Length Of Neutropenia Research Articles

C- reactive protein in autologous stem cell transplantation: prediction of clinical complication

Objective: The aim of this study was to evaluate C-reactive protein (CRP) as a predictor of complications during autologous stem cell transplant (HSCT). Methods: We analyzed a cohort of 340 transplants. Correlation analyses were performed, including CRP obtained before HSCT, on Day+3, Day+6, Day+9, after Day+11, and at the onset of febrile neutropenia, and the following outcomes: bacteremia, severity of mucositis, length of neutropenia and hospitalization, and death. Results: the median age was 54 years old (ranging from 20 to 75), and 62% and 20% were multiple myeloma and non-Hodgkin lymphoma cases, respectively. The median CRP levels increased from D+3 to D+9 and after that decreased progressively until discharge. CRP levels were associated with bacteremia, mucositis grade, length of neutropenia and hospitalization, and death. Variation in CRP values from D+3 to D+6 predicted complications. Mortality was associated with D+9 CRP levels (19 vs. 7.9 mg/dL; p<0.01), and a ROC curve area of 0.83 (95% CI 0.7 – 0.95) to predict mortality. At a cut-off of 8.5mg/dL, D+9 CRP had 83% and 79% sensitivity and specificity, respectively.
 Conclusions: In this study, CRP dynamics were associated with several HSCT complications. CRP levels curve could be applied to indicate poor outcomes during HSCT.

Clinical Features of Infection within 100 days after Hematopoietic Stem Cell Transplantation in 313 patients with Hematologic Diseases

To analyze the clinical characteristics of infection within 100 days after hematopoietic stem cell transplantation (HSCT) in patients with hematologic disease. The culture results of 313 HSCT patients infected in the hematology department of our hospital from January 2013 to January 2019 were collected, and the infection incidence, pathogen distribution, drug susceptibility test results and infection risk factors out of them all were analyzed. Among 313 HSCT patients, infection occurred within 100 days in 262(83.7%) patients, 234 (89.3%) cases were in neutropenic period at infection onset. 156 pathogen distributions showed that the bloodstream infection (64.1%) ranked first. Among isolates, Gram-negative bacteria was 86 (55.1%), which were higher than Gram-positive bacteria (49, 31.4%), and fungi was 21(13.5%). The prevalence of ESBLs in E.coli and Klebsiella pneumoniae were 36.4% and 31.6%, respectively. The drug resistance rates of E.coli and Klebsiella pneumoniae to carbapenems were 18.20% and 5.3%, respectively, and to amikacin were 29.5% and 10.5%, respectively. The antimicrobial resistance of fermentation bacteria was significantly different. The drug resistence rates of Pseudomonas aeruginosa and Acinetobacter baumannii to carbapenems were high. Only one strain of methicillin-resistant staphylococcus aureus (MRSA) was found. The drug resistence rates of enterococcus faecalis to linezolid was 14.30%. The sensitivity of other Gram-positive bacteria to vancomycin, teicolanin and linezolid was 100%. The HSCT in our hospital was mainly allogeneic, and univariate analysis showed that the risk factors for infection were status before trasplantion, HLA matching type,length of stay for the first transplant, and length of neutropenia, while Mulvariate analysis showed that only HLA matching type showed statistical significance. The infection of patients after HSCT occurrs in period of neutropenia, Most of pathogens are G- bacteria, and the resistance to antibiotics is quite common, HLA mismatch is allo-HSCT independent risk factors for infection. It is very imprtant to monitor actively the distribution of pathogenic bacteria, drug-resistance and risk factors of infection for guiding more reasonable and standardized clinical treatment.

Early versus late onset bloodstream infection during neutropenia after high-dose chemotherapy for hematologic malignancy.

The length of neutropenia has a significant impact on the incidence of bloodstream infection (BSI) in cancer patients, but limited information is available about the pathogen distribution in late BSI. Between 2002 and 2014, BSI episodes in patients with neutropenia receiving chemotherapy for hematologic malignancies were prospectively identified by multicenter, active surveillance in Germany, Switzerland and Austria. The incidence of first BSI episodes, their microbiology and time to BSI onset during the first episode of neutropenia of 15,988 patients are described. The incidence rate of BSI episodes was 14.7, 8.7, and 4.7 per 1000 patient-days in the first, second, and third week of neutropenia, respectively. BSI developed after a median of 5 days of neutropenia (interquartile range [IQR] 3-10days). The medium duration of neutropenia to BSI onset was 4 days in Escherichiacoli (IQR 3-7days), Klebsiella spp. (2-8days), and Staphylococcus aureus (3-6days). In contrast, BSI due to Enterococcus faecium occurred after a median of 9 days (IQR 6-14days; p < 0.001 vs. other BSI). Late onset of BSI (occurring after the first week of neutropenia) was also observed for Stenotrophomonas maltophilia (12days, IQR 7-17days; p < 0.001), and non-albicans Candida spp. (13days, IQR 8-19days; p < 0.001). Over the course of neutropenia, the proportion of difficult to treat pathogens such as E. faecium, S. maltophilia, and Candida spp. increased. Among other factors, prior duration of neutropenia may help to guide empiric antimicrobial treatment in febrile neutropenia.

