Performance of serum procalcitonin as a biochemical predictor of death in hematology patients with febrile neutropenia.

INTRODUCTION: Historically, the measurement of serum procalcitonin (PCT) levels in patients with leukopenia has been rejected without sufficient prospective evidence to justify this argument. On the other hand, the accumulated use of broad spectrum antibiotics in these patients and their consequences make the use of PCT attractive in an effort to reduce its use. PATIENTS AND METHODS: We conducted a prospective study between 2016 and 2018, recruiting newly diagnosed FN patients, evaluating them with PCT levels during the first 24 h. After this we evaluate them with overall survival throughout the follow-up. RESULTS: A total of 81 episodes of FN in 72 patients were included. We report a mortality of 27.2% in our cohort. The mean serum PCT in these patients was 4.01 ng/mL compared to 0.42 ng/mL in the survivors group (p < 0.01). Using ROC curves, we determined a cut-off point to predict septic shock/death at 0.46 ng/mL. Patients with a procalcitonin >0.46 ng/mL had an increased risk of death, with a HR of 4.43, (p = 0.048). CONCLUSION: In conclusion, in our trial a single PCT on admission at a cut-off value of 0.46 ng/mL was able to predict the occurrence of septic shock and death in FN patients.

Determination of the relationship between mortality and SOFA, qSOFA, MASCC scores in febrile neutropenic patients monitored in the intensive care unit.

PURPOSE: Febrile neutropenia (FN) is a hematological emergency. It is challenging and confusing for the clinicians to make the decision of the febrile neutropenic patients under chemotherapy to be monitored at intensive care unit (ICU). The aim of this study was to define the factors supporting decision-making for the critical patients with febrile neutropenia. METHODS: The data of 60 patients, who were taken to the ICU while they were under treatment in the Hematology Clinic with a diagnosis of febrile neutropenia, were analyzed retrospectively, in order to identify clinically useful prognostic parameters. RESULTS: The ICU mortality rate was 80%. Mortality was significantly associated with higher sequential organ failure assessment score (SOFA), quick sequential organ failure assessment score (qSOFA), and hematological SOFA (SOFAhem) scores on admission. All cases having SOFA score 10 and above and qSOFA score 2 and above died. In multivariate analysis, qSOFA score was found to be statistically significant in predicting mortality in regard to ICU admission (p = 0.004). CONCLUSION: Mortality of febrile neutropenic patients admitted to ICU is high. It would be appropriate to determine the extent of organ dysfunction instead of underlying disease, for making the decision of ICU admission. It should be noticed that the risk mortality is high for the FN cases with SOFA score 10 or above, qSOFA score 2 or above, and in need of mechanical ventilation and positive inotropic support; hence, early intervention is recommended. In our study, the most significant parameter in predicting ICU mortality was found to be qSOFA.

Analysis of blood stream infections, antibiograms and clinical outcomes in haematological patients with febrile neutropenia: data from a tertiary care haematology institute in India.

Timely administration of appropriate empirical antibiotics in febrile neutropenia is crucial for favourable patient outcomes. There are guidelines in place recommending such antibiotics. However, regional variations and local epidemiological data must be evaluated to tailor the antibiotics for best possible and rational use. In this study, we audited the clinical and microbiological data of febrile neutropenic episodes occurring at a tertiary care haematology institution. Three hundred and ninety-three febrile neutropenic episodes occurring in 123 patients over a 1-year period were analysed for microbial profile, sensitivity and resistance patterns, and finally clinical outcomes. Gram-negative bacilli (GNB) blood stream infections (46.9%) were more prevalent as compared to gram-positive infections (41.9%). Overall mortality due to complicated neutropenic sepsis was 19.5% (24/123 patients). Increased resistance to carbapenems, beta-lactam beta-lactamase inhibitor combinations, aminoglycosides, fluoroquinolones, and cephalosporins were observed. Cefepime and tigecycline resistance were seen in 20% and 15% GNB isolates, respectively. Chest was the most frequent focus of infection, and acute myeloid leukaemia (AML) was the most common underlying disorder which correlated with the likelihood of death (p < 0.01). Multidrug-resistant GNB (esp. Klebsiella sp.) are still most worrisome isolates in neutropenic patients. Single-agent cefepime or piperacillin-tazobactam/tigecycline combination may be considered empirical agents. Chest infections and AML were independent predictors of poor clinical outcome in neutropenic patients. Regular audit of infections and antibiotic susceptibility data is needed to improve clinical outcomes in patients with febrile neutropenia.

Effect of serum uric acid level and Multinational Association for Supportive Care in Cancer risk score on febrile neutropenia mortality.

