Elderly haematological patients with chemotherapy-induced febrile neutropenia have similar rates of infection and outcome to younger adults: a prospective study of risk-adapted therapy

We prospectively evaluated 131 consecutive episodes of fever and chemotherapy-induced neutropenia in 85 adults with haematological malignancies to determine whether older patients (aged < 60 years) have different causes of fever and outcome than younger adults (aged < 60 years). Patients were stratified into high-risk and low-risk groups according to previously published criteria. High-risk patients received ceftazidime plus amikacin and low-risk patients received ceftazidime alone. All patients were hospitalized until fever and neutropenia resolved. Ninety one high-risk episodes were documented: 56 occurring in older patients (mean age 69 years) and 35 in younger adults (mean age 45 years). Non-Hodkgin's lymphoma and acute myeloid leukaemia were the most frequent underlying neoplasias in both age groups. Intensity of chemotherapy was similar in both age groups. Mean neutrophil count at entry, median duration of neutropenia, rate of documented infection, incidence of bacteraemia, response to therapy, overall mortality and infectious mortality were similar in the two high-risk age subgroups. The elderly subgroup had a trend to have more Gram-negative infections and the younger patients more Gram-positive infections. In addition, 40 low-risk episodes were registered: 29 in elderly patients (mean age 68 years) and 11 in younger patients (mean age 44 years). Elderly low-risk patients had more concurrent diseases that younger ones (P = 0.124). Mean neutrophil count at entry, median duration of severe neutropenia and rate of response were similar in the two age subgroups. All low-risk patients survived. In conclusion, elderly haematological cancer patients with febrile neutropenia show similar rates of infection and outcome to younger ones.     

Compliance with a critical pathway for the management of febrile neutropenia and impact on clinical outcomes

Febrile neutropenia is associated with significant morbidity and mortality. Managing infectious in neutropenic patients remains a dynamic process, making necessary timely and efficient empirical antibiotic therapy. The implementation of critical pathways has been suggested as a strategy to improve clinical effectiveness. This study evaluated the compliance with an institutional critical pathway for the management of febrile neutropenia and the impact on clinical outcomes at Hospital de Clínicas de Porto Alegre, Brazil (HCPA). We performed a cohort study that prospectively included patients hospitalized from January 2004 to December 2005 and presented febrile neutropenia (190 episodes). Historical controls were selected from March 2001 to April 2003 (193 episodes) before the critical pathway was introduced. This study showed a low rate of full compliance (21.6%; 95% CI 15.7–27.5) with the critical pathway. In most cases, there was partial compliance (67.9%; 95% CI 61.3–74.5). Despite the moderate adherence observed, we recorded a decrease in in-hospital all-cause mortality in the sample studied after protocol implementation (from 24.4 to 14.4%; P = 0.017) and reduction in the length of use of cephalosporin and quinolones. In conclusion, implementation of a critical pathway seems to be an effective strategy to improve clinical outcomes in patients hospitalized with febrile neutropenia. Financial support: FIPE/HCPA (Fundo de Incentivo à Pesquisa).     

Diagnosis of sepsis with inflammatory biomarkers,cytokines, endothelial functional markers from SIRS patients

BackgroundSepsis is a life-threatening illness with a challenging diagnosis. Rapid detection is the key to successful treatment of sepsis. To investigate diagnostic value, the plasma protein profiles of inflammatory biomarkers, cytokines, and endothelial functional markers were compared between healthy controls, SIRS, and septic patients.MethodsThe plasma protein profiles were performed by Luminex Assay in a cohort of 50 SIRS patients, 82 septic patients and 25 healthy controls. Fourteen plasma proteins were analyzed in the same cohort: IL-1β, IL-6, IL-8, IL-10, CCL-2, VEGF, VEGF-C, VEGFR2, CD62E, CD62P, MFG-E8, ICAM-1, TFPI, Urokinase.ResultIL-2R, IL-6, IL-8, IL-10, CCL-2, ICAM-1, and Urokinase were significantly higher in sepsis patients than SIRS patients. VEGF, IL-1β, CD62E, CD62P, MFG-E8, and TFPI have no statistical difference. VEGF-C, VEGFR2 were significantly different in SIRS patients than sepsis patients. Urokinase, ICAM-1, and VEGFR2 were significantly different between sepsis group and SIRS group. The AUCs of Urokinase, ICAM-1, and VEGFR2 and the combination for the diagnosis of sepsis were 0.650, 0.688, 0.643, and 0.741, respectively.ConclusionsMost patients have the higher level of several cytokines and developed endothelial cell injury in the initial phase of sepsis, Urokinase, ICAM-1, and VEGFR2 may be useful to evaluate severity and prognosis of sepsis patients.     

