Tamara Viviani

Prospective, Multicenter Evaluation of Risk Factors Associated With Invasive Bacterial Infection in Children With Cancer, Neutropenia, and Fever

PURPOSE To identify clinical and laboratory parameters present at the time of a first evaluation that could help predict which children with cancer, fever, and neutropenia were at high risk or low risk for an invasive bacterial infection. PATIENTS AND METHODS Over a 17-month period, all children with cancer, fever, and neutropenia admitted to five hospitals in Santiago, Chile, were enrolled onto a prospective protocol. Associations between admission parameters and risk for invasive bacterial infection were assessed by univariate and logistic regression analyses. RESULTS A total of 447 febrile neutropenic episodes occurred in 257 children. Five parameters were statistically independent risk factors for an invasive bacterial infection. Ranked by order of significance, they were as follows: C-reactive protein levels of 90 mg/L or higher (relative risk [RR], 4.2; 95% confidence interval [CI], 3.6 to 4.8); presence of hypotension (RR, 2.7; 95% CI, 2.3 to 3.2); relapse of leukemia as cancer type (RR, 1.8, 95% CI, 1.7 to 2.3); platelet count less than or equal to 50,000/mm(3) (RR, 1.7; 95% CI, 1.4 to 2.2); and recent (< or = 7 days) chemotherapy (RR, 1.3; 95% CI, 1.1 to 1.6). Other previously postulated risk factors (magnitude of fever, monocyte count) were not independent risk factors in this study population. CONCLUSION In a large population of children, common clinical and laboratory admission parameters were identified that can help predict the risk for an invasive bacterial infection. These results encourage the possibility of a more selective management strategy for these children.

Early Hospital Discharge Followed by Outpatient Management Versus Continued Hospitalization of Children With Cancer, Fever, and Neutropenia at Low Risk for Invasive Bacterial Infection

PURPOSE To compare outcome and cost of ambulatory versus hospitalized management among febrile neutropenic children at low risk for invasive bacterial infection (IBI). PATIENTS AND METHODS Children presenting with febrile neutropenia at six hospitals in Santiago, Chile, were categorized as high or low risk for IBI. Low-risk children were randomly assigned after 24 to 36 hours of hospitalization to receive ambulatory or hospitalized treatment and monitored until episode resolution. Outcome and cost were determined for each episode and compared between both groups using predefined definitions and questionnaires. RESULTS A total of 161 (41%) of 390 febrile neutropenic episodes evaluated from June 2000 to February 2003 were classified as low risk, of which 149 were randomly assigned to ambulatory (n = 78) or hospital-based (n = 71) treatment. In both groups, mean age (ambulatory management, 55 months; hospital-based management, 66 months), sex, and type of cancer were similar. Outcome was favorable in 74 (95%) of 78 ambulatory-treated children and 67 (94%) of 71 hospital-treated children (P = NS). Mean cost of an episode was US 638 dollars (95% CI, 572 dollars to 703 dollars) and US 903 dollars (95% CI, 781 dollars to 1,025 dollars) for the ambulatory and hospital-based groups, respectively (P =.003). CONCLUSION For children with febrile neutropenia at low risk for IBI, ambulatory management is safe and significantly cost saving compared with standard hospitalized therapy.

Predictors of severe sepsis not clinically apparent during the first twenty-four hours of hospitalization in children with cancer, neutropenia, and fever: a prospective, multicenter trial.

Background: Severe sepsis is not clinically apparent during the first 24 hours of hospitalization in most children with cancer and febrile neutropenia (FN), delaying targeted interventions that could impact mortality. The aim of this study was to prospectively evaluate biomarkers obtained within 24 hours of hospitalization as predictors of severe sepsis before it becomes clinically evident. Methods: Children with cancer, admitted with FN at high risk for an invasive bacterial infection in 6 public hospitals in Santiago, Chile, were monitored throughout their clinical course for occurrence of severe sepsis. Clinical, demographic and 6 biomarkers [eg, blood urea nitrogen, serum glucose, lactic dehydrogenase, serum C-reactive protein (CRP), interleukin (IL)-8, and procalcitonin] were obtained at the time of admission and after 24 hours. Biomarkers independently associated with severe sepsis diagnosed after the first 24 hours of hospitalization were identified by logistic regression analysis. Results: A total of 601 high risk FN episodes were enrolled between June 2004 and October 2006; 151 (25%) developed severe sepsis of which 116 (77%) were not clinically apparent during the first 24 hours of hospitalization. Risk factors for severe sepsis were age ≥12 years [odds ratio (OR): 3.85; 95% confidence interval (CI): 2.41–6.15], admission CRP ≥90 mg/L (OR: 2.03; 95% CI: 1.32–3.14), admission IL-8 ≥200 pg/mL (OR: 2.39; 95% CI: 1.51–3.78), 24-hour CRP ≥100 mg/L (OR: 3.06; 95% CI: 1.94–4.85), and 24-hour IL-8 ≥300 pg/mL (OR: 3.13; 95% CI 1.92–5.08). Conclusions: Age ≥12 years and admission or 24-hour values of CRP ≥90/100 mg/L and IL-8 ≥200/300 pg/mL are predictors of sepsis not clinically apparent during the first 24 hours of hospitalization.