PURPOSE: The study was aimed to evaluate the effect of uric acid (UA) on the 30-day mortality of patients admitted to the tertiary referral hospital with a complaint of febrile neutropenia (FEN). The secondary aim was to evaluate the use of combining serum UA levels with the Multinational Association for Supportive Care in Cancer (MASCC) risk score. METHODS: A retrospective study in which the MASCC score and serum UA levels were used to evaluate the mortality risk within 30 days among patients with FEN. RESULTS: A total of 118 FEN episodes were included in the study and 17 (14%) of these patients died. While this rate is 23% in the high-risk group according to the MASCC score, it is 7% in the low-risk group (p = 0.011). In multivariate analysis of the parameters that significantly affect the 30-day FEN mortality, MASCC risk score (OR, 4.28; CI 95% 1.19-15.39, p = 0.013) and having a level of serum UA > 7 mg/dL (OR, 4.46; CI 95% 1.19-15.38, p = 0.032) was significantly increased the risk of in 30-day mortality of FEN. The rate of 30-day mortality of FEN was 0% in patients with a low MASCC risk score and UA level compared with 50% in the high MASCC risk score and high UA level group, and the difference was statistically significant (p < 0.001). CONCLUSION: Increased level of UA at the time of FEN diagnosis was independently associated with an increased rate of 30-day mortality of FEN. The combination of the MASCC risk score and serum UA level might thoroughly predict the 30-day mortality of FEN.

Evaluation of Risk Factors for Mortality in Febrile Neutropenia.

INTRODUCTION: We aimed to evaluate the epidemiology of infections and factors associated with mortality in patients with febrile neutropenia (FEN). METHODOLOGY: The adult patients, who developed FEN after chemotherapy due to a hematologic malignancy or a solid tumor in a training and research hospital were evaluated, retrospectively. The demographic data of the patients, underlying malignancy, administered antimicrobial therapy, microbiological findings, and other risk factors associated with mortality were evaluated. RESULTS: A total of 135 FEN episodes of 115 patients, who comprised of 72 (63%) patients with 89 FEN episodes due to hematologic malignancies (hemato-group) and 43 (37%) patients with 46 FEN episodes due to solid organ cancers (onco-group), were evaluated in the study. The median age was 47 years (range: 17-75 years) and 66 (57%) patients were male. A total of 12 patients (8.8%) died during 135 episodes of FEN including nine cases from hemato-group and three cases from onco-group. Those factors including a presence of pneumonia, advanced age, persistent fever despite an antimicrobial treatment, and need for mechanical ventilation in intensive care unit (ICU) with were determined as risk factors associated with mortality. CONCLUSIONS: Morbidity and mortality are more common in patients with hematological malignancies compared to patients with solid organ cancers due to prolonged neutropenia. In case of persistent fever, an invasive fungal infection (IFI) should be kept in mind in patients with hematologic malignancies and then antifungal treatment should be initiated. Although a persistent fever is also common in patients with solid tumors, the necessity of antifungal therapy is rare due to the short duration of neutropenia.

Outcomes of Febrile Neutropenia in Children With Cancer Managed on an Outpatient Basis: A Report From Tertiary Care Hospital From a Resource-limited Setting.

In low-risk febrile neutropenia (FN) patients, outpatient management is now an accepted treatment, but there is a scarcity of data on high-risk patients. The aim of our study was to describe the outcome of FN treated primarily in an outpatient setting on the basis of the severity of illness at presentation, irrespective of the intensity of chemotherapy, and absolute neutrophil count. In this prospective study, not severely ill (NSI) patients were treated with empiric antibiotics at the daycare center (outpatient) and were admitted subsequently if there was persistent fever or any complication arose. Severely ill (SI) children were admitted to the hospital upfront. A total of 118 FN episodes among children with cancer on chemotherapy 18 years of age and younger were studied. Among NSI patients managed as outpatients (n=103), 89 patients (86%) recovered with outpatient treatment, and 14 patients required hospitalization after the median duration of 5 days (interquartile range: 4 to 6 d) of antibiotic therapy. The main indication for hospital admission in the SI group was hypotension (n=5), and in the NSI group, it was persistent fever (n=11). Overall, 5% of patients (6/118) died, and 2 of these were in the NSI group. The results of this study suggest that carefully selected NSI patients could be successfully treated at outpatient management in resource-poor settings and subsequent admission if warranted.

Efficacy and safety of granulocyte transfusion in children: A single-center experience.

