Non-neutropenic Patients Research Articles

Safety and efficacy of amphotericin-B deoxycholate inhalation in critically ill patients with respiratory Candida spp. colonization: a retrospective analysis.

BackgroundCandida spp. are frequently cultured from the respiratory tract in critically ill patients. Most intensivists start amphotericin-B deoxycholate (ABDC) inhalation therapy to eradicate Candida spp. from the respiratory tract. However, the safety and efficacy of this treatment are not well established. The purpose of this study was to assess the safety and efficacy of ABDC inhalation for the treatment of respiratory Candida spp. colonization in critically ill patients.MethodsAll non-neutropenic patients admitted into the intensive care unit (ICU) of a university hospital from December 2010–2011, who had positive Candida spp. cultures of the respiratory tract for more than 1 day and required mechanical ventilation >48 h were retrospectively included. The decision to start ABDC inhalation had been made by attending intensivists on clinical grounds in the context of selective decontamination of the digestive tract. Infection characteristics and patient courses were assessed.ResultsHundred and thirteen consecutive patients were studied. Fifty-one of them received ABDC inhalation and their characteristics at baseline and day 1 of respiratory colonization did not differ from those of colonized patients not receiving treatment (n = 62). The ABDC-treated group had a similar Candida spp. load but did not decolonize more rapidly as compared to untreated patients. The clinical pulmonary infection and lung injury scores did not decrease as in the untreated group. In a Cox proportional hazard model, the duration of mechanical ventilation was increased (P < 0.003) by ABDC treatment independently of other potential determinants and Candida spp. colonization. No differences in ventilator-associated pneumonia or in overall mortality (up to day 90) were observed.ConclusionTreatment of respiratory Candida spp. colonization in non-neutropenic critically ill patients by inhaled ABDC may not affect respiratory colonization but may increase duration of mechanical ventilation, because of direct toxicity of the drug on the lung.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-014-0575-3) contains supplementary material, which is available to authorized users.

Evaluation of Febrile, Nonneutropenic Pediatric Oncology Patients with Central Venous Catheters Who Are Not Given Empiric Antibiotics

To evaluate the practice of empiric antibiotics for febrile, nonneutropenic pediatric oncology patients with a central venous catheter (CVC) in place. Episodes of fever without neutropenia (absolute neutrophil count [ANC] ≥500 cells/mm(3)) were reviewed retrospectively in pediatric oncology patients with a CVC undergoing chemotherapy. Characteristics and symptoms were compared between patients with bacteremia and patients without bacteremia. A total of 392 episodes of nonneutropenic fever in 138 subjects (52 females; 38%) were reviewed. In this cohort, the median age at an episode was 7 years, and the majority of patients had a diagnosis of acute leukemia (54%). Median ANC was 3100 cells/mm(3) (IQR, 1570-5980 cells/mm(3)). Median temperature was 38.7°C (IQR, 38.3-39.2°C). Twenty-four infectious episodes (6%) occurred in 18 subjects, and 5 CVCs required removal; all patients requiring removal admitted and received antibiotics owing to chills. There were no significant difference in age, sex, or ANC between patients with bacteremia and those without bacteremia; however, mean temperature was higher in the patients with bacteremia (39.4°C vs 38.7°C; P = .003). No deaths due to sepsis occurred, and no CVCs were removed because antibiotics were not administered empirically. Our practice of observing pediatric oncology patients undergoing chemotherapy with CVCs who are not neutropenic does not appear to lead to increased serious adverse outcomes and avoids antibiotic exposure for >90% of patients without a bacterial infection.

Management of invasive candidiasis in nonneutropenic ICU patients.

Invasive candidiasis (IC) is a leading cause of morbidity and mortality among nonneutropenic ICU patients and these life-threatening nosocomial infections require early diagnosis and prompt treatment. However, none of the predictive tools are sufficiently accurate to identify high-risk patients and the potential interest of IC prophylactic, empirical and preemptive treatment in the nonneutropenic ICU population has not yet been demonstrated. In the case of nosocomial severe sepsis after necrotizing pancreatitis or upper digestive anastomotic leakage, early probabilistic antifungals are probably indicated. In the remaining ICU surgical and medical patients, prophylactic and empirical strategies are highly debated because they may promote antifungal selective pressure through an overuse of these molecules. In this context, non-culture-based methods such as mannan or β-D glucan or polymerase chain reaction tests are promising. However, none of these tests used alone in ICU patients is sufficiently accurate to avoid overuse of empirical/preemptive treatment. The interest of strategies associating predictive clinical scores and non-culture-based methods still needs to be demonstrated by well-conducted randomized, controlled trials. While awaiting these studies, we consider that probabilist treatment should be stopped earlier if IC is not proven.

