfunction. Diagnostic accuracy also remains a challenge: false-positive results may lead to unnecessary antifungal use, whereas suboptimal sensitivity can delay diagnosis. Furthermore, the heterogeneity in galactomannan thresholds, access to PCR testing, and variable imaging protocols may influence diagnostic performance. Future studies should explore the applicability of pre-emptive strategies in high-risk hematological populations and evaluate the diagnostic performance and cost-effectiveness of fungal biomarkers in resource-limited settings. The authors declare no conflicts of interest. Acknowledgements: The authors used Open AI tools to assist with language editing during the manuscript preparation. The authors reviewed and verified all content and take full responsibility for its accuracy and integrity References: Anaissie, Elias J., Michael R. McGinnis, and Michael A. Pfaller. 2009. Clinical Mycology . Elsevier Health Sciences.Cordonnier, Catherine, Cécile Pautas, Sébastien Maury, Anne Vekhoff, Hassan Farhat, Felipe Suarez, Nathalie Dhédin, et al. 2009. “Empirical versus Preemptive Antifungal Therapy for High‐Risk, Febrile, Neutropenic Patients: A Randomized, Controlled Trial.” Clinical Infectious Diseases 48 (8): 1042–51. https://doi.org/10.1086/597395.De Pauw, Ben, Thomas J. Walsh, J. Peter Donnelly, David A. Stevens, John E. Edwards, Thierry Calandra, Peter G. Pappas, et al. 2008. “Revised Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group.” Clinical Infectious Diseases 46 (12): 1813–21. https://doi.org/10.1086/588660.Donnelly, J Peter, Sharon C Chen, Carol A Kauffman, William J Steinbach, John W Baddley, Paul E Verweij, Cornelius J Clancy, et al. 2020. “Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium.” Clinical Infectious Diseases 71 (6): 1367–76. https://doi.org/10.1093/cid/ciz1008.Freifeld, Alison G., Eric J. Bow, Kent A. Sepkowitz, Michael J. Boeckh, James I. Ito, Craig A. Mullen, Issam I. Raad, Kenneth V. Rolston, Jo-Anne H. Young, and John R. 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Von Lilienfeld-Toal. 2010. “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.” Journal of Antimicrobial Chemotherapy 65 (4): 761–68. https://doi.org/10.1093/jac/dkp507.Kaci, Zohra, Lobna Shalaby, Sherif Kamal, Nadia Boudjerra, Xin Gao, Mei Xue, Salim Ait Belkacem, Ahmed Gab Allah Ibrahim, Ramy Kotb, and Claudie Charbonneau. 2019. “Treatment of Immunocompromised Patients with Suspected Invasive Fungal Infections: Economic Analysis of Diagnostic-Driven versus Empirical Strategies in Algeria and Egypt.” Expert Review of Pharmacoeconomics & Outcomes Research 19 (6): 693–700. https://doi.org/10.1080/14737167.2019.1604225.Maertens, J., K. Theunissen, G. Verhoef, J. Verschakelen, K. Lagrou, E. Verbeken, A. Wilmer, J. Verhaegen, M. Boogaerts, and J. V. Eldere. 2005. “Galactomannan and Computed Tomography-Based Preemptive Antifungal Therapy in Neutropenic Patients at High Risk for Invasive Fungal Infection: A Prospective Feasibility Study.” Clinical Infectious Diseases 41 (9): 1242–50. https://doi.org/10.1086/496927.Maertens, Johan, Tom Lodewyck, J Peter Donnelly, Sylvain Chantepie, Christine Robin, Nicole Blijlevens, Pascal Turlure, et al. 2023. “Empiric vs Preemptive Antifungal Strategy in High-Risk Neutropenic Patients on Fluconazole Prophylaxis: A Randomized Trial of the European Organization for Research and Treatment of Cancer.” Clinical Infectious Diseases 76 (4): 674–82. https://doi.org/10.1093/cid/ciac623.Otto, William R., and Abby M. Green. 2020. “Fungal Infections in Children with Haematologic Malignancies and Stem Cell Transplant Recipients.” British Journal of Haematology 189 (4): 607–24. https://doi.org/10.1111/bjh.16452.Pagano, L., M. Caira, A. Nosari, C. Cattaneo, R. Fanci, A. Bonini, N. 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Tables Table 1. Baseline characteristics of febrile neutropenic episodes in the pre-emptive and empiric groups . Data are presented as median (IQR), mean (SD), or n (%), as appropriate. Age Mean 4.82 (3.40) 4.96 (3.19) Median 4.96 (3.19) 4.00 [0.800, 17.0] Sex Male 231 (54.7%) 179 (53.0%) Female 191 (45.3%) 159 (47.0%) Diagnosis Neuroblastoma 227 (53.7%) 210 (62.1%) CNS Tumors 84 (19.9%) 28 (8.2%) Renal Tumors 37 (8.7%) 49 (14.4%) Soft Tissue Sarcomas 60 (14.2%) 36 (10.6%) Retinoblastoma 4 (0.9%) 6 (1.7%) Hepatoblastoma 1 (0.2%) 6 (1.7%) Germ Cell Tumors 6 (1.4%) 3 (0.8%) Rare Tumors 3 ( 0.7%) 0 Duration of neutropenia Mean 7.84 (3.11) 10.2 (3.56) Median 7.00 [5.00, 33.0] 9.00 [5.00, 37.0] Missing 0 (0%) 1 (0.3%) Hospital Stay Duration Mean 8.44 (3.88) 12.1 (5.79) Median 7.00 [5.00, 33.0] 10.0 [5.00, 58.0] Missing 0 (0%) 1 (0.3%) Mucositis