A safety and feasibility study comparing an intermittent high dose with a daily standard dose of liposomal amphotericin B for persistent neutropenic fever.

A high intermittent dose regimen (group A: 10 mg kg(-1) on day 1, 5 mg kg(-1) on days 3 and 6) was compared with standard dosing (group B: 3 mg kg(-1) per day for 14 days) of liposomal amphotericin B (LAB) for empirical treatment of persistent febrile neutropenia. A total cumulative dose of 1275 mg (group A) and 2800 mg (group B) was administered. Infusion-related adverse drug events, mainly rigors/chills, occurred more frequently with group A (11/45, 24 % infusions) than with group B (12/201, 6 % infusions) (P=0.002), which extended the mean infusion time by 20 min (P=0.001). Creatinine levels were similar in the two regimens: the A : B ratio of the area under the curve for creatinine (AUC(CREATININE)) for days 2-7 was 1.09 (P=0.27) and for days 2-14 was 1.05 (P=0.51). Rises in creatinine were mild (clinical toxicity criteria 1) in all patients with elevations. Hypokalaemia tended to be less severe in group A with a lower proportion of hypokalaemic days [57/143 (39 %) vs 80/137 (58 %), P=0.21], a higher AUC(POTASSIUM) (A : B ratio of 1.06, P=0.12), a lower proportion of patients with hypokalaemia at the end of study (10 vs 61 %, P=0.01) and fewer potassium-supplemented days [12/210 (6 %) vs 41/210 (19.5 %), P<0.1]. There were mildly elevated median levels of serum bilirubin, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase, which were similar for the two regimens and were usually associated with other co-existing co-morbid conditions. The AUC for these enzymes was also similar in the two groups. No patient had discontinuation of the study drug due to toxicity. Composite success was identical for each regimen (11/15 patients, 73 %). Three of the fifteen patients in group B and none in group A developed invasive fungal infections (IFIs). Beta-D-Glucan levels were similar in both groups for patients without an IFI [AUC(GLUCAN) of 362 and 683 (P=0.36) for groups A and B, respectively]. The rate of defervescence was similar for each regimen (P=0.75). This feasibility study suggests that a short intermittent high-dose course of 10/5/5 mg LAB kg(-1) on days 1, 3 and 6 may be as safe and effective as a standard 14 day course of 3 mg kg(-1) per day, with drug-acquisition cost savings and reduced drug exposure. A larger study is indicated for confirmation of this.

Prospective evaluation of mannan and anti-mannan antibodies for diagnosis of invasive Candida infections in patients with neutropenic fever.

The diagnostic performance and usefulness of the Platelia antigen and antibody test (Bio-Rad) was investigated in a prospective study of haematological patients at risk for invasive Candida infections. Among 100 patients, 86 were eligible, of whom invasive candidiasis (IC) occurred in 12 (14%), according to the criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group. These included candidaemia due to Candida albicans (one patient) or Candida tropicalis (four patients), and hepatosplenic candidiasis (seven patients). The comparator group of 74 patients included 50 with febrile neutropenia alone and 24 with mould infections. A strategy was developed to determine diagnostic cut-offs from receiver operating characteristic curves with maximal sensitivity and, given this sensitivity, maximal specificity, both being greater than 0. In this patient population, these values were 0.25 ng ml(-1) for mannan (M) and 2.6 arbitrary units ml(-1) for anti-mannan (AM), which are lower than those recommended by the manufacturer. All patients developed at least one positive diagnostic M or AM result during the 10 days of persistent febrile neutropenia (PFN). The optimal overall performance was found when two consecutive positive tests for both M and AM were used [sensitivity, specificity, positive predictive value and negative predictive value (NPV) (95 % confidence intervals) of 0.73 (0.39-0.94), 0.80 (0.69-0.89), 0.36 (0.17-0.59) and 0.95 (0.86-0.99), respectively]. There was a positive correlation of M with beta-D-glucan (r=0.28, P=0.01). The first positive M test was found up to a mean+/-sd of 8.8+/-8.5 (range 2-23) days prior to a clinical/mycological diagnosis of IC. Day-to-day variation in quantitative M levels was high. High-level AM responses were delayed until leucopenia resolved. The low specificities of the test performance may have been due to some of the comparator patients having subclinical Candida infections as evidenced by the high incidence of colonization among them (60% had a colonization index of >or=0.5). The high NPVs suggest that the tests may be particularly useful in excluding IC. It is feasible to explore the use of serial measurements of M and AM as part of a broader diagnostic strategy for selecting PFN patients to receive antifungal drug therapy.