Early morning neutropenia in a patient with systemic lupus erythematosus

Abstract

An autopsy case of an 11-year-old boy with polyarteritis nodosa is described in which the onset of the disease was associated with the presence of hepatitis B (HB) antigens (Ag) in the cytoplasm and nuclei of hepatocytes as detected by immunohistological methods. Deposits of HBsAg, HBeAg, IgG, IgM, C3, and C1q were demonstrated in systemic vascular lesions. It is considered that the arteritis was due to deposition in the arteries of immune complexes formed by HBAg and HB antibodies.     

The relationship of clinical and inflammatory markers to outcome in stable patients with cystic fibrosis

Decreased survival in patients with cystic fibrosis has been related to FEV1, BMI, and infection with Burkholderia cepacia complex (BCC). We have assessed the relationship of blood, sputum, and urine inflammatory markers to lung function, BMI, colonization with B cenocepacia (Bc), and patient survival. Thirty-nine stable cystic fibrosis (CF) patients (10 with Bc) were enrolled in a study to determine the effect of alpha-1-antitrypsin on airways inflammation. Pre-treatment measurements were used in this study. Demographics, sputum microbiology, heart rate, oxygen saturation, lung function were recorded. Blood samples were obtained for white blood count (WBC), C-Reactive Protein (CRP), and plasma neutrophil elastase/AAT complexes (pNEC). Neutrophil elastase (NE), neutrophil elastase/AAT complexes (sNEC), interleukin-8 (IL-8), TNF-receptor 1 (sTNFr), and myeloperoxidase (MPO) were measured in sputum and urinary desmosine concentration determined. Patients with Bc had significantly higher levels of pNEC, 332 +/- 91.4 ng/ml (mean +/- SEM) versus 106 +/- 18.2 ng/ml (P = 0.0005) and sNEC, 369 +/- 76.6 ng/ml versus 197 +/- 36.0 ng/ml compared to those who were not. Five deaths were reported at the end of 1 year, (four with Bc) (P = 0.011). Patients who subsequently died had significantly lower lung function FEV1, 1.2 +/- 0.2 L versus 2.0 +/- 0.1 L (P = 0.03) and FVC, 2 +/- 0.3 L versus 3.1 +/- 0.2 L (P = 0.01), compared to those that survived. There was significantly higher NE activity, 3.6 +/- 1.6 U/ml versus 1.5 +/- 0.6 U/ml (P = 0.03), pNEC, 274 +/- 99 ng/ml versus 142 +/- 30 ng/ml (P = 0.05), MPO, 163 +/- 62 mcg/ml versus 54 +/- 6.9 mcg/ml (P = 0.03), and urinary desmosines 108 +/- 19.9 pM/mg creatinine versus 51.1 +/- 3.3 pM/mg creatinine (P = 0.001), in those patients who subsequently died compared to those that survived. These data suggest there is increased neutrophil degranulation in patients infected with Bc and these patients have a poor outcome.     

Early hospital discharge with oral antimicrobial therapy in patients with hematologic malignancies and low-risk febrile neutropenia

Although consensus exists relating criteria for the identification of low-risk patients with febrile neutropenia, no clear indication on how to manage these patients has been so far provided particularly in outpatients affected by hematologic malignancies. The feasibility and safety of early discharge was prospectively evaluated in 100 outpatients with hematologic malignancies and febrile neutropenia. A strategy considering the risk-index of the Multinational Association of Supportive Care in Cancer (MASCC) was applied. High-risk patients were entirely managed at hospital. Low-risk patients were early discharged if they were afebrile since 48 h and not on supportive therapy requiring hospitalization. Out of 90 low-risk episodes, in 69 instances (76.7%), patients were discharged after a median of 4 days and continued home therapy with oral cefixime (78%) or other antibiotics. Only five outpatients (7.2%) had fever recurrence. Twenty-one low-risk patients were not early discharged due to worsening conditions (three deaths), need of multiple daily dose therapy, or discharge refuse. No clinical characteristic was able to predict the eligibility for early discharge. The MASCC risk-index is a useful aid in the identification of high-risk febrile neutropenia needing whole in-hospital treatment. As for low-risk patients, hospitalization at least in the first days of fever is required. Cefixime could be included among the oral antibacterial drugs to be used in the outpatient treatment of adult patients with febrile neutropenia.     