BACKGROUND: Granulocyte suspension transfusion (GTx) can be used in severely neutropenic patients with infections that cannot be controlled despite appropriate antibiotic therapy. OBJECTIVE: We aimed to evaluate the effectiveness and safety of GTx for the treatment of febrile neutropenia (FEN) in the pediatric age group. METHODS: Patients who underwent GTx in the Hematology Clinic of Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital between 2013 and 2017 were evaluated retrospectively. Hematologic and clinical response rates, effects on survival, and adverse effects were investigated. Clinical response was defined at two time points: clinical response I was evaluated after each transfusion, while clinical response II was evaluated after the final GTx in a FEN episode. RESULTS: During the study period, 343 GTx were given 107 FEN episodes of 74 patients. The mean number of granulocyte suspensions administered per patient and per FEN episode was 4.6 units and 3.2 units. The mean GTx volume administered was 237 ± 40 mL, and the mean granulocyte count was 2.8 ± 1.3 x 1010 /unit. Hematologic response was attained in 163 (47.6%) of 343 transfusions. Clinical response I was obtained in 88 (25.7%) of the GTx, and clinical response II was attained in 83 (78.5%) of 107 episodes. Life-threatening adverse event was not observed. The cumulative 1-month and 3-month survival rates were 87.8% and 76.5%, respectively. CONCLUSION: High hematologic response and clinical recovery rates were achieved with GTx, with no limiting adverse effects. Granulocyte transfusion appears to be a safe and effective treatment in pediatric patients with FEN.

An eleven-year cohort of bloodstream infections in 552 febrile neutropenic patients: resistance profiles of Gram-negative bacteria as a predictor of mortality.

Antimicrobial stewardship is of major importance in patients with febrile neutropenia (FN). In this study, we aimed to investigate the trends in resistance and the relationship with mortality rates in patients with FN. The single-center surveillance data of inpatients with FN and diagnosed as microbiologically confirmed bloodstream infections (BSIs) between 2006 and 2016 were reviewed retrospectively. A total of 950 episodes in 552 patients with BSIs were analyzed. Of whom, 55.9% were male, the median age was 43 years, and 35.6% had acute myeloid leukemia. In total, 1016 microorganisms were isolated from blood cultures. Gram-negatives accounted for 42.4% (n = 403) of the episodes. Among Gram-negatives, Enterobacteriaceae accounted for 346 (86%) (E. coli, n = 197; 34% extended-spectrum ß-lactamases (ESBL) producers, and Klebsiella spp., n = 120; 48.3% ESBL producers). Also, 24 (20.0%) of Klebsiella spp. had carbapenemase activity. There were 6 (5.0%) colistin-resistant Klebsiella spp. Thirteen (26.5%) of Pseudomonas spp. and 17 (60.7%) of Acinetobacter spp. had carbapenemase activity. There were 2 (5.6%) colistin-resistant Acinetobacter spp. The 30-day mortality rates were 12.0%, 21.5%, 34.6%, and 29.0% in BSIs due to Gram-positive, Gram-negative bacterial, fungal, and polymicrobial etiology respectively (p = 0.001). BSIs with ESBL-producing (p = 0.001) isolates, carbapenem (p < 0.001), and colistin-resistant isolates (p < 0.001) were associated with increased mortality risk. The tremendous rise in resistance rates among Gram-negatives is dreadfully related to increasing mortality and leads to sharp shifts toward extreme restrictions of unnecessary antibiotic uses. Antimicrobial stewardship in patients with FN requires vigilance and tailoring of treatment upon local surveillance data.

Predictors of severe adverse outcomes in febrile neutropenia of pediatric oncology patients at a single institute in Thailand.

Febrile neutropenia in pediatric oncology patients may lead to severe infection, with adverse events including septic shock or death. The aim of the study was to investigate the prevalence of severe adverse outcomes and to determine the associated risk factors. This is a retrospective cohort study of pediatric oncology patients with febrile neutropenia from October 2013 to September 2017 at Thammasat University Hospital, Thailand. Clinical assessment and time-to-event of severe outcomes were analyzed. There were 95 febrile neutropenic episodes; severe adverse outcomes were documented in 11 (11.5%), with no infection-associated mortalities. Those with severe outcomes were older, received prophylactic granulocyte-colony stimulating factor (G-CSF), and had documented infection, lower initial ANC, and central venous catheter insertion. The proportional hazard regression model revealed age ≥ 10 years (hazard ratio [HR], 5.96; p = 0.005), prophylactic G-CSF (HR, 4.52; p = 0.028), and microbiologically documented infections (HR, 12.53; p = 0.017) independently predicted severe adverse outcomes. Although severe adverse outcomes occurred in only 11.5% of our febrile neutropenic episodes, we identified a few risk factors that may help predict those at highest risk.

De-escalation of empiric broad spectrum antibiotics in hematopoietic stem cell transplant recipients with febrile neutropenia.