Impact of recommended weight-based dosing of granulocyte-colony stimulating factors in acute leukemia and stem cell transplant patients.

Febrile neutropenia (FN) is a major risk factor for infection-related morbidity and mortality. The National Comprehensive Cancer Network recommends the prophylactic use of granulocyte-colony stimulating factors (G-CSF), dosed at 5mcg/kg and rounded to the nearest vial size. A previous medication use evaluation conducted within a multi-hospital healthcare system demonstrated that only 67% of patients were started on appropriate weight-based dosing. The purpose of this study was to evaluate the effect of appropriate weight-based G-CSF dosing in patients on clinical outcomes. A retrospective chart review of patients with acute leukemia or stem cell transplant recipients who received G-CSF from May 2009 to September2015 was conducted. Patient admissions were reviewed in regards to neutropenia length, incidence of FN, length of stay, and final disposition (alive or deceased). Admissions were divided into one of three weight-based dosing groups of under 5mcg/kg, recommended 5mcg/kg within a 10% range, and over 5mcg/kg which were named under, recommended, and over, respectively. Ninety-four admissions were included. Average age of this patient population was 58years old, and the majority of patients were male (53%) and Caucasian (55%). Majority of patients had been diagnosed with acute myeloid leukemia (91%). Data showed average duration of neutropenia was around 10days regardless if the patient received under 5mcg/kg, the recommended 5mcg/kg or over 5mcg/kg G-CSF (10.1±6.7days, 8.9±9.2days, 10.1±9.1days, respectively). Length of stay was similar for patients regardless of initial G-CSF dose (29.6±16.0days, 29.1±18.4days, and 24.5±17.0, respectively). However, the incidence of FN was significantly greater for those who received under 5mcg/kg of G-CSF (87% for under, 68% for recommended, and 54% for over). In this retrospective analysis, variations from the recommended 5mcg/kg G-CSF dose did not significantly impact length of neutropenia, length of stay, nor mortality. However, patients who received under the 5mcg/kg of G-CSF dose may be at a greater risk of FN.

Novel Risk Factors for Predicting the Development of Invasive Fungal Infections in Acute Myeloid Leukemia Patients Undergoing Induction and Re-Induction Chemotherapy