Grade < 3 373 (88.4%) 258 (76.3%) ≥ 3 49 (11.6%) 80 (23.7%) Persistent/Relapsing fever N 311 (73.7%) 125 (37.0%) Y 111 (26.3%) 213 (63.0%) Clinically detectable focus of infection Cellulitis 19 (4.5%) 21 (6.2%) Enter colitis 26 (6.2%) 24 (7.1%) Otitis externa 0 (0%) 1 (0.3%) Otitis media 2 (0.5%) 1 (0.3%) Parotitis 0 (0%) 1 (0.3%) Chest infection 1 (0.2%) 0 (0%) No detectable focus 374 (88.6%) 290 (85.8%) GM = galactomannan; IFI = invasive fungal infection; CT = computed tomography; BAL = bronchoalveolar lavage. Table 2. Invasive fungal infections by category, organism, and source in the pre-emptive and empiric groups . Data are presented as number (%) unless otherwise indicated. n Rate n Rate Total IFI 19 (4.5%) 19 (5.6%) IFI category Possible 13 (3.1%) 12 (3.6%) Probable 3 (0.7%) 0 (0%) Proven 3 (0.7%) 7 (2.1%) Candidemia 3 7 Species Candida Tropicalis 3 3 Candida Albicans 0 3 Other Candida species 0 1 Source Blood 3 2 BAL 0 1 CVL 0 2 Tissue 0 2 Aspergillosis Documented By GM blood 3 0 Documented By GM BAL 0 0 Documented by culture of BAL 0 0 Documented by culture of tissue 0 1 GM = galactomannan; BAL = broncho alveolar lavage; CVL = central venous line. Table 3. Causes of death within 42 days n n Total of deaths 2 18 Cause of death Disease progression 0 3 Cardiac failure 0 1 Respiratory failure 0 4 Septic shock 2 10 Table 4. Antifungal therapy uses in both groups Antifungal use No 401 (95.0%) 142 (42.0%) <0.001 Yes 21 (5.0%) 196 (58.0%) Table 5. Antifungal therapy use, class, and duration in the pre-emptive and empiric groups Antifungal Class Echinocandins 3 7 <0.001 Active azoles 6 5 Polyene 12 184 Antifungal Duration Mean (SD) 7.29 (4.58) 8·18 (5.33) Median [Min, Max] 6.00 [2.00, 21.0] 7·00 [3·00, 40.0] Figure Legends Figure 1. Diagnostic and therapeutic workflow for the pre-emptive group. Routine galactomannan surveillance and antibacterial therapy are followed by targeted diagnostic evaluation and antifungal treatment based on predefined clinical and diagnostic criteria. Abbreviations : GM = galactomannan; BAL = broncho alveolar lavage; IFI = invasive fungal infection; CT = computed tomography; PNS = paranasal sinuses. Figure 2. CONSORT-style flow diagram of episode selection. Febrile neutropenic episodes managed with pre-emptive or empiric antifungal strategies were assessed. A total of 422 pre-emptive episodes and 338 empiric episodes were included in the analysis. Figure 3: Kaplan–Meier survival curves for the pre-emptive and empiric antifungal strategy groups Survival was assessed over 42 days from onset of neutropenia. The pre-emptive strategy was non-inferior to the empiric approach (98.9% vs 94.6%). Abbreviations : ANC = absolute neutrophil count BAL = broncho alveolar lavage CI = confidence interval CT = computed tomography CVL = central venous line EIA = enzyme immune essay GM = galactomannan HRCT = high resolution computed tomography HSCT = hematopoietic stem cell transplantation IFD = invasive fungal Disease IFI = invasive fungal infection MENA = Middle East and North Africa PNS = paranasal sinuses Information & Authors Information Version history V1 Version 1 08 July 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Pediatric Blood & Cancer Keywords febrile neutropenia pediatric oncology solid tumors Authors Affiliations Omnia Al Qadi 0009-0008-1089-1659 [email protected] Children's Cancer Hospital Egypt 57357 View all articles by this author lobna shalaby Children's Cancer Hospital Egypt 57357 View all articles by this author Mervat Elanany Children's Cancer Hospital Egypt 57357 View all articles by this author Iman zaki Children's Cancer Hospital Egypt 57357 View all articles by this author Maggie Naguib Cairo University Pediatrics Department View all articles by this author Amr Kashef Children's Cancer Hospital Egypt 57357 View all articles by this author Omneya Hassanain Children's Cancer Hospital Egypt 57357 View all articles by this author Manal Zamzam Children's Cancer Hospital Egypt 57357 View all articles by this author Leslie Lehmann Dana-Farber/Boston Children's Cancer and Blood Disorders Center View all articles by this author Alaa Elhaddad Children's Cancer Hospital Egypt 57357 View all articles by this author Metrics & Citations Metrics Article Usage 420 views 238 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Omnia Al Qadi, lobna shalaby, Mervat Elanany, et al. PREEMPTIVE VERSUS EMPIRICAL ANTIFUNGAL THERAPY FOR HIGH-RISK, FEBRILE, NEUTROPENIC SOLID TUMOR PATIENTS IN A LMIC SETTING. Authorea . 08 July 2025. DOI: https://doi.org/10.22541/au.175198157.77006200/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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