Febrile neutropenia (FN) is a common serious complication in patients undergoing hematopoietic stem cell transplantation (HSCT) requiring urgent evaluation and initiation of empiric broad spectrum antibiotics (BSA). The appropriate duration of BSA for FN in patients with negative cultures and no identifiable infection remains undefined. We retrospectively analyzed allogenic and autologous HSCT patients with FN and negative infectious work-up at our facility from 2012 to 2018. The early de-escalation group (EDG) included those who had BSA de-escalation to fluoroquinolone prophylaxis at least 24 h prior to absolute neutrophil count (ANC) recovery after the patient was fever-free for at least 48 h. Among 297 patients undergoing their first HSCT who experienced FN with negative infectious work-up, 83 patients were de-escalated early with the remaining 214 in the standard of care group (SCG) whose BSA were continued until ANC was > 500. Duration of broad-spectrum antibiotics was shorter in EDG compared to SCG (3.86 days vs. 4.62 days, p = 0.03). Rates of mortality, new infections, and clinical decompensation requiring intensive care unit transfer and/or pressor use within 30 days were all similar between the two groups (0% vs. 0.4% p = 1.00, 0% vs. 1.4% p = 0.56, 13.2% vs. 8.4% p = 0.27). This indicates that it is safe to de-escalate antibiotics prior to ANC recovery, leading to less BSA exposure.

Predicting in-hospital mortality of patients with febrile neutropenia using machine learning models.

BACKGROUND: Febrile neutropenia (FN) has been associated with high mortality among adults with cancer. Current systems for early detection of inpatient FN mortality are based on scoring indexes that require intensive physicians' subjective evaluation. OBJECTIVE: In this study, we leveraged machine learning techniques to build a FN mortality risk evaluation tool focused on FN admissions without physicians' subjective evaluation. METHODS: We used the National Inpatient Sample and Nationwide Inpatient Sample (NIS) that included mortality data among adult inpatients who were diagnosed with FN during a hospital admission. Machine learning techniques that we compared included linear models (ridge logistic regression and linear support vector machine) and non-linear models (gradient boosting tree and neural network). The primary outcome for this study was death among individuals with a recorded FN admission. Model comparison was evaluated based on areas under the receiver operating characteristic curve (AUROC) and model performance was estimated using 30 % test set created via stratified split. RESULTS: Our analysis detected 126,013 adult admissions within the NIS data that were diagnosed with FN, among which 5,856 were declared as deceased (4.6 %). Our machine learning results demonstrate linear models and non-linear models achieved areas under the receiver operating characteristic (AUROC) around 92 % in survival prediction. CONCLUSIONS: We developed machine learning models that do not require physicians' subjective evaluation for FN mortality risk prediction.

Mortality and admission to intensive care units after febrile neutropenia in patients with cancer.

Febrile neutropenia (FN) is a critical complication of chemotherapy associated with increased in-hospital mortality. However, associations with increased mortality and intensive care unit (ICU) admissions during longer follow-up are not established. Patients treated with standard first-line chemotherapy for solid cancers at Rigshospitalet, Denmark in 2010-2016 were included. Incidence rate ratios (IRR) of all-cause, infectious and cardiovascular mortality, and ICU admissions after FN were analyzed by Poisson regression. Risk factors at the time of FN were analyzed in the subpopulation of patients with FN; all-cause mortality was further stratified by the time periods 0-30, 31-365, and 366+ days after FN. We included 9018 patients with gastric (14.4%) and breast (13.1%) cancer being the most common, 51.2% had locally advanced or disseminated disease and the patients had a median Charlson Comorbidity Index score of 0 (interquartile range, 0-0). During follow-up, 845 (9.4%) experienced FN and 4483 (49.7%) died during 18 775 person-years of follow-up. After adjustment, FN was associated with increased risk of all-cause mortality, infectious mortality, and ICU admissions with IRRs of 1.39 (95% CI, 1.24-1.56), 1.94 (95% CI, 1.43-2.62), and 2.28 (95% CI, 1.60-3.24). Among those with FN, having a positive blood culture and low lymphocytes were associated with excess risk of death and ICU admissions (predominantly the first 30 days after FN), while elevated C-reactive protein and low hemoglobin predicted mortality the first year after FN. The risk of death varied according to the time since FN; adjusted IRR per additional risk factor present for the time periods 0-30, 31-365, and 366+ days after FN were 2.00 (95% CI, 1.45-2.75), 1.36 (95% CI, 1.17-1.57), and 1.17 (95% CI, 0.98-1.41). FN was associated with increased mortality and risk of ICU admissions. An objectively identifiable subgroup of patients among those with FN carried this excess risk.

Cytogenetics and mutations could predict outcome in relapsed and refractory acute myeloid leukemia patients receiving BCL-2 inhibitor venetoclax.