The Value of C-Reactive Protein and Procalcitonin in the Differentiation of Infectious Fever and Tumor-Related Fever in Solid Tumors

Aim: The utility of C-reactive protein (CRP) in distinguishing infection from other fever causes is limited. Procalcitonin (PCT) is a protein linked to bacterial endotoxin, which rise specifically in infection and not in response to other inflammatory states. Nevertheless, in solid tumors with non-neutropenic patients, there are few studies with these biomarkers. Our aim was to study the usefulness of PCT and CRP as early diagnostic markers of infectious fever versus tumor-related fever in solid tumors. Methods: Rectrospective analysis of consecutive records of 141 patients with fever and solid tumors, who were admitted in our Institute between January 2010 and May 2012. CRP and PCT levels were evaluated in blood samples at baseline and 24 hours after hospitalization, and selecting the higher value. The cutoff values, were 10 mg/dL for CRP and 0.5 ng/mL for PCT. We considered 3 groups, sepsis, systemic inflammatory response syndrome (SIRS) and without SIRS, according to the 2012 definition of the Society of Critical Care Medicine. Statistical analysis was performed using SPSS v20. Results: Patients with sepsis had significantly higher CRP and PCT mean levels than those with SIRS (p < 0,001) and without SIRS (p = 0,001). In the subgroups sepsis vs non sepsis, the ROC curve analysis yielded a large area under the curve for PCT (0.92) compared to CRP (0.76). The 0.5 ng/mL cutoff (PCT), showed a sensitivity of 70% and a specificity of 92%. Moreover, in the 27 of 29 patients with tumor-related fever, PCT levels were under our cut-off, showing highly discriminative power (p < 0,001), that relation was not significant for CRP. In the sepsis group, we compared neutropenic vs non-neutropenic patients. The PCT was significantly higher in neutropenic patients (median 19,65 ng/mL vs 5,27 ng/mL, p = 0,002), we didn’t found significant difference for CRP. CRP and PCT median levels in patients did not correlate with metastization status. Conclusions: In this study, PCT showed accuracy in distinguishing tumor-related fever with a high negative predictive value. PCT was a better diagnostic discriminator than CRP to exclude the diagnosis of sepsis. Neutropenic patients had higher values of PCT. Disclosure: All authors have declared no conflicts of interest.

Prognostic value of serum galactomannan in mixed ICU patients: a retrospective observational study.

Little is known about serum galactomannan (GM) testing in (mostly non-neutropenic) mixed intensive care unit (ICU) patients. The aim of this study was to look for the incidence of invasive aspergillosis (IA) in critically ill patients, to validate previously reported GM thresholds, and to evaluate the prognostic value of GM. This was a retrospective study of 474 GM samples in 160 patients from the start of January 2003 until the start of February 2004. GM tests were ordered because of a clinical suspicion of IA or on a regular basis in immune compromised patients. The number of samples per patient was 3 ± 2.6. We used the criteria of the European Organisation for Research and Treatment of Cancer (EORTC) to define proven IA, probable IA, and possible IA. The number of positive samples, with GM optical density (OD) > 0.5 was 230 (48.5%). In our study population, five (3%) patients had proven IA, 11 (7%) had probable, 27 (17.5%) had possible, and 116 (72.5%) had no IA. We could not identify a GM threshold for IA with analysis of receiver operating characteristics (ROC) curves: with a sensitivity of (56.3%, 50%, 50%, 37.5%), specificity (38.2%, 67.5%, 68.8%, 72.9%), NPV (88.7%, 91.8%, 92.5%, 91.3%) and PPV (9.2%, 12.9%, 15.1%, 13.3%) for a cut-off of OD > 0.5, > 0.8, > 1.1 and > 1.5 respectively. IA was associated with high mortality of 87.5% and 100% in patients with probable and proven IA respectively. Patients with IA had a significant increase of GM during their stay (GMdelta 0.7 ± 1.5 vs -0.2 ± 1.5, P = 0.027). The overall ICU mortality was 41.9% and the hospital mortality was 58.1%. Patients who died in the ICU and in the hospital had higher APACHE- -II, SAPS-II and SOFA scores (P < 0.0001) and also a significant increase in GM during their stay with 0.27 ± 1.26 (ICU non-survivors) and 0.11 ± 1.55 (hospital non-survivors) compared to a decrease in GM -0.43 ± 1.7 (P = 0.004) and -0.48 ± 1.51 (P = 0.017) in ICU and hospital survivors respectively. Non-survivors also had higher mean GM values but this was not statistically significant. There was a trend towards higher GM values in patients treated with piperacillin/tazobactam (n = 34), but this did not reach statistical significance. Neutropenic patients (n = 31) showed an increase in GM during their stay 0.32 ± 1.3 vs a decrease with -0.43 ± 1.7 in non-neutropenic patients (P = 0.07). Patients on total parenteral nutrition (n = 125) had higher maximal GM levels (1.55 ± 1.94 vs 0.88 ± 1.25, P = 0.058). Patients who were mechanically ventilated had significantly higher mean (P = 0.038) and maximal (P = 0.007) GM levels. We found a high incidence of proven and probable IA in a group of mixed ICU patients (10%) and the presence of IA was associated with a high mortality. The serum GM antigen detection test may not be useful in the diagnosis of IA in mixed ICU patients, according to the results of the ROC analysis. We could not define a useful threshold.