Admission clinical and laboratory factors associated with death in children with cancer during a febrile neutropenic episode.

Background: Early identification of children with cancer at risk for death during a febrile neutropenic (FN) episode may increase their possibility for survival. Our aim was to identify at the time of admission, clinical and laboratory variables differing significantly among children who survived or died during a FN episode. Methods: In a prospective, multicenter study, children admitted with a high-risk FN episode were uniformly evaluated at enrollment and managed according to a national consensus protocol. Medical charts of children who died were evaluated to determine whether the death could be associated with an infection. Admission clinical and laboratory variables significantly associated with death were identified. Results: A total of 393 (70%) of 561 FN episodes evaluated from June 2004 to December 2005 were classified as high risk for invasive bacterial infection, of which 14 (3.6%) resulted in an infectious-related death. Deaths occurred from 2 to 27 days after admission, and most dying children were admitted with relapse of acute lymphocytic leukemia (36%), hypotension (71%), and a diagnosis of sepsis (79%), compared with surviving children (16%, 20%, and 5% respectively, P < 0.001). Children who died were admitted with lower absolute neutrophil count (P < 0.001) and absolute monocytes count levels (P = 0.008), higher blood urinary nitrogen (P = 0.03) and C-reactive protein values (P < 0.001), and had more positive cultures (79% versus 32%, P = 0.008). Conclusions: We identified early clinical and laboratory findings significantly associated with death occurring at a later stage. Routine evaluation of these variables may prove to be useful in the early identification of children with a high-risk FN episode at risk for death.

Risk Factors Associated With Invasive Fungal Disease in Children With Cancer and Febrile Neutropenia: A Prospective Multicenter Evaluation

Background: Empiric antifungal treatment has become standard of care in children with cancer and prolonged fever and febrile neutropenia (FN), with the downside that it leads to significant over treatment. We characterized epidemiologic, clinical, and laboratory features of invasive fungal disease (IFD) in children with cancer and FN with the aim to identify risk factors for IFD that can aid in better selecting children who require antifungal treatment. Methods: In a prospective, multicenter study, children admitted with FN at high-risk for sepsis, in 6 hospitals in Santiago, Chile were monitored from admission until the end of the FN episode. Monitoring included periodic evaluation of clinical findings, absolute neutrophil count, absolute monocyte count (AMC), serum C-reactive protein (CRP), bacterial cultures, imaging studies, and galactomannan antigen. A diagnosis of proven, probable, and possible IFD was made after episode resolution based on European Organization for Research and Treatment of Cancer classification. Results: A total of 646 high-risk FN episodes were admitted during the study period, of which 604 were enrolled. IFD was diagnosed in 35 episodes (5.8%) of which 7 (1.2%) were proven, 10 (1.6%) probable, and 18 (3.0%) possible. Four variables obtained on day 4 were significantly more common in IFD cases, which were presence of fever, absolute neutrophil count ≤500/mm3, AMC ≤100/mm3, and CRP ≥90 mg/L. The combination of fever, AMC ≤100/mm3, and CRP ≥90 at day 4 provided a RR for IFD of 5.4 (99% CI, 3.2–9.2) with a sensitivity of 75%, specificity of 87%, positive and negative predictive values of 13% and 99%, respectively. Conclusions: Fever persisting at day 4 of admission, together with AMC ≤100 and CRP ≥90 significantly increased the risk for IFD in children with cancer.

Diagnosis of bacteremia in febrile neutropenic episodes in children with cancer: microbiologic and molecular approach.

Background: Bacterial isolation using conventional microbiologic techniques rarely surpasses 25% in children with clinical and laboratory findings indicative of an invasive bacterial infection. The aim of this study was to determine the role of real-time polymerase chain reaction (RT-PCR) from whole blood samples compared with automated blood cultures (BC) in detection of relevant microorganisms causing bacteremia in episodes of high-risk febrile neutropenia (HRFN) in children with cancer. Methods: Children presenting with HRFN at 6 hospitals in Santiago, Chile, were invited to participate. Blood samples were obtained at admission for BC, and at admission and 24 hours for RT-PCR targeting DNA of Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa causing bacteremia in children with HRFN. Results: A total of 177 HRFN episodes were evaluated from May 2009 to August 2010, of which 29 (16.3%) had positive BC, 9 (5%) positive for 1 of the 3 selected bacterial species: 5 for E. coli, 3 for S. aureus, and 1 for P. aeruginosa. RT-PCR detected 39 bacteria in 36 episodes (20%): 14 E. coli, 20 S. aureus, and 5 P. aeruginosa. The sensitivity, specificity, and positive and negative predictive values of RT-PCR compared with BC were 56%, 80%, 13%, and 97%. The final clinical diagnosis was compatible with an invasive bacterial infection in 30/36 (83%) RT-PCR-positive episodes. Conclusions: In our series, RT-PCR significantly improved detection of the most relevant bacteria associated with HRFN episodes. Large number of patients and close clinical monitoring, in addition to improved RT-PCR techniques will be required to fully recommend RT-PCR-based diagnosis for the routine workup of children with cancer, fever, and neutropenia.

