Efficacy and safety of withholding antimicrobial therapy in children with cancer, fever, and neutropenia, with a demonstrated viral respiratory infection: a randomized clinical trial.

OBJECTIVES: To validate the efficacy and safety of withholding antimicrobial therapy in a new cohort of children with cancer and febrile neutropenia (FN) having a demonstrated viral respiratory tract infection. METHODS: Prospective, multicenter, noninferiority, randomized study, approved by the ethical committee, in children presenting with FN at seven hospitals in Chile, evaluated at admission for diagnosis of bacterial and viral pathogens. Children who were positive for a respiratory virus, negative for a bacterial pathogen, and had a favourable evolution after 48-72 hours of antimicrobial therapy were randomized to either maintain or withhold antimicrobial therapy. The primary endpoint was the percentage of episodes with an uneventful resolution, whereas the secondary endpoints were days of fever, days of hospitalization, requirement of antimicrobial treatment readministration, sepsis, paediatric intensive care unit admission, and death. RESULTS: A total of 301 of 939 children with FN episodes recruited between March 2021 and December 2023 had a respiratory virus as a unique identified microorganism, of which 139 had a favourable evolution at 48-72 hours and were randomized, 70 to maintain and 69 to withdraw antimicrobial therapy. The median days of antimicrobial therapy was 5 (IQR 3-6) versus 3 (IQR 3-6) days (p < 0.001), with similar frequency of uneventful resolution 66/70 (94%) and 66/69 (96%); relative risk, 1.01; (95% CI, 0.93 to 1.09), absolute risk difference 0.01; (95% CI, -0.05 to 0.08) and similar number of days of fever and days of hospitalization. No cases of sepsis, paediatric intensive care unit admission, or death were reported. DISCUSSION: We validated the strategy of withdrawal antimicrobial therapy in children with FN and viral respiratory tract infection based on clinical and microbiological/molecular diagnostic criteria. This will enable advances in antimicrobial stewardship strategies with a possible future impact on antimicrobial resistance.

Usefulness of Peripheral Blood Cultures in Children With Cancer and Episodes of Fever and Neutropenia.

BACKGROUND: The collection of blood cultures (BC) is key for guiding antimicrobial therapy in children with febrile neutropenia (FN), more than 90% have central venous catheters (CVC). There is no consensus on the need for peripheral BC over central BC in this population. The aim of this study was to determine the contribution of peripheral BC over central BC in the diagnosis of bloodstream infections in children with FN. METHODS: Descriptive, retrospective study, episodes of FN recorded prospectively in 6 hospitals in Santiago, Chile, from 2016 to 2021. Central and peripheral BC were drawn upon admission. All episodes with at least one (+) BC were allocated to one of these groups: consistent (+) BC, inconsistent (+) BC, only CVC (+) BC and only peripheral (+) BC. The volume of the samples was recorded. RESULTS: The analysis included 241 episodes of FN with at least one (+) BC. The median age was 7.2 years, 51% were female, 84% had hematological cancer and 98% had episodes of high-risk FN. Of a total of 241 episodes, 135 (56%) had consistent (+) BC, 13 (5%) had inconsistent (+) BC, 35 (15%) had only CVC (+) BC and 58 (24%) had only peripheral (+) BC. There were no significant differences in the volume of the samples between central and peripheral BC. CONCLUSIONS: The proportion of bloodstream infections detected only through peripheral BC was 24%, higher than previously reported, not due to sample volume. We recommend obtaining peripheral as well CVC BC in children with FN.

Clinical Outcome in Children With Cancer With Two or More Microorganisms Isolated From Blood Cultures During Episodes of Fever and Neutropenia.

BACKGROUND: Bacterial bloodstream infections are a major cause of morbidity and mortality in children with cancer and episodes of fever and neutropenia (FN). The aim of this study was to evaluate the clinical outcome in children with cancer with 2 or more microorganisms isolated from blood cultures during their episodes of FN. METHODS: Between 2016 and 2021, children presenting with high-risk FN, admitted to any of the 6 participating hospitals in Santiago, Chile, were included in this study if they have positive blood cultures. We compared the clinical outcome of children with 2 or more microorganisms versus those with single agent isolation. RESULTS: A total of 1074 episodes of high-risk FN were enrolled in the study period, of which 27% (298) had positive blood cultures and 3% (32) had 2 or more microorganisms isolated from blood cultures. The most frequent identified agents were Viridans group streptococci and Escherichia coli in 20%, followed by Coagulase negative staphylococci in 14%. Children with 2 or more microorganisms presented more days of fever (7 vs. 4 days, P = 0.02), needed longer courses of antimicrobial therapy (16 vs. 14 days, P = 0.04) and had higher mortality at day 30 (13% vs. 1%, P = 0.003). CONCLUSIONS: Children with cancer and FN with 2 or more microorganisms isolated from blood cultures had a worse clinical outcome than children with single agent isolation.