How to manage aspergillosis in non-neutropenic intensive care unit patients.

Invasive aspergillosis has been mainly reported among immunocompromised patients during prolonged periods of neutropenia. Recently, however, non-neutropenic patients in the ICU population have shown an increasing risk profile for aspergillosis. Associations with chronic obstructive pulmonary disease and corticosteroid therapy have been frequently documented in this cohort. Difficulties in achieving a timely diagnosis of aspergillosis in non-neutropenic patients is related to the non-specificity of symptoms and to lower yields with microbiological tests compared to neutropenic patients. Since high mortality rates are typical of invasive aspergillosis in critically ill patients, a high level of suspicion and prompt initiation of adequate antifungal treatment are mandatory. Epidemiology, risk factors, diagnostic algorithms, and different approaches in antifungal therapy for invasive aspergillosis in non-neutropenic patients are reviewed.

Rothia bacteremia: a 10-year experience at Mayo Clinic, Rochester, Minnesota.

Rothia spp. are Gram-positive cocco-bacilli that cause a wide range of serious infections, especially in immunocompromised hosts. Risk factors for Rothia mucilaginosa (previously known as Stomatococcus mucilaginosus) bacteremia include prolonged and profound neutropenia, malignancy, and an indwelling vascular foreign body. Here, we describe 67 adults at the Mayo Clinic in Rochester, MN, from 2002 to 2012 with blood cultures positive for Rothia. Twenty-five of these patients had multiple positive blood cultures, indicating true clinical infection. Among these, 88% (22/25) were neutropenic, and 76% (19/25) had leukemia. Common sources of bacteremia were presumed gut translocation, mucositis, and catheter-related infection. One patient died with Rothia infection. Neutropenic patients were less likely to have a single positive blood culture than were nonneutropenic patients. Antimicrobial susceptibility testing was performed on 21% of the isolates. All of the tested isolates were susceptible to vancomycin and most beta-lactams; however, four of six tested isolates were resistant to oxacillin. There was no difference between the neutropenic and nonneutropenic patients in need of intensive care unit care, mortality, or attributable mortality.

Identification and management of invasive mycoses in internal medicine: a road-map for physicians.

Invasive mycoses are a rising problem, not only in traditional categories of patients like hematologic or neutropenic ones, but also in elderly non-neutropenic patients admitted to internal medicine wards. Patients being admitted to medical wards are usually older, have multiple comorbidities, e.g., liver cirrhosis or chronic obstructive respiratory disease, may be malnourished or receive peripheral or total parenteral nutrition, and frequently are undergoing chronic corticosteroid therapy, chemotherapy for cancer or monoclonal antibodies for autoimmune diseases. Such risk factors may be contemporarily present in a single patient increasing the risk for the development of invasive mycoses. Diagnosis of candidemia and invasive aspergillosis is particularly difficult in patients hospitalized on medical wards, since symptoms and signs have low specificity, and most diagnostic tests have been only validated in neutropenic hematologic patients, but not in those without neutropenia. Both candidemia and invasive aspergillosis carry significant morbidity and mortality. The aim of this paper is to provide a simple guide to physicians for a prompt identification and treatment of patients with possible or suspected invasive mycoses.