Venetoclax, a selective B cell leukemia/lymphoma-2 (BCL2) inhibitor, has recently shown activity in relapsed or refractory (R/R) acute myeloid leukemia (AML). Effective biomarkers for identifying patients most likely to respond to venetoclax-based treatment are of clinical utility. In this study, we aimed to evaluate the efficacy and safety profiles of venetoclax-based therapy in a total 40 R/R AML patients and identify the potentially predictive factors for response. Overall response rate was 50%, including 9 (22.5%) complete response (CR) or CR with incomplete hematologic recovery of either neutrophil or platelet counts (CRi). Median time to best response was 1.4 months and the median overall survival (OS) was 6.6 months. Presence of intermediate-risk cytogenetics predicted better OS compared to unfavorable-risk cytogenetics. Patients harboring NPM1, RUNX1, or SRSF2 mutations seemed to have higher CR/CRi rates and median OS was significantly longer in RUNX1-mutated patients. On the contrary, patients with FLT3-ITD, TP53, or DNMT3A mutations did not reach any objective response and had worse OS. No laboratory or clinical tumor lysis syndrome was observed and the most common adverse events were prolonged cytopenias which resulted in 67.5% of febrile neutropenia. Patients with concurrent use of azole antifungals had similar incidence of cytopenias compared with those without azole antifungals. In summary, we demonstrate that venetoclax is an effective and well-tolerated salvage option for R/R AML patients. Survival benefits were particularly remarkable in patients with intermediate-risk cytogenetics or RUNX1 mutations. In contrast, TP53, NRAS, and DNMT3A mutations as well as FLT3-ITD conferred negative impact on survival.

CISNE versus MASCC: Identifying low risk febrile neutropenic patients.

OBJECTIVE: Febrile neutropenia though a dreaded complication of chemotherapy, not all patients need inpatient treatment. Risk score indices like MASCC and CISNE have been developed to identify low risk patients eligible for outpatient management. We undertook this study to compare the performances of MASCC and CISNE. METHODS: This was a prospective observational study conducted in a tertiary care centre from August 2017 to April 2019 where patients with chemotherapy induced febrile neutropenia were included. Basic demographic data and primary site of cancer were collected with characteristics required to calculate both MASCC and CISNE scores. The primary outcome measure was 30-day mortality. Apart from the 3 group risk stratification of CISNE, apriori it was decided that two-tier CISNE score will be calculated with 0 or 1 score as low risk and ≥2 as high risk. Descriptive statistics are reported and predictive performance of each score was analysed. RESULTS: Total of 129 patients were recruited. The performance of three-tier CISNE score was more specific (90.6%, 95% CI 76.9-96.9) but sensitivity (25.1%, 95% CI 17.0-36.3) was low compared to that of MASCC score (sensitivity 58.1%, 95% CI 47.0-68.5; specificity 65.1, 95% CI 49.0-78.5%). However, analysis with two-tier CISNE score demonstrated a better sensitivity (56.9%, 95%CI 45.8-67.4). Kappa for agreement between the two scores was 0.520 (95% CI 0.373-0.667, p < 0.001). CONCLUSION: CISNE and MASCC have fair discriminatory power in identifying low risk febrile neutropenia cases. Two group stratification on CISNE scoring will help in better decision making in emergency department.

PROGNOSIS OF THE COURSE OF CHORNOBYL-ORIGINATED ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN IN UKRAINE DEPENDING ON THE REASON OF STANDARD CHEMOTHERAPY INTERRUPTION. / PROGNOZ PEREBIGU GOSTRYKh LIMFOBLASTNYKh LEY̆KEMIY̆ ChORNOBYL'S'KOGO POKhODZhENNIa U DITEY̆ UKRAÏNY ZALEZhNO VID PRYChYN PERERV PRY PROVEDENNI STANDARTNOÏ KhIMIOTERAPIÏ.

OBJECTIVE: Estimation of the bone marrow haemopoietic status depending on the reasons and duration of breaks in a standard chemotherapy (BFM-ALL protocol) to predict the course of acute lymphoblastic leukemia (ALL) in chil- dren exposed to low doses of ionizing radiation after the Chornobyl accident. MATERIALS AND METHODS: The ALL patients (n = 34) were examined within 5 stages of a program chemotherapy. The clinical symptoms, hemogram and myelogram data were analyzed. The radiation dose on bone marrow, initial leuko- cyte count, variants and prognosis of ALL course were accounted. Days of the stopped chemotherapy, type and fre- quency of complications (septic processes, febrile neutropenia, toxic hepatitis, granulocytopenia degree), and the prognosis of disease course (child living status, i.e. alive or died) were estimated. RESULTS: There were abnormal differentiation processes and high percentage of lymphoblasts (86.2 ± 3.3) % in bone marrow in the 1st acute period. Hematological remission was established in all patients on the 33rd day of chemothe- rapy. In a half of cases the haematopoietic recovery occurred by a granulocyte-monocyte type. One third of patients presenting an erythroid type of haemopoiesis died later. The inverse correlation was found between the number of myelocaryocytes and disease prognosis (rs = -0.49). Breaks in chemotherapy for various reasons were recorded. The number of patients with granulocytopenia was greater at the phase 1 and 2 of protocol I and protocol M application, coinciding with a higher incidence of complications. An inverse correlations between the prediction of ALL course and sum of days of breaks between the protocol M and phase 1 of protocol II (rs = -0.56), as well as the duration of the phase 2 of protocol II (rs = -0.62) were found. The radiation dose on bone marrow was (5.37 ± 1.23) mSv. No relationship was found between the radiation doses, ALL variants and disease course. CONCLUSIONS: Prognosis of ALL course in children depends on the type of haemopoietic recovery and reasons of breaks in a standard chemotherapy. Interaction between the haemopoiesis functioning and microenvironment and that of their regulation are the key mechanisms of above-mentioned abnormalities, which is the basis for further research.