Cytokine and chemokine profiles in episodes of persistent high-risk febrile neutropenia in children with cancer.

BACKGROUND: In children with cancer and persistent high-risk febrile neutropenia (HRFN), cytokines/chemokines profiles can guide the differentiation of febrile neutropenia (FN) due to infections and episodes of unknown origin (FN-UO). METHODS: A prospective, multicenter study in Santiago, Chile included patients ≤ 18 years with cancer and HRFN. Clinical and microbiological studies were performed according to validated protocols. Serum levels of 38 cytokines/chemokines were determined on day 4 of persistent HRFN. We performed comparisons between i) HRFN episodes with a detected etiological agent (FN-DEA) and FN-UO, and ii) bacterial versus viral infections. ROC curves were used to assess the discriminatory power of the analytes. RESULTS: 110 HRFN episodes were enrolled (median age 8 years, 53% female). Eighty-four patients were FN-DEA: 44 bacterial, 32 viral, and 8 fungal infections. Twenty-six cases were categorized as FN-UO. Both groups presented similar clinical and laboratory characteristics. Nineteen out of 38 analytes had higher concentrations in the FN-DEA versus FN-UO group. G-CSF, IL-6, and Flt-3L showed the highest discriminatory power to detect infection (AUC 0.763, 0.741, 0.701). Serum levels of G-CSF differentiated bacterial infections and IP-10 viral agents. A combination of G-CSF, IL-6, Flt-3L, and IP-10 showed an AUC of 0.839, 75% sensitivity, and 81% specificity. CONCLUSION: A specific immune response is present on day four of persistent HRFN in children with cancer. We propose a combined measure of serum concentrations of G-CSF, IL-6, IP-10, and Flt-3L, in order to predict the presence of an infectious agent as compared to an episode of FN with unknown origin.

Infecciones respiratorias virales en episodios de fiebre en niños con trasplante de precursores hematopoyéticos / Respiratory viral infections during episodes of fever in children undergoing hematopoietic stem cell transplantation

Resumen Introducción: Los niños que reciben trasplante de precursores hematopoyéticos (TPH) pueden presentar infecciones respiratorias virales (IRV) durante episodios febriles. Los datos sobre su evolución clínica son escasos, así como la comparación de ellos con infecciones bacterianas (IB). Objetivo: Caracterizar la evolución clínica de pacientes con IRV, en comparación con IB en niños con TPH, cursando un episodio febril. Método: Estudio prospectivo en pacientes ≤ 18 años con cáncer y TPH ingresados por fiebre en el Hospital Luis Calvo Mackenna (2016-2019). Se realizó evaluación clínica y de laboratorio: hemocultivos, RPC para patógenos respiratorios (Filmarray®), cuantificación viral y medición de citoquinas en muestra nasal (Luminex®, 38 citoquinas). Se compararon los grupos IRV, IB y los de etiología no precisada (ENP) en relación con: infección respiratoria aguda (IRA), citoquinas nasales, ingreso a UCI, necesidad de ventilación mecánica, mortalidad y suspensión de antimicrobianos. Resultados: De 56 episodios febriles, 35 fueron IRV, 12 IB y 9 de ENP. Mediana de edad fue 8,5 años, 62% masculino. Un 94% de los casos IRV presentó IRA sintomática, versus 33% en los grupos IB y ENP (p < 0,001), con IRA baja en 69% de las IRV (p < 0,001). Rinovirus (54%) y coronavirus (15%) fueron las etiologías más frecuentemente detectadas. No hubo diferencias en citoquinas nasales entre los grupos IRV e IB. Ingreso a UCI: 11% del grupo IRV, 17% de IB y 11% de ENP (p = 0,88). Requirieron ventilación mecánica sólo 2 pacientes (p = 0,37) sin fallecimiento. Tras la detección viral respiratoria por RPC, se suspendió antimicrobianos en 26% de los casos con IRV (p = 0,04). Conclusión: Las IRV son frecuentes en niños con TPH y episodios febriles. La detección viral podría optimizar y racionalizar el uso de antimicrobianos en esta población.