Prospective validation of a risk prediction model for severe sepsis in children with cancer and high risk fever and neutropenia

Background: We previously created a risk prediction model for severe sepsis not clinically apparent during the first 24 hours of hospitalization in children with high-risk febrile neutropenia (HRFN), which identified 3 variables, age ≥12 years, serum C-reactive protein (CRP) ≥90 mg/L and interleukin-8 ≥300 pg/mL, evaluated at the time of admission and at 24 hours of hospitalization. The combination of these 3 variables identified a risk for severe sepsis ranging from 8% to 73% with a relative risk of 3.15 (95% confidence interval: 1.1–9.06). The aim of this study was to validate prospectively our risk prediction model for severe sepsis in a new cohort of children with cancer and HRFN. Methods: Predictors of severe sepsis identified in our previous model (age, CRP and interleukin-8) were evaluated at admission and at 24 hours of hospitalization in a new cohort of children with HRFN between April 2009 and July 2011. Diagnosis of severe sepsis, not clinically apparent during the first 24 hours of hospitalization, was made after discharge by a blind evaluator. Results: A total of 447 HRFN episodes were studied, of which 76 (17%) had a diagnosis of severe sepsis. The combination of age ≥12 years, CRP ≥90 mg/L and interleukin-8 ≥300 pg/mL at admission and/or at 24 hours in the new cohort identified a risk for severe sepsis ranging from 7% to 46% with an RR of 6.7 (95% CI: 2.3–19.5). Conclusions: We validated a risk prediction model for severe sepsis applicable to children with HRFN episodes within the first 24 hours of admission. We propose to incorporate this model in the initial patient assessment to offer a more selective management for children at risk for severe sepsis.

Agentes causantes de bacteriemia en niños con cáncer y neutropenia febril de alto riesgo en seis hospitales de Santiago, Chile, período 2004-2009

Introduccion: Conocer la etiologia de los episodios de neutropenia febril de alto riesgo (NFAR) en pacientes con cancer tiene importancia para implementar tratamientos antimicrobianos ajustados a la epidemiologia local, lo que tiene impacto en la morbilidad y mortalidad. Objetivo: Describir la etiologia de las bacteriemias en ninos con cancer y NFAR en el periodo 2004-2009, en la red PINDA de Santiago (Region Metropolitana), Chile, y comparar estos agentes y su susceptibilidad antimicrobiana con un estudio previo realizado en el periodo 1994-1998. Material y Metodos: Se registraron prospectivamente los agentes causantes de bacteriemia y su susceptibilidad a antimicrobianos de los pacientes bajo 18 anos de edad en tratamiento quimioterapico por cancer, ingresados con diagnostico de NFAR a los seis hospitales de la red, durante el periodo 2004-2009. Resultados: De 839 episodios de NFAR, 181 tuvieron hemocultivos positivos, correspondientes a cocaceas grampositivas (56%), bacilos gramnegativos (42%) y levaduras (2%). Los agentes mas frecuentemente aislados fueron: Staphylococcus coagula-sa negativa (25%), Escherichia coli (20%), Streptococcus grupo viridans (14%), Staphylococcus aureus (13%) y Pseudomonas spp (9%). Al comparar los dos periodos de tiempo, destacan los siguientes cambios significativos: disminucion en frecuencia relativa de Staphylococcus coagulasa negativa (desde 44 a 25%), aumento de Streptococcus spp (desde 4 a 17%), y aumento de la resistencia de Staphylococcus coagulasa negativa a oxacilina (desde 55 a 77%). Conclusiones: Se dan a conocer los principales agentes etiologicos de los episodios de NFAR y la susceptibilidad a antimicrobianos en un periodo de cinco anos. Esto permite racionalizar el manejo antimicrobiano empirico de los episodios de NFAR en esta poblacion.

[Cancer, febrile neutropenia and pulmonary images: Findings in bronchoalveolar lavage in children].