Assessment of the clinical utility of serial beta-D-glucan concentrations in patients with persistent neutropenic fever.

The performance of the Fungitell assay was investigated in 100 patients with haematological malignancy undergoing chemotherapy who developed antibiotic-unresponsive neutropenic fever (AUNF). Serum beta-D-glucan (BG) concentrations were significantly elevated on the first day of AUNF and all subsequent alternate days to day 10 in 38 patients who developed an invasive fungal infection (IFI) compared to 42 patients remaining free of such infections. The mean and median values of BG were 171.9+/-29.6 and 95.8 pg ml(-1), respectively, for patients with IFI and 64.4+/-17.1 and 32.9 pg ml(-1) for patients with only AUNF (P<0.0001). The differences remained significant over the 10 days despite antifungal therapy. The occurrence of > or =2 sequential concentrations of > or =80 pg ml(-1) ('positive' test) was found to give the best overall option for diagnosis, with an accuracy of 81.3%, sensitivity of 86.8%, positive predictive value of 76.7% and negative predictive value of 86.5%. Of the patients with an IFI, 78% developed a positive test at or before the clinical diagnosis was made -- this occurred at a mean (range) of 1.25 (-14 to +14) days prior to the IFI diagnosis. By starting sampling of blood from the first day of neutropenia rather than from the first day of AUNF, 50% of the patients with subsequent IFI would have been identified 5 days earlier. Increasing sampling to daily from alternate-day frequency did not further improve this earlier timing of an IFI diagnosis. A greater proportion of patients with persistent high levels of BG without overt IFI had severe enterocyte damage or mucositis than those with lower levels of BG without IFI (P=0.002). If the results of the initial BG test had been acted on to change antifungal therapy, discontinuation would have been inappropriate in 30% of patients and would have delayed definitive antifungal therapy. Although the findings for the cohort of patients studied are very useful, there is inter-patient variability in the test's performance. An holistic diagnostic approach is therefore necessary to interpret the test results optimally. Future studies should address this in further detail as well as the impact of empirical antifungal drug use and patient outcome.

Initial symptoms in pulmonary embolism differ from those in pneumonia: a retrospective study during seven years.

OBJECTIVE: To compare initial symptoms in pulmonary embolism with community-acquired pneumonia and relate to C-reactive protein and pulmonary infiltrates in order to improve the clinical assessment at the emergency department. METHODS: A retrospective review of patients with pulmonary embolism diagnosed in the clinic for infectious diseases (CID), (n=25), and a randomized sample of patients with pulmonary embolism diagnosed in the department of medicine (n=64), and a randomized sample of patients with community-acquired pneumonia (n=54) diagnosed in the clinic for infectious diseases. RESULTS: Initial symptoms in pulmonary embolism, dominated by dyspnoea and/or pleuritic chest pain were significantly different from those in community-acquired pneumonia, dominated by fever, chills and/or cough (P<0.001). On admission, C-reactive protein and body temperature were significantly higher and pulmonary infiltrates were more common in pneumonia compared with randomized pulmonary embolism patients. Twenty-five patients with a final diagnosis of pulmonary embolism were erroneously suspected of having lung infection, owing to increased C-reactive protein, presence of pulmonary infiltrates and/or high fever. However, they had classical symptoms of pulmonary embolism. CONCLUSIONS: Pulmonary infiltrates, high fever and a high level of C-reactive protein can deceive the physician to suspect pneumonia instead of pulmonary embolism. Classical initial symptoms ought to direct the physician in diagnosing pulmonary embolism. We emphasize a detailed patient history of initial symptoms.