Abstract Background: Children undergoing hematopoietic stem cell transplant (HSCT) can develop respiratory viral infections (RVI) during fever episodes. There are few data about clinical outcomes in RVI and compared to bacterial infections (BI) in this population. Aim: To determine clinical outcome of RVI, compared to BI in children with HSCT. Methods: Prospective study, patients ≤ 18 years with cancer and HSCT admitted with fever at a National Bone Marrow Transplant Center (Hospital Calvo Mackenna), Chile, (April-2016 to May-2019). Clinical assessment, laboratory tests, blood cultures, nasopharyngeal sample for multiplex-PCR (Filmarray®), viral loads by PCR and cytokine panel (Luminex®, 38 cytokines) were performed. The following outcomes were evaluated: upper/lower respiratory tract disease (RTD), admission to ICU, mechanical ventilation, mortality and antimicrobial withdrawal. Results: Of 56 febrile episodes, 35 (63%) were RVI, 12 (21%) BI and 9 (16%) with unknown etiology (UE). Median of age was 8.5 years, 62% male gender. Rhinovirus (54%) and coronavirus (15%) were the more frequent detected viruses. No significant differences in cytokine levels were observed between RVI and BI. 94% of RVI patients had symptomatic RTD, versus 33% in BI and 33% in UE group (p < 0.001), with lower-RTD in 69% of RVI group (p < 0,001). Admission to ICU was 11% in RVI, 17% in BI and 11% in UE group (p = 0.88); only 2 patients required mechanical ventilation (p = 0.37) and no mortality was reported. After an RVI was detected by PCR, antimicrobials were withdrawal in 26% of patients with RVI (p: 0.04). Conclusion: RVI are frequent etiologic agents in febrile episodes of patients with HSCT. Viral detection might help to rationalize the use of antimicrobials in this population.

Caracterización clínica y microbiológica de episodios de bacteriemia por Streptococcus grupo viridans en niños con cáncer y neutropenia febril de alto riesgo / Clinical characteristics and microbiological profile of viridans group streptococci bacteremia in children with cancer and high-risk febrile neutropenia

Resumen Introducción: Streptococcus grupo viridans (SGV) ha adquirido relevancia como microorganismo causante de neutropenia febril, asociándose a morbilidad significativa. Objetivo: Caracterizar episodios de bacteriemia causados por SGV en niños con cáncer que desarrollaron neutropenia febril de alto riesgo (NFAR) desde abril de 2004 a junio de 2018 en seis hospitales pediátricos de Santiago, Chile. Pacientes y Métodos: Análisis retrospectivo de bases de datos de cuatro proyectos FONDECYT sucesivos, prospectivos y multicéntricos, registrando características clínicas y de laboratorio de los pacientes, además de patrón de resistencia antimicrobiana de las cepas aisladas. Resultados: Se registraron 95 episodios de bacteriemia asociada a SGV en 91 niños con NFAR. Destacan: leucemia mieloide aguda como enfermedad de base, neutropenia profunda, hospitalización prolongada (15 días), uso extendido de antimicrobianos (14 días), uso de citarabina en esquemas de quimioterapia (86% episodios). Las manifestaciones clínicas más frecuentes fueron respiratoria y gastrointestinal, asociándose en 26% a síndrome de shock por Streptococcus grupo viridans. Hubo elevada resistencia a β lactámicos, sin cepas no susceptibles a vancomicina. Discusión: SGV es un patógeno relevante en niños con cáncer, fiebre y neutropenia en nuestro medio, asociado a casos de sepsis. La resistencia a β lactámicos es un aspecto que requiere vigilancia epidemiológica estricta en esta población.

Abstract Background: Viridans group streptococci (VGS) has acquired relevance as a microorganism causing febrile neutropenia, associated with significant morbidity. Aim: To characterize episodes of bacteremia caused by VGS in children with cancer who developed high-risk febrile neutropenia (HRFN) during the period from April 2004 to June 2018 in six pediatric hospitals of Santiago, Chile. Method: Database analysis of 4 successive, prospective and multicentric studies recording clinical and laboratory characteristics of patients, as well as antimicrobial susceptibility pattern of isolated strains. Results: 95 episodes of VGS bacteremia in 91 children with HRFN were analyzed. It emphasizes acute myeloid leukemia as cancer type, deep neutropenia, prolonged hospitalization (15 days), with extended use of antimicrobials (14 days) and use of cytarabine in chemotherapy schemes (86% episodes). The most frequent clinical manifestations were respiratory and gastrointestinal, associating up to 26% viridans group shock syndrome. There was high resistance to β lactams. As expected, there were not non-susceptible strains to vancomycin. Discussion: VGS is a relevant microorganism in children with cancer, fever and neutropenia, with a high percentage of sepsis. Resistance to β lactams is an issue that requires strict epidemiological surveillance in this population.

Utility of basic clinical and laboratory parameters to predict Serious Bacterial Infection in children younger than 3 months old hospitalized for Febrile Syndrome without Source. / Utilidad de los parámetros clínicos y de laboratorio básicos para predecir infección bacteriana seria en menores de 3 meses que se hospitalizan por síndrome febril sin foco.