Primary autoimmune neutropenia in children: a study of neutrophil antibodies and clinical course

BACKGROUND AND OBJECTIVES: Primary autoimmune neutropenia (AIN) in children is characterized by severe neutropenia, but mild bacterial infections and a spontaneous resolution. Neutrophil autoantibodies are involved in the disease. The precise relationship between the specificity and level of reactivity of the antibodies with the absolute neutrophil count and frequency of infections is not known. To obtain a better insight into this relationship, we performed a follow-up study in 15 patients with primary AIN. In addition, we performed two different neutrophil antibody tests to evaluate their sensitivity and specificity. MATERIALS AND METHODS: Blood samples from 15 children were tested for neutrophil antibodies, at different time-points during the disease, by using the indirect granulocyte immunofluorescence test (GIFT) and the monoclonal antibody-specific immobilization of granulocyte antigens (MAIGA) assay. Clinical data related to the occurrence of bacterial infections and treatment, and neutrophil counts were collected. RESULTS: Early in the disease, antibodies with pan-FcRIIIb specificity were detected, and HNA-1a or HNA-1b specificity of the antibodies developed over time. The sensitivity and specificity of neutrophil antibody detection tests were higher in the GIFT than in the MAIGA assay. Variables predicting time of recovery from neutropenia were not found. Prophylactic antibiotics led to the almost complete disappearance of infections. CONCLUSIONS: In patients with primary neutropenia, neutrophil antibody specificity changes over time. Prophylactic antibiotics do benefit the patients.     

Multivariate analysis of febrile neutropenia occurrence in patients with non-Hodgkin lymphoma: data from the INC-EU Prospective Observational European Neutropenia Study

Myelosuppression, particularly febrile neutropenia (FN), are serious dose-limiting toxicities that occur frequently during the first cycle of chemotherapy. Identifying patients most at risk of developing FN might help physicians to target prophylactic treatment with colony-stimulating factor (CSF), in order to decrease the incidence, or duration, of myelosuppression and facilitate delivery of chemotherapy as planned. We present a risk model for FN occurrence in the first cycle of chemotherapy, based on a subgroup of 240 patients with non-Hodgkin lymphoma (NHL) enroled in our European prospective observational study. Eligible patients had an International Prognostic Index of 0–3, and were scheduled to receive a new myelosuppressive chemotherapy regimen with at least four cycles. Clinically relevant factors significantly associated with cycle 1 FN were older age, increasing planned cyclophosphamide dose, a history of previous chemotherapy, a history of recent infection, and low baseline albumin (<35 g/l). Prophylactic CSF use and higher weight were associated with a significant protective effect. The model had high sensitivity (81%) and specificity (80%). Our model, together with treatment guidelines, may rationalise the clinical decision of whether to support patients with CSF primary prophylaxis based on their risk factor profile. Further validation is required.     

Plasma IL-8 and IL-6 levels can be used to define a group with low risk of septicaemia among cancer patients with fever and neutropenia

The standard therapy for patients with fever and chemotherapy-related neutropenia is hospitalization and infusion of broad-spectrum antibiotics. Early discharge of a defined group of patients at low risk for septicaemia would be of great advantage for these patients. In this study plasma interleukin-8 (IL-8) and interleukin-6 (IL-6) levels measured at start of fever (n = 72) could define a low-risk group of febrile patients with neutropenia due to chemotherapy. For this purpose we collected and analysed data on 72 fever episodes from 53 patients with chemotherapy-related neutropenia, aged between 1 and 66 years. Of the 72 episodes, 18 were classified as bacteraemia and/or clinical sepsis (sepsis group). The IL-6 and IL-8 plasma concentration were significantly increased in patients with chemotherapy-related neutropenia and fever due to bacteraemia versus fever of non-bacterial origin (P = 0.043 and P = 0.022 respectively). Logistic regression analysis, with sepsis as the outcome variable, revealed significant effects of age combined with either IL-6 or IL-8. Sepsis occurrence was lowest for patients <16 years and highest in patients between 16 and 50 years, and was higher in patients with increased IL-6 (P = 0.032) or IL-8 (P = 0.049). No significant effect of leucocyte count, C-reactive protein, sex or underlying malignancy at presentation was detected. The plasma IL-6 and IL-8 levels were fairly strongly correlated (Pearson r = 0.62). Using a cut-off value with 100% sensitivity, both IL-8 and IL-6 could define a low-risk group of neutropenic patients of 28% (CI 15-40%) at the start of the febrile period. Intervention studies are warranted to confirm this result and to investigate whether an early discharge based on IL-8 or IL-6 measurement is safe, increases the quality of life, and results in cost savings.     