Modulation of the systemic inflammatory response by recombinant human interleukin-11: a prospective randomized placebo controlled clinical study in patients with hematological malignancy.

The immunomodulatory activities of recombinant human interleukin-11 (rhIL-11) were investigated in a clinical trial among patients with hematological malignancy, randomized to either rhIL-11 or placebo throughout chemotherapy. Daily serum concentrations of sTNFRI, IL-6, IL-8, TNFalpha, and CRP were measured. Higher sTNFRI levels [mean pg/ml (95% CI)] were detected in patients receiving rhIL-11 compared to placebo [1749.7 (1626-1882.9) versus 1038.5 (953.3-1131.3)] respectively (P = 0.01) for all 898 observations and during febrile days [2327.6 (2142.6-2528.2) versus 1308.9 (1163-1473.2), P = 0.12] and during days without infection [1406.6 (1266.1-1563) versus 871.3 (774.9-979.6), P < 0.001]. A similar pattern in CRP concentrations was observed. Multivariate analysis indicated rhIL-11 was associated with elevated sTNFRI or CRP independent of infectious episodes and other factors. 7 patients (all receiving placebo) of 40 had elevated TNFalpha levels. IL-6 and IL-8 levels were not substantially affected by rhIL-11. Bacteremia, fungal infections, and fever of unknown origin (FUO) were reduced in rhIL-11-treated patients. Given the role of sTNFRI in dampening the deleterious effects of a hyperactive TNFalpha environment, rhIL-11-induced upregulation of sTNFRI shedding is a potentially important mechanism for modulating immune and inflammatory responses in humans.

Invasive fungal infections are associated with severe depletion of circulating RANTES.

Serum RANTES (regulated on activation, normal T-cell expressed and secreted) concentrations were measured in 14 patients who had haematological malignancies and developed invasive fungal infections (three of them definite, eight probable and three possible). RANTES levels fell substantially from pre-chemotherapy values at the start of and throughout the fungal infection, and recovered in patients who survived the fungal infection. However, in patients who died from the invasive fungal infection, RANTES levels did not recover. For survivors the mean +/- sd levels for RANTES were 7656 +/- 877 pg ml(-1) on the day prior to chemotherapy, 3723 +/- 2443 pg ml(-1) on the first day of fungal infection diagnosis (significantly different from baseline; P = 0.001) and 9078 +/- 2256 pg ml(-1) at recovery from the fungal infection (significantly different from lowest value; P < 0.0001). Platelet counts were closely correlated with the RANTES levels (r = 0.63, P < 0.001). The RANTES concentrations for the three patients who died were similar to those who survived at all equivalent timepoints, but were significantly lower at the time of death (792 +/- 877) compared to the values at recovery for survivors (P = 0.005). The finding that patients who died from an invasive fungal infection had very low platelet counts and RANTES concentrations suggests that these could play a role in host response to such infections.

Significance of the CC chemokine RANTES in patients with haematological malignancy: results from a prospective observational study.

Regulated on activation, normal T cell expressed and secreted (RANTES) serum concentrations were explored in a prospective observational study of haematological-malignancy patients undergoing chemotherapy. During systemic inflammatory response syndrome/sepsis or severe sepsis/septic shock mean concentrations were 3394 or 2939 pg/ml, respectively, significantly lower than those prior to fever (6031 pg/ml) (P < 0.01) or at bone-marrow recovery (6433 pg/ml, P < 0.001). Levels during febrile-bacteraemia were lower compared with febrile-non-bacteraemia (3022 pg/ml vs. 5111 pg/ml, respectively, P < 0.01). Sixty-three of 67 infection episodes resolved despite low RANTES concentrations, suggesting RANTES is not a prerequisite for recovering from most infection events. However, in four patients dying from septic shock associated with aspergillosis, candidosis, pneumonia or infectious colitis, RANTES concentrations were persistently and extremely low (1629 pg/ml), compared with four matched patients who recovered (6780 pg/ml). RANTES concentrations were highly correlated to platelet counts [median correlation coefficient 0.82 (inter-quartile range, 0.72-0.89)]. RANTES concentrations rose 4.5 d before platelet counts (P < 0.001), suggesting an additional extra-platelet source for RANTES. A nested mixed model regression analysis demonstrated that platelet level was the only independent variable associated with RANTES concentration (P < 0.001) among steroids, haematopoietic-colony-stimulating-factor, recombinant-human-interleukin-11, sepsis status, and neutropenia. A significant 'hypo-RANTES' serum environment occurs following chemotherapy, is driven by thrombocytopenia, but does not affect the ability of most patients to recover from infection.