INTRODUCTION: In 20% of children with febrile syndrome, it appears as fever of unknown origin (FUO) syndrome. Management strategies in this group have high sensitivity but low specificity. OBJECTIVES: To cha racterize serious bacterial infections (SBI) in children younger than three months old hospitalized because of FUO syndrome and to evaluate the utility of clinical and laboratory parameters in the identification of patients that are at high risk of SBI. PATIENTS AND METHOD: Prospective study in patients aged < 3 months hospitalized due to FUO syndrome between January 2014 and November 2015 in two pediatric hospitals in the Metropolitan Region. INCLUSION CRITERIA: age 4 days - 3 months, fever > 38°C longer than 72 hours after onset without demonstrable cause. EXCLUSION CRITERIA: anti microbial use up to 7 days before admission, preterm infants < 34 weeks, birth weight < 2 kg, and im munocompromised. Demographic, clinical, and laboratory tests data were recorded as well as blood count and CRP, discharge diagnosis, and ruled out, probable or confirmed SBI. RESULTS: 32% of the patients were discharged with diagnosis of SBI, 28% with diagnosis of viral or probably viral infec tion, 34% with diagnosis of not specified FUO syndrome, and 6% due to other causes. There were no significant differences in the CRP value, altered WBCs count, toxic aspect, or hours of fever at the admission when comparing groups with and without SBI (p < 0.05). The combination of clinical and laboratory parameters showed 27% of sensitivity, 90% of specificity, 60% of PPV, and 71% of NPV. CONCLUSION: It was not possible to establish clinical and laboratory parameters that allow the identifi cation of children younger than 3 months old at high risk of SBI, however, they maintain their value as low risk indicators. It is necessary further investigation of other clinical and laboratory elements that allow discriminating SBI from viral infections.

Usefulness of serum galactomannan in initiating and modifying antifungal therapy in children with cancer and persistent high-risk febrile neutropenia.

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

Utilidad de los parámetros clínicos y de laboratorio básicos para predecir infección bacteriana seria en menores de 3 meses que se hospitalizan por síndrome febril sin foco / Utility of basic clinical and laboratory parameters to predict Serious Bacterial Infection in children younger than 3 months old hospitalized for Febrile Syndrome without Source

Resumen: Introducción: Un 20% de los niños con síndrome febril se presenta como síndrome febril sin foco (SFSF). Las es trategias de manejo en este grupo presentan alta sensibilidad, pero baja especificidad. Objetivos: Ca racterizar las infecciones bacterianas serias (IBS) en menores de 3 meses hospitalizados por SFSF, y evaluar utilidad de parámetros clínicos y de laboratorio en la identificación de pacientes con alto riesgo de IBS. Pacientes y Método: Estudio prospectivo en pacientes < 3 meses hospitalizados entre enero 2014 y noviembre 2015 por SFSF en dos hospitales pediátricos de la Región Metropolitana. Criterios de inclusión: edad 4 días - 3 meses, fiebre > 38°C de < 72 h de evolución sin causa demostra ble. Criterios de exclusión: uso de antimicrobianos hasta 7 días previo a su ingreso, prematuros < 34 semanas, peso de nacimiento < 2 kg e inmunocomprometidos. Se registraron datos demográficos, clínicos, y exámenes de laboratorio, hemograma y PCR, diagnóstico de egreso, IBS descartada, IBS probable o confirmada. Resultados: 32% de los pacientes egresó con diagnóstico de IBS, 28% con diagnóstico de infección viral o probablemente viral, 34% con diagnóstico de SFSF no especificado y 6% SFSF por otras causas. No se encontraron diferencias significativas en PCR, leucocitosis, aspecto tóxico ni horas de fiebre al ingreso al comparar los grupos con y sin IBS (p > 0,05). La combinación de parámetros clínicos y de laboratorio mostro sensibilidad de 27%, especificidad de 90%, VPP 60% y VPN 71%. Conclusión: No fue posible establecer que parámetros clínicos y de laboratorio permitan identificar menores de 3 meses con alto riesgo de IBS, manteniendo su utilidad como indicadores de bajo riesgo. Es necesario contar con otros elementos clínicos y de laboratorio que permitan discrimi nar IBS de infecciones virales.