Predictors of mortality in non-neutropenic patients with invasive pulmonary aspergillosis: does galactomannan have a role?

We aimed to investigate the role of several host factors as predictors of mortality in non-neutropenic patients with invasive pulmonary aspergillosis (IPA). Contribution of respiratory galactomannan (GM) index was evaluated as well. In this retrospective study, we examined 27 patients with “proven” and “probable” IPA. Outcome measured was death within 6-week from diagnosis of possible IPA. Overall mortality was 33.3%. At univariate analysis, nonsurvivors were statistically more likely to be affected with cirrhosis. No independent variables predicting mortality were identified in the multivariate model. Mean bronchoalveolar lavage (BAL) GM index value in the nonsurvivor group was significantly higher. A GM index cutoff value ≥2.0 is able to classify patients with a poor outcome with a sensitivity of 100% and a specificity of 77%. Liver cirrhosis is a predictor of mortality in patients with IPA. GM index in BAL might be considered as a valuable tool in classifying patients at risk of poor outcome.

Clinical approach to non-neutropenic fever in pediatric oncology patients.

e21031 Background: There are no clear guidelines on standard management of fever in non-neutropenic pediatric oncology patients. Methods: We analyzed the clinical characteristics and outcome of feb...

Management of sepsis in neutropenic patients: 2014 updated guidelines from the Infectious Diseases Working Party of the German Society of Hematology and Medical Oncology (AGIHO).

Sepsis is a major cause of mortality during the neutropenic phase after intensive cytotoxic therapies for malignancies. Improved management of sepsis during neutropenia may reduce the mortality of cancer therapies. Clinical guidelines on sepsis treatment have been published by others. However, optimal management may differ between neutropenic and non-neutropenic patients. Our aim is to give evidence-based recommendations for haematologist, oncologists and intensive care physicians on how to manage adult patients with neutropenia and sepsis.

Traitements antifongiques en réanimation au cours des infections fongiques invasives documentées ou suspectées

ObjectiveDescribe systemic antifungal therapy in non-neutropenic adult patients in intensive care unit (ICU). Patients and methodA prospective, observational study was conducted during the first half of 2010 in the 7 ICU in a hospital with medical consultant on antimicrobial therapy. All non-neutropenic consecutive adult patients receiving systemic antifungal therapy for documented or suspected invasive fungal infection (IFI) apart from aspergillosis were included. ResultsOut of 1502 patients admitted in ICU, 104 (7 %) underwent systemic antifungal therapy, including 30 (29 %) for a documented IFI and 74 (71 %) for a suspected IFI. Candida albicans was identified in 23 (77 %) of the IFI and 45/52 (86 %) of the broncho-pulmonary and/or urinary colonizations in suspected IFI. Echinocandin was significantly more prescribed in patients with a documented infection (19/30 patients) and fluconazole in patients with a suspected infection (48/74 patients). The first line therapy was primarily stopped after recovery (11/30 patients) or de-escalation (9/30 patients) in documented infections, and for lack of indication (34/74 patients) or due to recovery (21/74 patients) in suspected infections after on average of 7 days of treatment. ConclusionFor ICU non-neutropenic adult patients in our center, antifungal therapy is prescribed two times out of three for suspected, unproved infections, in most cases with fluconazole. Documented infections were more often treated by echinocandin with secondary de-escalation. An interventional prospective study to assess the role of antifungal pre-emptive or empirical therapy is necessary.