Cancer, febrile neutropenia and pulmonary images: Findings in bronchoalveolar lavage in children Introduction: Lung infections are a serious complication in children with cancer. Bronchoalveolar lavage (BAL) has been demonstrated to be an effective procedure for achieving etiologic diagnosis. Method: We did a retrospec- tive analysis of BAL data performed between November 2005 and October 2008 in children with cancer, severe neutropenia and lung infiltrates for assessing its performance, clinical utility and safety. Thirty-seven BAL were evaluated in 35 patients. Results: Focal infiltrates were demonstrated in imaging studies associated with 19/37 BAL; in 8 an infectious agent was found. Interstitial pattern was observed in 15/37, in which there were 4 positive studies, proving a higher microbiological performance in BAL associated with focal lesions. BAL yielded significant microbiological findings in 32.4% (12/37). Sixteen microorganisms were identified in the study: bacteria in 8 cases, Mycobacterium tuberculosis (n: 2), Pseudomonas aeruginosa (n: 2), Acinetobacter baumannii (n: 1), A. lwoffii (n: 1), group viridans Streptococcus (n: 1), Mycoplasma pneumoniae (n: 1); viruses in 3 cases, metapneumovirus (n: 2) cytomegalovirus (n: 1) and fungal infection in 5 cases, Pneumocystis jiroveci (n: 2) Aspergillus fumigatus (n: 1), Aspergillus niger (n: 1), Candida albicans (n: 1). Therapeutic adjustments were done in 6/37 episodes (16.2%). Conclusion: BAL has a significant role in the evaluation of pulmonary infiltrates in pediatric oncological patients, requiring a prompt and safe diagnosis, which is crucial for the survival with minimal morbidity. Our results suggestINTRODUCTION Lung infections are a serious complication in children with cancer. Bronchoalveolar lavage (BAL) has been demonstrated to be an effective procedure for achieving etiologic diagnosis. METHOD We did a retrospective analysis of BAL data performed between November 2005 and October 2008 in children with cancer, severe neutropenia and lung infiltrates for assessing its performance, clinical utility and safety. Thirty-seven BAL were evaluated in 35 patients. RESULTS Focal infiltrates were demonstrated in imaging studies associated with 19/37 BAL; in 8 an infectious agent was found. Interstitial pattern was observed in 15/37, in which there were 4 positive studies, proving a higher microbiological performance in BAL associated with focal lesions. BAL yielded significant microbiological findings in 32.4% (12/37). Sixteen microorganisms were identified in the study: bacteria in 8 cases, Mycobacterium tuberculosis (n: 2), Pseudomonas aeruginosa (n: 2), Acinetobacter baumannii (n: 1), A. Iwoffii (n: 1), group viridans Streptococcus (n: 1), Mycoplasma pneumoniae (n: 1); viruses in 3 cases, metapneumovirus (n: 2) cytomegalovirus (n: 1) and fungal infection in 5 cases, Pneumocystis jiroveci (n: 2) Aspergillus fumigatus (n: 1), Aspergillus niger (n: 1), Candida albicans (n: 1). Therapeutic adjustments were done in 6/37 episodes (16.2%). CONCLUSION BAL has a significant role in the evaluation of pulmonary infiltrates in pediatric oncological patients, requiring a prompt and safe diagnosis, which is crucial for the survival with minimal morbidity. Our results suggest that BAL by fiberbronchoscopy should be considered as an initial diagnostic tool in these patients.

Caracterización de los episodios de neutropenia febril en niños con leucemia mieloide aguda y leucemia linfoblástica aguda

Introduction: Leukemia is the most common cancer in Chilean children. Acute lymphoblastic leukemia (ALL) is more prevalent and longer survival compared to acute myeloid leukemia (AML). Aims: To describe episodes of febrile neutropenia (FN) in children with AML, determining frequency of infections as agent, focus and evolution, comparing children with ALL episodes. Method: A prospective multicenter study. Children presenting with FN at six hospitals in Santiago, Chile, were invited to participate in two consecutive FONDECYT projects, from April 2004 to June 2011. All patients were uniformly evaluated, recording epidemiological, clinical and laboratory variables. Information regarding FN episodes of children with LMA and LLA was used to this study. Results: We evaluated 506 episodes of FN in children with leukemia: 173 children with AML and 333 in children with ALL. NF episodes in children with AML showed significantly greater depth and duration of neutropenia, febrile remained a > period of time and had a worse clinical outcome, as evidenced by > hemodynamic instability, > sepsis, CRP > 90 mg/L for a longer time, more days of hospitalization, > frequency of hospitalization in ICU, > bacteremia, mainly by Streptococcus viridans group, > change of antimicrobial treatment, > use of antifungal therapy. Conclusions: This study demonstrates that FN episodes in children with AML further evolve unfavorably, compared with episodes of FN in children with ALL. FN episodes in children with AML require a more aggressive