Abstract: Introduction: In 20% of children with febrile syndrome, it appears as fever of unknown origin (FUO) syndrome. Management strategies in this group have high sensitivity but low specificity. Objectives: To cha racterize serious bacterial infections (SBI) in children younger than three months old hospitalized because of FUO syndrome and to evaluate the utility of clinical and laboratory parameters in the identification of patients that are at high risk of SBI. Patients and Method: Prospective study in patients aged < 3 months hospitalized due to FUO syndrome between January 2014 and November 2015 in two pediatric hospitals in the Metropolitan Region. Inclusion criteria: age 4 days - 3 months, fever > 38°C longer than 72 hours after onset without demonstrable cause. Exclusion criteria: anti microbial use up to 7 days before admission, preterm infants < 34 weeks, birth weight < 2 kg, and im munocompromised. Demographic, clinical, and laboratory tests data were recorded as well as blood count and CRP, discharge diagnosis, and ruled out, probable or confirmed SBI. Results: 32% of the patients were discharged with diagnosis of SBI, 28% with diagnosis of viral or probably viral infec tion, 34% with diagnosis of not specified FUO syndrome, and 6% due to other causes. There were no significant differences in the CRP value, altered WBCs count, toxic aspect, or hours of fever at the admission when comparing groups with and without SBI (p < 0.05). The combination of clinical and laboratory parameters showed 27% of sensitivity, 90% of specificity, 60% of PPV, and 71% of NPV. Conclusion: It was not possible to establish clinical and laboratory parameters that allow the identifi cation of children younger than 3 months old at high risk of SBI, however, they maintain their value as low risk indicators. It is necessary further investigation of other clinical and laboratory elements that allow discriminating SBI from viral infections.

[Respiratory viral infections during episodes of fever in children undergoing hematopoietic stem cell transplantation]. / Infecciones respiratorias virales en episodios de fiebre en niños con trasplante de precursores hematopoyéticos.

BACKGROUND: Children undergoing hematopoietic stem cell transplant (HSCT) can develop respiratory viral infections (RVI) during fever episodes. There are few data about clinical outcomes in RVI and compared to bacterial infections (BI) in this population. AIM: To determine clinical outcome of RVI, compared to BI in children with HSCT. METHODS: Prospective study, patients ≤ 18 years with cancer and HSCT admitted with fever at a National Bone Marrow Transplant Center (Hospital Calvo Mackenna), Chile, (April-2016 to May-2019). Clinical assessment, laboratory tests, blood cultures, nasopharyngeal sample for multiplex-PCR (Filmarray®), viral loads by PCR and cytokine panel (Luminex®, 38 cytokines) were performed. The following outcomes were evaluated: upper/lower respiratory tract disease (RTD), admission to ICU, mechanical ventilation, mortality and antimicrobial withdrawal. RESULTS: Of 56 febrile episodes, 35 (63%) were RVI, 12 (21%) BI and 9 (16%) with unknown etiology (UE). Median of age was 8.5 years, 62% male gender. Rhinovirus (54%) and coronavirus (15%) were the more frequent detected viruses. No significant differences in cytokine levels were observed between RVI and BI. 94% of RVI patients had symptomatic RTD, versus 33% in BI and 33% in UE group (p < 0.001), with lower-RTD in 69% of RVI group (p < 0,001). Admission to ICU was 11% in RVI, 17% in BI and 11% in UE group (p = 0.88); only 2 patients required mechanical ventilation (p = 0.37) and no mortality was reported. After an RVI was detected by PCR, antimicrobials were withdrawal in 26% of patients with RVI (p: 0.04). CONCLUSION: RVI are frequent etiologic agents in febrile episodes of patients with HSCT. Viral detection might help to rationalize the use of antimicrobials in this population.

[Clinical characteristics and microbiological profile of viridans group streptococci bacteremia in children with cancer and high-risk febrile neutropenia]. / Caracterización clínica y microbiológica de episodios de bacteriemia por Streptococcus grupo viridans en niños con cáncer y neutropenia febril de alto riesgo.

BACKGROUND: Viridans group streptococci (VGS) has acquired relevance as a microorganism causing febrile neutropenia, associated with significant morbidity. AIM: To characterize episodes of bacteremia caused by VGS in children with cancer who developed high-risk febrile neutropenia (HRFN) during the period from April 2004 to June 2018 in six pediatric hospitals of Santiago, Chile. METHOD: Database analysis of 4 successive, prospective and multicentric studies recording clinical and laboratory characteristics of patients, as well as antimicrobial susceptibility pattern of isolated strains. RESULTS: 95 episodes of VGS bacteremia in 91 children with HRFN were analyzed. It emphasizes acute myeloid leukemia as cancer type, deep neutropenia, prolonged hospitalization (15 days), with extended use of antimicrobials (14 days) and use of cytarabine in chemotherapy schemes (86% episodes). The most frequent clinical manifestations were respiratory and gastrointestinal, associating up to 26% viridans group shock syndrome. There was high resistance to ß lactams. As expected, there were not non-susceptible strains to vancomycin. DISCUSSION: VGS is a relevant microorganism in children with cancer, fever and neutropenia, with a high percentage of sepsis. Resistance to ß lactams is an issue that requires strict epidemiological surveillance in this population.

A prospective, multi-center study of Candida bloodstream infections in Chile.