A multicenter prospective study of 515 febrile neutropenia episodes in Argentina during a 5-year period.

For better management of patients with febrile neutropenia, our study investigated the epidemiologic, microbiologic, and clinical characteristics of adult inpatients with febrile neutropenia and their mortality-associated factors. To this end, we carried out a prospective, observational, multicenter study in 28 Argentinian hospitals between 2007 and 2012. We included 515 episodes of febrile neutropenia from 346 patients, median age 49 years. Neutropenia followed chemotherapy in 77% of cases, half of the cases due to hematological malignancies. Most episodes were classified as high-risk according to MASCC criteria, and 53.6% of patients were already hospitalized at the onset of febrile neutropenia. Bloodstream infections were detected in 14% episodes; whereas an infectious source of fever was identified in 80% of cases. Mortality rate achieved to 14.95%. The binary regression analysis showed that persistence of fever at day 7, or neutropenia at day 14, dehydration and tachycardia at the onset of febrile neutropenia as well as prior infections were significantly associated with mortality. In addition to expanding our current knowledge on the features of adult patients with febrile neutropenia, present findings provide useful information for better management of them in Argentina, given the appropriate representativeness of centers participating in the study.

Shock and Early Death in Hematologic Patients with Febrile Neutropenia.

Empirical antibiotic therapy with a beta-lactam is the standard of care in febrile neutropenia (FN) and is given to prevent early death. The addition of vancomycin is recommended in certain circumstances, but the quality of evidence is low, reflecting the lack of clinical data. In order to characterize the epidemiology of early death and shock in FN, we reviewed all episodes of FN from 2003 to 2017 at University Hospital, Federal University of Rio de Janeiro, and looked at factors associated with shock at first fever and early death (within 3 days from first fever) by univariate and multivariate analyses. Among 1,305 episodes of FN, shock occurred in 42 episodes (3.2%) and early death in 15 (1.1%). Predictors of shock were bacteremia due to Escherichia coli (odds ratio [OR], 8.47; 95% confidence interval [95% CI], 4.08 to 17.55; P < 0.001), Enterobacter sp. (OR, 7.53; 95% CI, 1.60 to 35.33; P = 0.01), and Acinetobacter sp. (OR, 6.95; 95% CI, 1.49 to 32.36; P = 0.01). Factors associated with early death were non-Hodgkin's lymphoma (OR, 3.57; 95% CI, 1.18 to 10.73; P = 0.02), pneumonia (OR, 21.36; 95% CI, 5.72 to 79.72; P < 0.001), shock (OR, 11.64: 95% CI, 2.77 to 48.86; P = 0.01), and bacteremia due to Klebsiella pneumoniae (OR, 5.91; 95% CI, 1.11 to 31.47; P = 0.03). Adequate empirical antibiotic therapy was protective (OR, 0.23; 95% CI, 0.07 to 0.81; P = 0.02). Shock or early death was not associated with Gram-positive bacteremia; catheter-related, skin, or soft tissue infection; or inadequate Gram-positive coverage. These data challenge guideline recommendations for the empirical use of vancomycin at first fever in neutropenic patients.

Impact of Preemptive Granulocyte Infusions During Febrile Neutropenia in Patients Colonized with Carbapenem-Resistant Gram-Negative Bacteria Undergoing Haploidentical Transplantation.