Chemotherapy-induced neutropenia as a biomarker of survival in advanced ovarian carcinoma: An exploratory study of the Gynecologic Oncology Group

ObjectiveTo determine whether chemotherapy-induced neutropenia (C-iN) is associated with improved survival in a population of primary advanced ovarian cancer and peritoneal carcinoma patients treated with a carboplatin plus paclitaxel chemotherapy backbone. MethodsA post-hoc exploratory analysis of Gynecologic Oncology Group (GOG) protocol 182 was performed. Landmark analysis was conducted on all patients with progression-free survival >18weeks from the time of study entry. Neutropenia was defined as the absolute neutrophil count <1000mm3. The occurrence of C-iN was analyzed according to demographic, clinicopathologic, and therapeutic intent, including age, body surface area, and treatment arm. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. The Cox proportional hazards model was used to evaluate independent prognostic factors and to estimate their effects on PFS and OS. ResultsNeutropenic data was available for 3447 patients. Neutropenic (n=3196) and non-neutropenic groups (n=251) were similar in demographic and clinicopathologic characteristics. Neutropenic patients experienced significantly improved survival compared to non-neutropenic patients with the adjusted hazard ratio (HR) for death being 0.86 (95% confidence interval 0.74–0.99; p=0.041). There was no survival benefit associated with any of the treatment arms among patients with C-iN. ConclusionThese data suggest that C-iN may represent a clinical biomarker associated with a survival advantage for patients with untreated advanced ovarian cancer. The absence of C-iN may indicate under-dosing and ultimately attenuated anti-neoplastic effect in vulnerable populations.

English

&nbsp; This work aimed at identifying&nbsp;Candida&nbsp;species isolated from blood stream infection in non-neutropenic cancer patients by conventional and molecular methods. Out of 200 blood samples from cancer patients with blood stream infection, 89 were positive forCandida&nbsp;which were identified using chromogenic medium (CHROMagar&nbsp;Candida), and real-time polymerase chain reaction (RT-PCR) assays targeting the fungal ITS2 region using a LightCycler instrument. The present study revealed that non-albicans Candidaspecies caused most of the cases of candidaemia in the cancer patients. A total of 89Candida&nbsp;isolates were obtained, Candida albicans&nbsp;represent 15/89 patients (16.85%) and non-albicans Candida&nbsp;species accounts for 74/89 patients (83.1 %)&nbsp;of which&nbsp;Candida tropicalis&nbsp;represent 32.6% followed by&nbsp;Candida parapsiliosis&nbsp;23.6%, and then&nbsp;Candida rugosa&nbsp;(21,4%) and the lowest percentage was in&nbsp;Candida glabrata&nbsp;(5.6%).&nbsp;The results of the study revealed that real time-PCR could detect 81 out of 89 cases of candidaemia with sensitivity of 91.01%, specificity of 95.6%, PPV of 94.18% and NPV of 92.30%. The high prevalence of non-albicans&nbsp;candidaemia should be considered prior to antimicrobical therapy in non-neutropenic cancer patients with candidaemia. Real-time PCR represents a rapid and accurate method for diagnosis of candidaemia. &nbsp; Key words:&nbsp;Candidaemia,&nbsp;Candida albicans, real-time polymerase chain reaction (RT-PCR).

Clinical practice guidelines for the management of invasive Candida infections in adults in the Middle East region: Expert panel recommendations

Invasive Candida infections contribute to significant morbidity and mortality in patients with healthcare-associated infections. They represent a major burden on the public health system, and are challenging to diagnose and treat. A multidisciplinary expert panel critically reviewed available evidence to provide consensus recommendations for the management of invasive Candida infections in the Middle East. Based on diagnosis, recommendations were provided for the management of Candida infections in non-neutropenic and neutropenic patients. Polyenes (amphotericin B-deoxycholate [AmB-d] and lipid formulations amphotericin B [LFAmB]), triazoles (fluconazole, itraconazole and voriconazole), echinocandins (caspofungin, anidulafungin, and micafungin) and flucytosine are the recommended categories of antifungal agents for treatment of Candida infections. Echinocandins are preferred for treatment of proven and suspected Candida infections, especially in critically ill patients or those with previous exposure to azoles. Recommendations were also provided for infections caused by specific Candida species as well as management of different disease conditions. The experts highlighted that the guidelines should be used along with clinical judgment. Given the paucity of published data from the region, research in the form of randomized clinical trials should be given priority.