BACKGROUND: Active surveillance is necessary for improving the management and outcome of patients with candidemia. The aim of this study was to describe epidemiologic and clinical features of candidemia in children and adults in tertiary level hospitals in Chile. METHODS: We conducted a prospective, multicenter, laboratory-based survey study of candidemia in 26 tertiary care hospitals in Chile, from January 2013 to October 2017. RESULTS: A total of 780 episodes of candidemia were included, with a median incidence of 0.47/1,000 admissions. Demographic, clinical and microbiological information of 384 cases of candidemia, from 18 hospitals (7,416 beds), was included in this report. One hundred and thirty-four episodes (35%) occurred in pediatric patients and 250 (65%) in adult population. Candida albicans (39%), Candida parapsilosis (30%) and Candida glabrata (10%) were the leading species, with a significant difference in the distribution of species between ages. The use of central venous catheter and antibiotics were the most frequent risk factors in all age groups (> 70%). Three hundred and fifteen strains were studied for antifungal susceptibility; 21 strains (6.6%) were resistant to fluconazole, itraconazole, voriconazole, anidulafungin or micafungin. The most commonly used antifungal therapies were fluconazole (39%) and echinocandins (36%). The overall 30-day survival was 74.2%, significantly higher in infants (82%) and children (86%) compared with neonates (72%), adults (71%) and elderly (70%). CONCLUSIONS: Our prospective, multicenter surveillance study showed a low incidence of candidemia in Chile, with high 30-day survival, a large proportion of elderly patients, C. glabrata as the third most commonly identified strain, a 6.6% resistance to antifungal agents and a frequent use of echinocandins.

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

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.

Intestinal Inflammation in Chilean Infants Fed With Bovine Formula vs. Breast Milk and Its Association With Their Gut Microbiota.

Introduction: Compared to bovine formula (BF), breast milk (BM) has unique properties. In the newborn intestine, there is a homeostatic balance between the counterparts of the immune system, which allows a physiological inflammation, modulated by the gut microbiota. Many studies have attempted to understand the effect of BF vs. BM, and the changes in the gut microbiota, but few also focus on intestinal inflammation. Methods: We conducted a cohort study of newborn infants during their first 3 months. In stool samples taken at 1 and 3 months (timepoints T1 and T3), we quantified calprotectin, IL-8 and α1-antitrypsin by ELISA and we evaluated the expression of IL8 and IL1ß genes by RT-qPCR. To determine the microbiota composition, the 16S rRNA gene was amplified and sequenced using 454 pyrosequencing. Sequences were clustered into operational taxonomic units (OTUs). Results: In total 15 BM and 10 BF infants were enrolled. In the BM group, we found calprotectin and α1-antitrypsin levels were significantly elevated at T3 compared to T1; no differences were found between T1 and T3 in the BF group. A comparison between the BM and BF groups showed that calprotectin levels at T1 were lower in the BM than the BF group; this difference was not observed at T3. For IL-8 levels, we found no differences between groups. A gene expression analysis of the IL8 and IL1ß genes showed that infants from the BF group at T1 have a significantly increased expression of these markers compared to the BM group. Gut microbiota analyses revealed that the phylum Bacteroidetes was higher in BM than BF, whereas Firmicutes were higher in BF. A redundancy analysis and ANOVA showed BM has a community structure statistically different to BF at T1 but not at T3. Compared to BF, BM at T1 showed a higher representation of Enterococcus, Streptococcus, Enterobacter, Lactococcus, and Propionibacterium. Conclusions: We found a basal state of inflammation in the infants' intestine based on inflammation markers. One month after birth, infants receiving BF exhibited higher levels of inflammation compared to BM.

[Pharmacokinetics of posaconazol in the prophylaxis and treatment of invasive fungal infection in immunocompromised children in a pediatric hospital]. / Farmacocinética de posaconazol en la profilaxis y tratamiento de la infección fúngica invasora en niños inmunocomprometidos en un hospital pediátrico.

Background There is no consensus on the optimal dosage use of posaconazole (PSC) for invasive fungal infection (IFI) in pediatric patients and normally it is adjusted with drug levels (DLs) ≥ 0.7 µg/ml and ≥ 1.25 µg/ml for prophylaxis and treatment, respectively. Objective To describe the experience of monitoring DLs of PSC in immunocompromised pediatric patients with IFI and to determine if the recommended doses reach CP effective in prophylaxis (≥ 0.7 µg/mL) and treatment (≥ 1.25 µg/mL). Method A retrospective analysis in children who received PSC from January 2012 to October 2016, in the Oncology and Bone Marrow Transplant units at Hospital Calvo Mackenna was done Six patients with 78 DLs were reviewed (4 prophylaxis and 4 treatment). Median PSC dose was 12.5 and 18.8 mg/kg/d for prophylaxis and treatment, resulting in mean DLs of 0.97 and 1.8 µg/mL respectively. In prophylaxis 40/67 (60%) were recorded with DLs ≥ 0.70 µg/mL receiving a median dose of 12.5 mg/kg/d. While for treatment: 5/11 (46%) presented DLs ≥ 1.25 µg/mL, receiving a median dose of 18 mg/kg/d. Conclusion Our results are in line with the recommended for PSC dosage, but individualized monitoring is required to maintain adequate DLs.