We prospectively studied the impact of preemptive granulocyte infusions (pGIs) in 69 patients colonized with carbapenem-resistant gram-negative bacteria (CRGNB) undergoing haploidentical hematopoietic cell transplantation (HCT) compared with a previous cohort of 33 patients who received only antimicrobials directed toward CRGNB at the onset of neutropenic fever (non-pGI group). All patients developed neutropenic fever at a median of day +8 (range, -4 to +12) after transplantation. Engraftment kinetics were similar for both groups. The median number of GIs was 2 (range, 1 to 7), and the median dose of granulocytes infused was 5 × 1010 granulocytes per infusion (range, 1 to 30). The overall incidence of CRGNB bloodstream infections (BSIs) was 21.2% in non-pGI group (7/33) and 17.5% (12/69) in the pGI group (P = .8). However, the CRGNB-related mortality among those with BSI was 100% (7/7) in the non-pGI group versus 16.6% (2/12) in the pGI group (P = .001). The day 100 (4.4% versus 24.4%, P = .002) and 2-year nonrelapse mortality (7.5% versus 35.6%, P = .0001) were significantly reduced in the pGI group. The overall survival at 2 years was 75.6% in the pGI group versus 21.2% in the non-pGI group (P = .0001). Colonization and subsequent BSI with CRGNB are associated with a high incidence of mortality in patients undergoing HCT. pGI reduced early mortality associated with CRGNB in colonized patients undergoing post-transplant cyclophosphamide-based haploidentical HCT.

Outpatient treatment for people with cancer who develop a low-risk febrile neutropaenic event.

BACKGROUND: People with febrile neutropaenia are usually treated in a hospital setting. Recently, treatment with oral antibiotics has been proven to be as effective as intravenous therapy. However, the efficacy and safety of outpatient treatment have not been fully evaluated. OBJECTIVES: To compare the efficacy (treatment failure and mortality) and safety (adverse events of antimicrobials) of outpatient treatment compared with inpatient treatment in people with cancer who have low-risk febrile neutropaenia. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 11) in the Cochrane Library, MEDLINE via Ovid (from 1948 to November week 4, 2018), Embase via Ovid (from 1980 to 2018, week 48) and trial registries (National Cancer Institute, MetaRegister of Controlled Trials, Medical Research Council Clinical Trial Directory). We handsearched all references of included studies and major reviews. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing outpatient with inpatient treatment for people with cancer who develop febrile neutropaenia. The outpatient group included those who started treatment as an inpatient and completed the antibiotic course at home (sequential) as well as those who started treatment at home. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility, methodological quality, and extracted data. Primary outcome measures were: treatment failure and mortality; secondary outcome measures considered were: duration of fever, adverse drug reactions to antimicrobial treatment, duration of neutropaenia, duration of hospitalisation, duration of antimicrobial treatment, and quality of life (QoL). We estimated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous data; we calculated weighted mean differences for continuous data. Random-effects meta-analyses and sensitivity analyses were conducted. MAIN RESULTS: We included ten RCTs, six in adults (628 participants) and four in children (366 participants). We found no clear evidence of a difference in treatment failure between the outpatient and inpatient groups, either in adults (RR 1.23, 95% CI 0.82 to 1.85, I2 0%; six studies; moderate-certainty evidence) or children (RR 1.04, 95% CI 0.55 to 1.99, I2 0%; four studies; moderate-certainty evidence). For mortality, we also found no clear evidence of a difference either in studies in adults (RR 1.04, 95% CI 0.29 to 3.71; six studies; 628 participants; moderate-certainty evidence) or in children (RR 0.63, 95% CI 0.15 to 2.70; three studies; 329 participants; moderate-certainty evidence).According to the type of intervention (early discharge or exclusively outpatient), meta-analysis of treatment failure in four RCTs in adults with early discharge (RR 1.48, 95% CI 0.74 to 2.95; P = 0.26, I2 0%; 364 participants; moderate-certainty evidence) was similar to the results of the exclusively outpatient meta-analysis (RR 1.15, 95% CI 0.62 to 2.13; P = 0.65, I2 19%; two studies; 264 participants; moderate-certainty evidence).Regarding the secondary outcome measures, we found no clear evidence of a difference between outpatient and inpatient groups in duration of fever (adults: mean difference (MD) 0.2, 95% CI -0.36 to 0.76, 1 study, 169 participants; low-certainty evidence) (children: MD -0.6, 95% CI -0.84 to 0.71, 3 studies, 305 participants; low-certainty evidence) and in duration of neutropaenia (adults: MD 0.1, 95% CI -0.59 to 0.79, 1 study, 169 participants; low-certainty evidence) (children: MD -0.65, 95% CI -0.1.86 to 0.55, 2 studies, 268 participants; moderate-certainty evidence). With regard to adverse drug reactions, although there was greater frequency in the outpatient group, we found no clear evidence of a difference when compared to the inpatient group, either in adult participants (RR 8.39, 95% CI 0.38 to 187.15; three studies; 375 participants; low-certainty evidence) or children (RR 1.90, 95% CI 0.61 to 5.98; two studies; 156 participants; low-certainty evidence).Four studies compared the hospitalisation time and found that the mean number of days of hospital stay was lower in the outpatient treated group by 1.64 days in adults (MD -1.64, 95% CI -2.22 to -1.06; 3 studies, 251 participants; low-certainty evidence) and by 3.9 days in children (MD -3.90, 95% CI -5.37 to -2.43; 1 study, 119 participants; low-certainty evidence). In the 3 RCTs of children in which days of antimicrobial treatment were analysed, we found no difference between outpatient and inpatient groups (MD -0.07, 95% CI -1.26 to 1.12; 305 participants; low-certainty evidence).We identified two studies that measured QoL: one in adults and one in children. QoL was slightly better in the outpatient group than in the inpatient group in both studies, but there was no consistency in the domains included. AUTHORS' CONCLUSIONS: Outpatient treatment for low-risk febrile neutropaenia in people with cancer probably makes little or no difference to treatment failure and mortality compared with the standard hospital (inpatient) treatment and may reduce time that patients need to be treated in hospital.