BACKGROUNDInvasive fungal infections (IFI) occur in 5% to 40% of patients with hematologic malignancies, most commonly in patients with acute myeloid leukemia (AML). Historically, at the University of Virginia (UVA), antifungal prophylaxis was not routinely used in patient undergoing induction chemotherapy for AML. With an antifungal treatment naïve patient cohort, this study had the unique opportunity to examine if specific patient characteristics, comorbidities, or diagnostic criteria were predictive for the development of an IFI. METHODSA retrospective chart review of 126 consecutive patients undergoing induction or re-induction chemotherapy for AML at UVA from July 2011 to December 2015 was conducted. The primary endpoint was to determine the rate of probable or biopsy proven IFIs within ninety days of chemotherapy initiation as characterized by the European Organization for Research and Treatment of Cancer/Invasive Fungal Cooperative Group and the National Institute of Allergy and Infectious Disease Mycoses Study Group criteria. Secondary endpoints include patient comorbidity and disease specific indices associated with IFI. Each induction or re-induction regimen was counted as a distinct event. Statistical methods include pairwise Wilcoxon tests, univariate analyses, and Kruskal-Wallis tests. Statistical significance was defined as a p-value <0.05. RESULTSOf 126 patients, there were a total of 176 distinct induction or re-induction events. Thirty-eight patient events (22%) received antifungal prophylaxis with fluconazole per attending physician preference. In patients (n=102, 81%) who did not receive antifungal prophylaxis during induction, there were a total of 19 (19%) patients with probable/proven IFI. There was a significant association with probable/proven IFI in regards to decreased bone marrow cellularity (p-value 0.018). There were no correlations between probable/proven IFI and body mass index, age of diagnosis, gender, nicotine abuse, length of neutropenia, cytogenetics, and bone marrow blast percentage. In the antifungal prophylaxis cohort, 3 patients (8%) had probable/proven IFI.Another aspect reviewed is the potential concept of an immune reserve ratio (IRR). The IRR is the percentage of the bone marrow core cellularity divided by blasts - representing the bone marrow functionality at the time of leukemia diagnosis or relapse. IRR was 1.9 vs 1.4 vs 1.2 (p-value 0.038) for none vs possible vs probable/proven IFI cohorts. DISCUSSIONThis study reveals that decreased bone marrow cellularity and decreased IRR may be used to predict which AML patients undergoing induction chemotherapy are at higher risk of developing an IFI. Traditional risk factors, such as tobacco use, length and degree of neutropenia, were not found to be significant in this review. Other patient co-morbidities, such as hypertension, COPD, and chronic kidney disease, and AML disease specific characteristics, such as cytogenetic and bone marrow blasts, also did not demonstrate clinical significance.To date, studies have not developed a method to quantify a patient's immune reserve at the time of AML diagnosis and risk of IFI. The IRR attempts to use the ratio of bone marrow cellularity and blasts as a surrogate marker of functional immune activity. This review suggests that the IRR is highly correlative of IFI development. Future studies need to be performed to validate this prospectively. UVA is currently conducting a prospective clinical trial examining the utility of IRR to predict IFI in adults with AML induction chemotherapy. DisclosuresNo relevant conflicts of interest to declare.

Association of proton pump inhibitors with the occurrence of gut-derived bacteraemia in patients with haematological malignancy after chemotherapy

Background: Gut-derived bacteraemia is a major complication in patients with haematological malignancy after chemotherapy.Objective: Our study aimed to investigate the role of proton pump inhibitors (PPIs) in the occurrence of gut-derived bacteraemia.Methods: We compared data from 92 hospitalized haematological malignancy patients after chemotherapy with gut-derived bacteraemia, collected from January 2009 to July 2015, with those of 92 contemporaneous, hospitalized haematological malignancy patients without bacteraemia. We evaluated PPIs use and analysed the effects of covariates.Results: Patients with gut-derived bacteraemia had a significantly higher incidence of PPIs use (69.6%) than that of controls (47.8%). Of the patients with gut-derived bacteraemia, only 44.6% had a documented indication for PPIs therapy. The antibacterial prophylaxis rate was 38.0% in the bacteraemia group and 58.7% in the non-antibacterial group. Based on multivariable logistic regression analysis, only PPIs use (P = 0.00, odds ratio (OR) = 0.546) was found to be associated with the risk of bacteraemia whereas antibacterial prophylaxis (P = 0.00, OR = 0.652) was protective. There were no significant differences in demographics, malignancy status, length of neutropenia, complications, or steroid use between the gut-derived bacteraemia and control group.Conclusions: This study suggests a potential association between PPIs use and development of gut-derived bacteraemia in haematological malignancy patients after chemotherapy.

Palifermin reduces infection rate and hyperfibrinogenemia in patients treated with high-dose chemotherapy based on beam or BU-thiothepa.

We performed a retrospective study in patients who underwent high-dose chemotherapy and auto-SCT because of haematological malignancies. Forty patients were treated with palifermin while 80 were controls selected after being matched for diagnosis and length of neutropenia. Patients treated with BEAM or BU-CY or THIO-CY (BEAM/BUS) displayed, after palifermin, a lower rate of severe oral mucositis (P=0.03). This beneficial effect of palifermin was not evident in the stratum of patients treated with high-dose melphalan (HD-PAM). After palifermin, we observed in the whole treated population a reduced rate of 'fever of unknown origin' (FUO, P=0.02) and of severe infections not related to Gram-positive bacteria (FUO, Gram-negative bacteremia or pneumonia) (P=0.003). This effect of palifermin on infections not related to Gram-positive bacteria was evident only in patients receiving BEAM/BUS (P=0.01) and not in patients treated with HD-PAM (P=0.11). Fibrinogen peak in plasma was found to be reduced after palifermin in the whole population (P=0.01) and in the stratum who received BEAM/BUS (P=0.02) but not in the stratum of HD-PAM. In conclusion, anti-infectious beneficial effects of palifermin are more evident in BEAM/BUS-treated patients and toward some types of infections. Reduction of fibrinogen level after palifermin suggests that this agent reduces not only the rate of infections but also their severity.