Farmacocinética de posaconazol en la profilaxis y tratamiento de la infección fúngica invasora en niños inmunocomprometidos en un hospital pediátrico / Pharmacokinetics of posaconazol in the prophylaxis and treatment of invasive fungal infection in immunocompromised children in a pediatric hospital

Resumen Introducción En pediatría no existe consenso en la dosificación de posaconazol (PSC) para profilaxis y tratamiento de la infección fúngica invasora (IFI), usándose la medición de concentraciones plasmáticas (CPs) del fármaco. Objetivo Describir la experiencia de monitoreo de las CPs de PSC en niños inmunocomprometidos con IFI y determinar si las dosis recomendadas alcanzan CPs efectivas en profilaxis (≥ 0,7 µg/mL) y tratamiento (≥ 1,25 µg/mL). Método Análisis retrospectivo en niños que recibieron PSC suspensión como profilaxis o tratamiento entre enero de 2012 y octubre de 2016, en las unidades de Oncología y Trasplante de Médula Ósea del Hospital Calvo Mackenna. Resultados 78 CPs en seis pacientes (4 indicaciones de profilaxis y 4 tratamientos) fueron revisados. La mediana de dosis de PSC fue de 12,5 y 18,8 mg/kg/d para profilaxis y tratamiento, respectivamente, resultando CP mediana de 0,97 y 1,8 μg/mL, respectivamente. En profilaxis, se registraron 40/67 (60%) con CP ≥ 0,70 μg/mL recibiendo una mediana de dosis de 12,5 mg/kg/d. Mientras que para el tratamiento: 5/11 (46%), presentaron CP ≥ 1,25 μg/mL, recibiendo una mediana de dosis de 18 mg/kg/d. Conclusión Nuestros resultados se ajustan a lo recomendado para la dosificación de PSC, pero evidencian una necesidad de realizar una monitorización individualizada para mantener adecuadas CPs.

Background There is no consensus on the optimal dosage use of posaconazole (PSC) for invasive fungal infection (IFI) in pediatric patients and normally it is adjusted with drug levels (DLs) ≥ 0.7 μg/ml and ≥ 1.25 μg/ml for prophylaxis and treatment, respectively. Objective To describe the experience of monitoring DLs of PSC in immunocompromised pediatric patients with IFI and to determine if the recommended doses reach CP effective in prophylaxis (≥ 0.7 μg/mL) and treatment (≥ 1.25 μg/mL). Method A retrospective analysis in children who received PSC from January 2012 to October 2016, in the Oncology and Bone Marrow Transplant units at Hospital Calvo Mackenna was done Six patients with 78 DLs were reviewed (4 prophylaxis and 4 treatment). Median PSC dose was 12.5 and 18.8 mg/kg/d for prophylaxis and treatment, resulting in mean DLs of 0.97 and 1.8 μg/mL respectively. In prophylaxis 40/67 (60%) were recorded with DLs ≥ 0.70 μg/mL receiving a median dose of 12.5 mg/kg/d. While for treatment: 5/11 (46%) presented DLs ≥ 1.25 μg/mL, receiving a median dose of 18 mg/kg/d. Conclusion Our results are in line with the recommended for PSC dosage, but individualized monitoring is required to maintain adequate DLs.

Corrigendum: Helicobacter pylori cagA+ Is Associated with Milder Duodenal Histological Changes in Chilean Celiac Patients.

[This corrects the article on p. 376 in vol. 7, PMID: 28879170.].

Helicobacter pylori cagA+ Is Associated with Milder Duodenal Histological Changes in Chilean Celiac Patients.