Comparative evaluation of galactomannan optical density indices and culture results in bronchoscopic specimens obtained from neutropenic and non‐neutropenic patients

Aspergillus infections are major causes of morbidity and mortality among immunocompromised patients. This study was designed to investigate the galactomannan assay optical density (OD) indices relative to the culture results in bronchoscopic samples obtained from neutropenic and non-neutropenic patients. Galactomannan OD indices from 1427 samples from 2005 to 2012, which were sent from 839 patients and were composed of bronchial lavage (BL=727) and bronchoalveolar lavage fluids (BAL=700), were retrospectively analysed. The recovery rates of Aspergillus species from these specimens were 9.4% from the combined patient group and 13.3% from the neutropenic group. Aspergillus fumigatus complex was the most frequently isolated species. The mean and median OD indices of the positive and negative culture samples are approximately 5 and 1, respectively, and 91% of all culture-positive samples have ≥1 OD index value. The receiver-operating characteristics curve analysis demonstrated that the feasibility of the Aspergillus galactomannan assay and Aspergillus galactomannan test has superior accuracy in BAL compared to BL fluids, and the test is not affected by the immune status of the patient. We suggest that the Aspergillus galactomannan test, which uses bronchoscopic material, leads to an earlier diagnosis and if the OD index is found ≥1, fungal growth can be expected.

Bronchoscopy as an indicator of tracheobronchial fungal infection in non-neutropenic intensive-care unit patients

We aimed to establish that a bronchoscopic view can be as reliable as microbiology, and support an empirical tracheobronchial fungal infection (TBFI) treatment decision. We retrospectively studied 95 respiratory failure patients with suspected TBFI admitted to the intensive-care unit (ICU) in 2008 with sticky secretions, hyperaemic mucosa, and whitish plaques on bronchoscopic view. Patients not suspected of having TBFI were chosen as a control group (n = 151). Broncheoalveolar lavage (BAL) fluid was cultured, and biopsy samples were taken from the lesions. Biopsy samples positive for fungi were defined as ‘proven', only BAL-positive (+ fungi) cases were ‘probable TBFI', and BAL-negative (– fungi) cases were ‘possible TBFI'. BAL (+ fungi) and BAL (– fungi) in the control group were defined as ‘colonization' and ‘no TBFI', respectively. The sensitivity, specificity and positive and negative predictive values of BAL (+ fungi) were 85.1% (63/74), 81.4% (140/172), 66.3% (63/95), and 92.7% (140/151), respectively. Biopsies were performed in 78 of 95 patients, and 28 were proven TBFI with fungal elements, and 100% were BAL (+ fungi). Probable TBFI was seen in 30 of 95 patients with BAL (+ fungi), and possible TBFI (BAL(– fungi)) in 25 of 95. Among the 95 patients, microbiology revealed fungi (90.5% Candida species; 9.5% Aspergillus) in 63 (66.3%). In the controls, the colonization and no TBFI rates were 11 of 151 and 140 of 151, respectively. Observing sticky secretions, hyperaemic mucosa and whitish plaques by bronchoscopy is faster than and may be as reliable as microbiology for diagnosing TBFI. These findings are relevant for empirical antifungal therapy in suspected TBFI patients in the ICU.

The effects of virulence factors on invasion in various species of Candida

In the present study, we determined the in vitro and in vivo virulence characteristics ofCandida isolates from 75 non-neutropenic patients with candidemia and analyzed the isolates by receiver-operating characteristics (ROC) analysis to define threshold values of adhesion and hydrophobicity occurring in invasive Candida isolates. Specific virulence traits that were measured included hydrophobicity, epithelial cell adhesion, phospholipase and proteinase activity. In our in vivo investigations, all isolates were diluted in phosphate-buffered saline (PBS) and were administered to mice (Swiss albino) through tail-vein injection. Liver and spleen tissues were evaluated for evidence of invasion. Though onlyCandida albicans isolates produced detectable phospholipase activity, all isolates secreted proteinase enzyme. However, while this observation was significant among C. albicans and Candida parapsilosis isolates, the reverse was seen for Candida tropicalisand Candida krusei isolates. Interestingly, in contrast with C. parapsilosis and C. tropicalis, lower median adhesion values were determined for C. albicans and C. krusei, particularly in isolates that showed invasion in mouse experiments. It has not been possible to identify meaningful threshold values for adhesion and hydrophobicity in the repeated ROC analysis on the sub-groups in differentiating the isolates that cause and do not cause invasion in mice among the various Candida isolates. Key words: Candidemia, virulence factors, ROC analysis

Impaired bactericidal but not fungicidal activity of polymorphonuclear neutrophils in patients with chronic lymphocytic leukemia