Recombinant human interleukin 11 and bacterial infection in patients with [correction of] haematological malignant disease undergoing chemotherapy: a double-blind placebo-controlled randomised trial.

BACKGROUND: Bacteraemia in patients with haematological malignant disease causes substantial morbidity. Recombinant human interleukin 11 (rhIL-11) prevents gastrointestinal epithelial disintegrity and has immunomodulatory actions. Our aim was to ascertain whether or not treatment with rhIL-11 can prevent gut-associated infections. METHODS: We did a double-blind placebo-controlled randomised trial, to which we enrolled 40 patients with haematological malignant disease who were undergoing chemotherapy. Patients received either rhIL-11 50 microg/kg (n=20) or placebo (n=20) daily by subcutaneous injection from the day before the start of chemotherapy until resolution of neutropenia or for 21 days, whichever was longer. Our primary outcome measure was a reduction in bacteraemia. Analysis was by intention to treat. FINDINGS: Significantly fewer patients who received rhIL-11 rather than placebo developed bacteraemia, particularly of gastrointestinal origin: the proportion of patients with at least one positive blood culture was 0.65 and 0.25, respectively (p=0.02). The numbers of patients (placebo vs rhIL-11) for each number of distinct isolates were: no organism isolated seven versus 15, one organism nine versus four, two organisms two versus one, three organisms one versus none, and four organisms one versus none (p=0.01), suggesting a lower bacterial load in the rhIL-11 than in the placebo group. Time to first bacteraemic event was longer in patients who received rhIL-11 (p=0.03) than in those who received placebo. INTERPRETATION: rhIL-11 reduces the frequency and load of bacteraemia in patients with haematological malignant disease undergoing chemotherapy, possibly by gastrointestinal cytoprotective or immunological mechanisms [corrected].

Epidemiology, presentation, management and outcome of candidemia in a tertiary care teaching hospital in the United Arab Emirates, 1995-2001.

Sixty episodes of candidemia among hospitalized patients in the United Arab Emirates (0.77/1000 discharges) in 1995-2001 were identified through case retrieval. All patients had malignancy (65%) or serious non-malignant disease (35%). Candida albicans accounted for 45% of isolates. Non-C. albicans Candida species occurred more frequently than C. albicans in adults (67%), hematologic-malignancy patients (58%), and cases of breakthrough candidemia (83%) and were prevalent overall in 2000-2001 (67-73%). C. tropicalis was identified in 15% of cases, C. glabrata in 5%, C. parapsilosis in 5%, C. inconspicua in 2%, C. famata in 2% and C. lusitaniae in 1%. Delayed diagnosis or treatment was common, as was Karnofsky scale < or = 40%, septic shock, and inadequate dosage or duration of antifungal drug therapy. Crude mortality was 50%, and mortality attributable to candidemia was 30%. Univariate analysis indicated patients were more likely to die (odds ratio for death [95% CI]) if they had been stationed in the intensive care unit (ICU) (4.76 [1.31-17.2]), had a Karnofsky scale < or = 40% (38.76 [4.66-322.47]), or suffered septic shock (9.88 [2.9-33.65]). They were more likely to survive in cases with concomitant bacteremia (0.25 [0.07-0.91]), adequate antifungal dose (0.28 [0.08-0.94]), and removal of central lines (0.26 [0.07-0.95]). The high association of bacteremia with candidemia (70% of cases) is unusual. The apparent survival benefit experienced by patients who had bacteremia (odds ratio for survival on multivariate analysis = 2.40 [0.28-20.17], P < 0.03) is novel.