Severe sepsis in autologous stem cell transplant recipients: Microbiological aetiology, risk factors and outcome

Infectious complications are the main reason for early treatment-related mortality after autologous stem cell transplantation (ASCT). We evaluated retrospectively microbiological aetiology, risk factors and clinical consequences of severe sepsis in this patient cohort. From 1996 to 2006 a total of 319 patients underwent ASCT at our institution. Antibacterial prophylaxis was not used. Neutropenic fever occurred in 83% (n=265) and was complicated by severe sepsis in 5% (n=17) of patients. Severe sepsis tended to be more common in patients with non-Hodgkin's lymphoma (NHL) than in other patients (9% vs 3%, p=0.009). Bacteraemia was observed more commonly in patients with severe sepsis (76% vs 22%, p<0.001); Pseudomonas sp. was found in 30% (n=5) of these patients. Kinetics of C-reactive protein (CRP) more commonly coincided with, rather than predicted, the development of severe sepsis. All other observed risk factors for severe sepsis (length of neutropenia, fever and blood culture findings) were late indicators. Severe sepsis was fatal in 9 patients (53%), and all had NHL (p=0.003 compared to other patients). Severe sepsis is an important cause of early mortality after ASCT, especially in NHL patients. Ways to prevent development of severe sepsis or predict its development might reduce early mortality among ASCT recipients.

Intermediate dose etoposide plus G-CSF 16 g/kg is more effective than cyclophosphamide 4 g/m2 plus G-CSF 10 g/kg in PBSC mobilization of lymphoma patients

We designed intermediate dose etoposide + G-CSF 16 µg/kg as a Peripheral Blood Stem Cell (PBSC) mobilization schedule suitable for outpatient administration. Forty-one Lymphoma patients received intermediate dose etoposide (200 mg/m2 i.v. day +1, +2, +3) +G-CSF 16 µg/kg/day. Results of PBSC mobilization in these patients were compared with those of a group of 37 lymphoma patients mobilized using cyclophosphamide (CTX) at dosage of 4 g/m2 + G-CSF 10 µg/kg/die. Mean peak of CD34+ cells achieved in P.B. and total CD34+ cells harvested were higher in patients mobilized with intermediate dose etoposide (p = 0.003 and p = 0.004, respectively). After transplantation recovery of polymorphonucleate neutrophils (PMN) > 0.5 × 109/L did not differ significantly between groups: 11.7 days in intermediate dose etoposide group and 11.5 days in CTX group (p = 0.7). Intermediate dose etoposide + G-CSF 16 µg/kg resulted in a maximum length of neutropenia (PMN < 0.5 × 109/L) of 2 days and neutropenic fever was registered during only 3/41 courses (7.3%). Intermediate dose etoposide + G-CSF 16 µg/kg is a highly effective mobilizing therapy, further, it has the advantage of low hematologic toxicity and can be easily administered as outpatient treatment.

Survival of Patients with Hematological Malignancy Admitted to the Intensive Care Unit (ICU): Prognostic Factors and Outcome Compared to Unselected Medical ICU Admissions.