We examined the qualitative polymorphonuclear neutrophil (PMN)-associated immune impairment in patients with chronic lymphocytic leukemia (CLL) by characterizing phagocytic killing of key non-opsonized bacterial (Staphylococcus aureus and Pseudomonas aeruginosa) and fungal (Candida albicans and Aspergillus fumigatus) pathogens. Neutrophils were collected from 47 non-neutropenic patients with CLL (PMN count > 1000/mm3) and age-matched and young healthy controls (five each). A subset of patients (13%) had prior or subsequent infections. We found that the patients with CLL had diminished PMN microbicidal response against bacteria but not against fungi compared with the controls. Compared to patients with effective PMN responses, we did not identify differences of basal PMN pathogen-associated molecular pattern receptor gene expression, soluble pathogen-associated molecular pattern gene expression or inflammatory cytokine signatures in patients with impaired PMN responses when PMNs were analyzed in multiplex real-time polymerase chain reaction assays. However, differences in PMN microbicidal response against A. fumigatus in patients with CLL were associated with the degree of hypogammaglobulinemia.

Development and validation of a risk model for identification of non-neutropenic, critically ill adult patients at high risk of invasive Candida infection: the Fungal Infection Risk Evaluation (FIRE) Study

There is increasing evidence that invasive fungal disease (IFD) is more likely to occur in non-neutropenic patients in critical care units. A number of randomised controlled trials (RCTs) have evaluated antifungal prophylaxis in non-neutropenic, critically ill patients, demonstrating a reduction in the risk of proven IFD and suggesting a reduction in mortality. It is necessary to establish a method to identify and target antifungal prophylaxis at those patients at highest risk of IFD, who stand to benefit most from any antifungal prophylaxis strategy. To develop and validate risk models to identify non-neutropenic, critically ill adult patients at high risk of invasive Candida infection, who would benefit from antifungal prophylaxis, and to assess the cost-effectiveness of targeting antifungal prophylaxis to high-risk patients based on these models. Systematic review, prospective data collection, statistical modelling, economic decision modelling and value of information analysis. Ninety-six UK adult general critical care units. Consecutive admissions to participating critical care units. None. Invasive fungal disease, defined as a blood culture or sample from a normally sterile site showing yeast/mould cells in a microbiological or histopathological report. For statistical and economic modelling, the primary outcome was invasive Candida infection, defined as IFD-positive for Candida species. Systematic review: Thirteen articles exploring risk factors, risk models or clinical decision rules for IFD in critically ill adult patients were identified. Risk factors reported to be significantly associated with IFD were included in the final data set for the prospective data collection. Data were collected on 60,778 admissions between July 2009 and March 2011. Overall, 383 patients (0.6%) were admitted with or developed IFD. The majority of IFD patients (94%) were positive for Candida species. The most common site of infection was blood (55%). The incidence of IFD identified in unit was 4.7 cases per 1000 admissions, and for unit-acquired IFD was 3.2 cases per 1000 admissions. Statistical modelling: Risk models were developed at admission to the critical care unit, 24 hours and the end of calendar day 3. The risk model at admission had fair discrimination (c-index 0.705). Discrimination improved at 24 hours (c-index 0.823) and this was maintained at the end of calendar day 3 (c-index 0.835). There was a drop in model performance in the validation sample. Economic decision model: Irrespective of risk threshold, incremental quality-adjusted life-years of prophylaxis strategies compared with current practice were positive but small compared with the incremental costs. Incremental net benefits of each prophylaxis strategy compared with current practice were all negative. Cost-effectiveness acceptability curves showed that current practice was the strategy most likely to be cost-effective. Across all parameters in the decision model, results indicated that the value of further research for the whole population of interest might be high relative to the research costs. The results of the Fungal Infection Risk Evaluation (FIRE) Study, derived from a highly representative sample of adult general critical care units across the UK, indicated a low incidence of IFD among non-neutropenic, critically ill adult patients. IFD was associated with substantially higher mortality, more intensive organ support and longer length of stay. Risk modelling produced simple risk models that provided acceptable discrimination for identifying patients at 'high risk' of invasive Candida infection. Results of the economic model suggested that the current most cost-effective treatment strategy for prophylactic use of systemic antifungal agents among non-neutropenic, critically ill adult patients admitted to NHS adult general critical care units is a strategy of no risk assessment and no antifungal prophylaxis. Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research.