Carmen Salgado

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.

Frequency and clinical outcome of respiratory viral infections and mixed viral-bacterial infections in children with cancer, fever and neutropenia.

Background: The role of respiratory viral infections (RVIs) as a cause of overall fever and neutropenia (FN) episodes in children with cancer has been less characterized than bacterial infections. We conducted a study aimed to determine the frequency of RVI in children with low compared with high risk for invasive bacterial infection (IBI) FN episodes and compare the clinical outcome of RVI and mixed RV-bacterial infections. Methods: Prospective, multicenter study in children with cancer and FN admitted to pediatric hospitals in Chile between May 2009 and January 2011. Children were evaluated by clinical examination and laboratory tests, including bacterial cultures and their risk for IBI. Nasopharyngeal sample was obtained for the detection of 17 respiratory viruses using polymerase chain reaction−DNA microarray platform. Results: A total of 331 episodes of FN in 193 children were enrolled of whom 55% were male, with the median age of 7 years and 61% had a hematological malignancy. A viral and/or bacterial pathogen was detected in 67% (224/331) episodes. Overall, RVIs were associated with 57% of FN of which one-third were mixed RV-bacterial infections. Bacterial infection was detected in 29% (97/331). Children classified at admission as high risk for IBI had a similar overall proportion of RVI compared with low-risk group. Respiratory syncytial virus (31%) and rhinovirus (23%) were the most frequently detected respiratory viruses, followed by parainfluenza (12%) and influenza A (11%). Children detected with any respiratory virus had fewer days of hospitalization and a significantly lower probability of hypotension and admission to pediatric intensive care unit irrespective of their risk classification status at admission when compared with children with mixed RV-bacterial or bacterial infections (P < 0.05). All children with a sole RVI had favorable outcome. Conclusions: RVIs were the most frequently detected agents irrespective of their initial risk assessment for IBI. The clinical outcome of mixed RVI was similar to sole RVI episodes as well as for bacterial infections compared with mixed viral-bacterial infections. Systematic and early detection of RVI in children with cancer and FN might help to optimize their management by reducing hospitalization and antimicrobial use.

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.

Multimodal therapy for children and adolescents with Ewing sarcoma: results of the First National Chilean Trial (1986-1991).

Thirty-seven patients with Ewing sarcoma were treated in the First National Chilean Trial for Ewings Sarcoma (1986-1991), which comprised the St. Jude Ewings 78 Study. All patients received cyclophosphamide, doxorubicin, vincristine, and Dactinomycin for a total treatment period of about 10 months, and all prescribed therapy was administered. Local therapy consisted of irradiation (RT) to the primary tumor, complete surgical resection, or a combination of both surgery and RT. Twenty-nine of these patients had localized tumors, 24% had pelvic primary tumors, 21 were males, and 20 were greater than 10 years of age at diagnosis. Twenty-one patients had tumors that were greater than 8 cm in largest diameter. Fourteen of the 29 patients with localized disease remain disease free at 23 to 91 months from diagnosis. Fourteen patients have died of-tumor-related complications and 1 of a secondary malignancy. Relapse was local only in 4, metastatic in 9, and local plus metastatic in 1. Only 1 of the 8 patients with metastatic disease at presentation remains disease free. Toxicity consisted primarily of myelosuppression and mucositis. We conclude that this form of relative intense multimodal therapy for children/adolescents with localized Ewing sarcoma is curative in about half of affected children as in the original St. Jude study, and that it can be safely given in a developing country, provided that careful attention to supportive care and treatment planning is given. Although these results represent improvement in outcome for our patients, more effective therapy is needed for children with Ewing sarcoma, especially those with metastatic disease at presentation.

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.

Respiratory Viral Infections and Coinfections in Children With Cancer, Fever and Neutropenia: Clinical Outcome of Infections Caused by Different Respiratory Viruses.

Background: Respiratory viral infections in episodes of fever and neutropenia (FN) in children with cancer are not well characterized. We compared the clinical outcome of infections caused by different respiratory viruses (RVs) and by RV coinfection in this population. Methods: Children with cancer and FN at 3 hospitals in Chile were prospectively evaluated by clinical examination, blood cultures and detection of 17 RVs using multiplex polymerase chain reaction (nasopharyngeal samples). Clinical characterization and outcome variables were determined and compared by the type of RV detected. Results: A total of 1044 episodes of FN in 525 children were included. At least 1 RV was detected in 46%. In 350 of 1044 (34%) episodes, we detected only RVs, of which 284 (81%) were classified as a single-RV infection and 66 (19%) as a viral coinfection. Respiratory symptoms were present at admission in 65% of the episodes with any detected RV. Median age was 6 years (interquartile range, 3–10), and 51% were women. The most common RVs detected were rhinovirus, respiratory syncytial virus, parainfluenza, influenza, adenovirus and human metapneumovirus. Episodes caused by different types of RVs had no differences in the clinical outcome (days of hospitalization, days of fever, O2 requirement, admission to the intensive care unit and death) and when comparing single and viral coinfection. Conclusions: To our knowledge, this is the largest report comparing clinical outcome in FN episodes caused by different RVs in children with cancer. A positive polymerase chain reaction for RV at admission was significantly associated with the presence of respiratory symptoms. Our data showed a favorable outcome in all episodes with RV detection, including single and viral coinfections.