Cancer patients have historically had a very poor outcome following ICU admission. Outcome has however improved over the last decade. We aim to identify factors that predict survival for critically ill patients with hematological malignancy and which can be readily identified prior to admission. This would improve selection of patients suitable for ICU admission, which represents a limited resource. We also assessed the ability of the APACHE II score to predict prognosis in these patients. Since the ICU admission case mix will vary between hospitals, one non-surgical admission within +/− 1 week of each hematological admission acted as a control group. Factors which might affect outcome were assessed by multivariate regression analysis. Factors included were age, hematological diagnosis (acute or chronic leukemia, myeloma, lymphoma), time from hematological diagnosis to ICU admission (0–6 months, 6–12 months, >12 months), degree of prior treatment (admission prior to diagnosis, during first line therapy, after first line), remission status, prior stem cell transplant, documented infection and length of neutropenia (none, 1–10 days, >10 days). For hematology patients, predicted hospital mortality was calculated from the APACHE II score by the formula of Knaus et al (Critical Care Medicine 1985). The APACHE scores of hematology patients were compared to controls by a two-sample t test. Predicted and actual mortalities were compared using a one sample test of proportion. The impact of mechanical ventilation (MV) on mortality was assessed by risk ratios. We identified 111 patients with hematological malignancy (acute leukemia n=42, chronic leukemia n=11, myeloma n=19 and lymphoma n=39) admitted to ICU in one teaching and three district general hospitals (November 2000 - January 2006). Median age of hematological patients was 59 years (range 17–84) and M: F ratio 1.22:1. Control patients (n=111) were similar with median age 63 years (range 17–86) and M: F ratio 1.09:1. For control patients, overall ICU and hospital survival rates were 70% and 55% respectively while survival for hematology patients was approximately half at 44% and 24% respectively. In multivariate regression analysis, only increasing age predicted poor outcome (p=0.016). There was a trend to poor outcome if patients were not in complete remission (p=0.066) or had documented infection (p=0.06). All other variables were not significant. APACHE scores were significantly higher in hematology patients (median 27) compared to controls (median 19) p<0.001. Predicted hospital mortality for hematology patients was 56%, significantly lower than actual mortality (77%) p<0.001. For controls, hospital survival was slightly reduced for MV v's not receiving MV (risk ratio = 1.37; 95% C.I. = 0.91, 2.05). Hematology patients hospital survival was significantly worse for MV - 5/55, 9% v's no MV 20/44, 45% (risk ratio = 5.00; 95% CI = 2.04, 12.50). The pre-admission variables assessed did not predict mortality and should not be used for this. Despite high APACHE scores, predicted hospital mortality underestimated mortality for patients with hematological malignancy. Need for MV still predicts poor outcome in this group but without MV nearly half survive to hospital discharge.

Fluoroquinolone resistance in hematopoietic stem cell transplant recipients with infectious complications

The infectious complications are an important cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) recipients. Our retrospective study has the objective to evaluate the incidence, clinical and bacteriologic features of documented infections in these patients. The frequency of infectious complications was analysed in 42 patients with hematologic malignancies who received HSCT from January to December 2002 at Pisa General Hospital. Thirty-three patients underwent autologous HSCT and 9 received allogeneic HSCT. All patients reiceved acyclovir, fluconazole and floroquinolones as prophylaptic regimen. A total of 38 infectious episodes were recognized in 22 patients during the early post-HSCT period ( N = 27) and in the late post-HSCT period ( N = 11). Infectious complications rate correlated positively with the deepness and length of neutropenia in the early period. There were 21 episodes of sepsis (the majority by coagulase negative staphylococci), 2 pneumonias and 1 vertebral osteomyelitis. All staphyloccus strains were, in vitro, resistant to oxacillin and ciprofloxacin and 8 out of 15 Gram negative rods were resistant to ciprofloxacin. Most of the infectious complications were cured with appropriated antimicrobial therapy and/or with engraftment and, in 4 cases, with central catheter removal. One patient developed a positive CMV antigenemia; a pre-core mutant form of HBV reactivation was diagnosed in another patient. No cases of invasive fungal infections were recognised. Five patients died but only one from infection (septic shock). Pneumonia was a coexisting cause of death in 2 patient in the late period. We can conclude that most of infectious complications, that occurred in the early period post-HSCT were due to coagulase negative staphylococci and Gram negative rods resistant to ciprofloxacin. For this reason, the usefulness of fluoroquinolone prophylaxis in HSCT recipients should be revaluated.

Treatment of Documented and Suspected Neutropenia-Associated Invasive Fungal Infections

Factors such as the intensification of anti-tumor regimens have enhanced both the depth and length of neutropenia and endorsed severe deficiencies in other immune systems. As a result, the risk of fungal infections has increased substantially. Clinicians should be aware of the possibility to enable a timely diagnosis because many of the problems in the management of invasive fungal infections during neutropenia are as much the consequence of diagnostic shortcomings as of lack of therapeutic options. About 7% of all febrile episodes during neutropenia can ultimately be attributed to fungi, Candida and Aspergillus species being the paramount pathogens. Although the data in favor of prophylactic use of antifungals are not convincing, prophylaxis is still recommended in an attempt to protect particularly high-risk patients. Fluconazole still appears a suitable agent in recipients of a bone marrow transplant. Given the paucity of data, reappraisal of the value of empirical antifungal therapy is warranted. Amphotericin B with or without 5-flucytosine is considered the standard therapy for acute candidiasis with fluconazole as an alternative. Amphotericin B is also first-line therapy for invasive aspergillosis in neutropenic patients; lipid-based formulations are recommended for patients who develop nephrotoxity. Recovery of the granulocytes and other immune systems has shown to be of critical importance in the management of all invasive fungal infections.