Early discontinuation of antibiotics for febrile neutropenia versus continuation until neutropenia resolution in people with cancer.

BACKGROUND: People with cancer with febrile neutropenia are at risk of severe infections and mortality and are thus treated empirically with broad-spectrum antibiotic therapy. However, the recommended duration of antibiotic therapy differs across guidelines. OBJECTIVES: To assess the safety of protocol-guided discontinuation of antibiotics regardless of neutrophil count, compared to continuation of antibiotics until neutropenia resolution in people with cancer with fever and neutropenia, in terms of mortality and morbidity. To assess the emergence of resistant bacteria in people with cancer treated with short courses of antibiotic therapy compared with people with cancer treated until resolution of neutropenia. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 10) in the Cochrane Library, MEDLINE, Embase, and LILACS up to 1 October 2018. We searched the metaRegister of Controlled Trials and the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov for ongoing and unpublished trials. We reviewed the references of all identified studies for additional trials and handsearched conference proceedings of international infectious diseases and oncology and haematology conferences. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared a short antibiotic therapy course in which discontinuation of antibiotics was guided by protocols regardless of the neutrophil count to a long course in which antibiotics were continued until neutropenia resolution in people with cancer with febrile neutropenia. The primary outcome was 30-day or end of follow-up all-cause mortality. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed all studies for eligibility, extracted data, and assessed risk of bias for all included trials. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) whenever possible. For dichotomous outcomes with zero events in both arms of the trials, we conducted meta-analysis of risk differences (RDs) as well. For continuous outcomes, we extracted means with standard deviations (SD) from the studies and computed mean difference (MD) and 95% CI. If no substantial clinical heterogeneity was found, trials were pooled using the Mantel-Haenszel fixed-effect model. MAIN RESULTS: We included eight RCTs comprising a total of 662 distinct febrile neutropenia episodes. The studies included adults and children, and had variable design and criteria for discontinuation of antibiotics in both study arms. All included studies but two were performed before the year 2000. All studies included people with cancer with fever of unknown origin and excluded people with microbiological documented infections.We found no significant difference between the short-antibiotic therapy arm and the long-antibiotic therapy arm for all-cause mortality (RR 1.38, 95% CI 0.73 to 2.62; RD 0.02, 95% CI -0.02 to 0.05; low-certainty evidence). We downgraded the certainty of the evidence to low due to imprecision and high risk of selection bias. The number of fever days was significantly lower for people in the short-antibiotic treatment arm compared to the long-antibiotic treatment arm (mean difference -0.64, 95% CI -0.96 to -0.32; I² = 30%). In all studies, total antibiotic days were fewer in the intervention arm by three to seven days compared to the long antibiotic therapy. We found no significant differences in the rates of clinical failure (RR 1.23, 95% CI 0.85 to 1.77; very low-certainty evidence). We downgraded the certainty of the evidence for clinical failure due to variable and inconsistent definitions of clinical failure across studies, possible selection bias, and wide confidence intervals. There was no significant difference in the incidence of bacteraemia occurring after randomisation (RR 1.56, 95% CI 0.91 to 2.66; very low-certainty evidence), while the incidence of any documented infections was significantly higher in the short-antibiotic therapy arm (RR 1.67, 95% CI 1.08 to 2.57). There was no significant difference in the incidence of invasive fungal infections (RR 0.86, 95% CI 0.32 to 2.31) and development of antibiotic resistance (RR 1.49, 95% CI 0.62 to 3.61). The data on hospital stay were too sparse to permit any meaningful conclusions. AUTHORS' CONCLUSIONS: We could make no strong conclusions on the safety of antibiotic discontinuation before neutropenia resolution among people with cancer with febrile neutropenia based on the existing evidence and its low certainty. Results of microbiological outcomes favouring long antibiotic therapy may be misleading due to lower culture positivity rates under antibiotic therapy and not true differences in infection rates. Well-designed, adequately powered RCTs are required that address this issue in the era of rising antibiotic resistance.