Applying the Multinational Association for Supportive Care in Cancer risk scoring in predicting outcome of febrile neutropenia patients in a cohort of patients

The purpose of this study was to determine if the Multinational Association for Supportive Care in Cancer (MASCC) risk-index score is able to predict the outcome of febrile neutropenia in patients with underlying hematological malignancy and to look at the other possible predictors of outcome. A retrospective study of 116 episodes of febrile neutropenia in patients who were admitted to the hematology ward of a local medical center in Malaysia between January 1st 2004 and January 31st 2005. Patient characteristics and the MASCC score were compared with outcome. The MASCC score predicted the outcome of febrile neutropenic episodes with a positive predictive value of 82.9%, a sensitivity of 93%, and specificity of 67%. Other predictors of a favorable outcome were those patients who had lymphomas versus leukemias, duration of neutropenia of less than 7 days, low burden of illness characterized by the absence of an infective focus and absence of lower respiratory tract infection, a serum albumin of >25 g/l, and the absence of gram-negative bacteremia on univariate analysis but only serum albumin level, low burden of illness, and presence of respiratory infection were significantly associated with unfavorable outcome after multivariate analysis. The MASCC score is a useful predictor of outcome in patients with febrile neutropenia with underlying hematological malignancies. This scoring system may be adapted for use in local settings to guide the clinical management of patients with this condition.     

Evolution of the clinical manifestations of infection during the course of febrile neutropenia in patients with malignancy

Summary The impact of a standardized set of diagnostic interventions on the further management of 968 episodes of fever in neutropenic cancer patients who did not respond to initial therapy was assessed prospectively. At the onset of fever, 65% of patients had no additional signs of infection, whereas skin and soft tissue infections were present in 12% and clinical sepsis and gastrointestinal infections in 8% each. After 72h, 41% of the fevers still remained unexplained. New foci of infection emerged in 11% of the cases involving mainly the lungs, skin and soft tissues, and urinary tract. The presence of a lower respiratory tract infection or a microbiologically defined infection of any sort was associated with higher mortality than other types of infection were. Changes in initial antibiotic therapy were, based on the results of the diagnostic measures specified in the protocol in only 15% of the cases.     

Local inflammation occurs before systemic inflammation in patients with COPD

Background and objective: COPD is associated not only with an abnormal inflammatory response in the lung but also with systemic inflammation, including systemic oxidative stress, activation of circulating inflammatory cells and increased circulating levels of inflammatory cytokines. Understanding the nature and course of systemic inflammation in COPD is important given the potential for anti‐inflammatory therapy. This study explored whether local and systemic inflammation occur concurrently in patients with COPD. Methods: Forty‐four patients with stable COPD, 10 smoking controls and 10 non‐smoking controls were enrolled in this observational study. Induced sputum and peripheral blood samples were obtained simultaneously for measurement of inflammatory cell numbers and the concentrations of IL‐6 and CRP. Results: The total number of cells in the sputum total cell number, percentage of neutrophils and the concentration of IL‐6 were significantly higher in smoking controls and patients with COPD than in non‐smoking controls (P < 0.05 and P < 0.01, respectively). As the disease stage progressed, airway inflammatory cells and IL‐6 levels increased. CRP levels in sputum were significantly higher in stage II, III and IV COPD patients than in smoking and non‐smoking controls (P < 0.01). However, the peripheral WCC and percentage of neutrophils were similar in patients with COPD, smoking and non‐smoking controls. Circulatory concentrations of IL‐6 and CRP in stages III and IV COPD patients were significantly higher than in smoking and non‐smoking controls (P < 0.05 and P < 0.01, respectively). Additionally, there were positive correlations between sputum and blood IL‐6 and CRP levels (r = 0.566, P < 0.01 and r = 0.443, P < 0.01, respectively). Conclusions: The increase in the inflammatory cell population and IL‐6 and CRP levels in the airway may occur earlier than in the peripheral blood, and reflect the degree of airflow limitation better than do peripheral blood measurements. Systemic inflammation may be present in patients with severe or very severe COPD.