HIGHLIGHTS What is already known about this subject?Celiac disease (CD) has a high clinical and histological diversity and the mechanisms underlying this phenomenon remain elusive.H. pylori is a bacterium that chronically infect gastric and duodenal mucosa activating both a Th1/Th17 and T-reg pathways.The role of H. pylori (and the effect of their virulence factors) in CD have not yet completely elucidated.What are the new findings?cagA+ H. pylori strains are associated to milder histological damage in infected CD patients.In active-CD patients the presence of cagA+ H. pylori is associated to an increase in T-reg markers, contrasting with a downregulation in cagA+ infected potential-CD individuals.How might it impact on clinical practice in the foreseeable future?The identification of microbiological factors that could modulate inflammation and clinical expression of CD may be used in the future as preventive strategies or as supplementary treatment in patients that cannot achieve complete remission, contributing to the better care of these patients. Background: Mechanisms underlying the high clinical and histological diversity of celiac disease (CD) remain elusive. Helicobacter pylori (Hp) chronically infects gastric and duodenal mucosa and has been associated with protection against some immune-mediated conditions, but its role (specifically of cagA+ strains) in CD is unclear. Objective: To assess the relationship between gastric Hp infection (cagA+ strains) and duodenal histological damage in patients with CD. Design: Case-control study including patients with active-CD, potential-CD and non-celiac individuals. Clinical presentation, HLA genotype, Hp/cagA gene detection in gastric mucosa, duodenal histology, Foxp3 positive cells and TGF-ß expression in duodenal lamina propria were analyzed. Results: We recruited 116 patients, 29 active-CD, 37 potential-CD, and 50 non-CD controls. Hp detection was similar in the three groups (~30-40%), but cagA+ strains were more common in infected potential-CD than in active-CD (10/11 vs. 4/10; p = 0.020) and non-CD (10/20; p = 0.025). Among active-CD patients, Foxp3 positivity was significantly higher in subjects with cagA+ Hp+ compared to cagA- Hp+ (p < 0.01) and Hp- (p < 0.01). In cagA+ Hp+ individuals, Foxp3 positivity was also higher comparing active- to potential-CD (p < 0.01). TGF-ß expression in duodenum was similar in active-CD with cagA+ Hp+ compared to Hp- and was significantly downregulated in cagA+ potential-CD subjects compared to other groups. Conclusion: Hp infection rates were similar among individuals with/without CD, but infection with cagA+ strains was associated with milder histological damage in celiac patients infected by Hp, and in active-CD cases with higher expression of T-reg markers. Results suggest that infection by cagA+ Hp may be protective for CD progression, or conversely, that these strains are prone to colonize intestinal mucosa with less severe damage.

[Celiac disease, non celiac gluten sensitivity and wheat allergy: comparison of 3 different diseases triggered by the same food]. / Enfermedad celíaca, sensibilidad no celíaca al gluten y alergia al trigo: comparación de patologías diferentes gatilladas por un mismo alimento.

Gluten and other related proteins of the wheat, rye and barley, have antigenic properties that may trigger adverse reactions in susceptible individuals. Celiac disease was the first pathology with clear causal association related to the intake of these proteins. Recently, wheat allergy and non celiac gluten sensitivity have been described. Although, clinical presentation and its relation with protein ingestion may be similar and elicit confusion, their pathogenic mechanism, diagnosis and treatment are quite different. Since the prevalence of these diseases is relatively high as a whole, it is essential that these become familiar to primary care doctors and general pediatricians, thus they will know how to differentiate and face them. The aim of this review is to compare the main aspects of epidemiology, pathofisiology, diagnosis and treatment of these 3 conditions.

Enfermedad celíaca, sensibilidad no celíaca al gluten y alergia al trigo: comparación de patologías diferentes gatilladas por un mismo alimento / Celiac disease, non celiac gluten sensitivity and wheat allergy: comparison of 3 different diseases triggered by the same food

El gluten y otras proteínas relacionadas del trigo, centeno y cebada, tienen propiedades antigénicas que pueden desencadenar reacciones adversas en individuos susceptibles. La enfermedad celíaca fue la primera patología en que se estableció relación causal con estas proteínas alimentarias. Recientemente se han descrito la alergia al trigo y la sensibilidad no celíaca al gluten. Si bien sus formas de presentación clínica y su relación con la ingesta pueden ser similares, sus mecanismos patogénicos, forma de diagnóstico y tratamiento difieren. Dado que su prevalencia en conjunto es relativamente alta, resulta necesario que los médicos de atención primaria y pediatras se familiaricen con estas patologías, sepan cómo diferenciarlas y enfrentarlas. El objetivo de esta revisión es comparar los principales aspectos de epidemiología, fisiopatología, diagnóstico y tratamiento de estas 3 condiciones.

Gluten and other related proteins of the wheat, rye and barley, have antigenic properties that may trigger adverse reactions in susceptible individuals. Celiac disease was the first pathology with clear causal association related to the intake of these proteins. Recently, wheat allergy and non celiac gluten sensitivity have been described. Although, clinical presentation and its relation with protein ingestion may be similar and elicit confusion, their pathogenic mechanism, diagnosis and treatment are quite different. Since the prevalence of these diseases is relatively high as a whole, it is essential that these become familiar to primary care doctors and general pediatricians, thus they will know how to differentiate and face them. The aim of this review is to compare the main aspects of epidemiology, pathofisiology, diagnosis and treatment of these 3 conditions.