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Risk prediction tools, early diagnosis & infectionInvasive candidiasis in the intensive care unitInvasive candidiasis (IC) is a frequent life-threat-ening complication in critically ill patients, and Professor Thierry Calandra discussed early detec-tion and treatment strategies of IC in the inten-sive care unit. Delays in treatment of candidemia have been associated with increased mortality [1], and thus, the aim of early diagnosis is to initiate prompt treatment to improve patient outcomes. Such measures should also minimize unnecessary antifungal usage.

In order to optimize resources, correct selection of the at-risk patient for early treatment or sur-veillance for infection with biomarker testing is key and can be improved by combining Candida colonization data and clinical risk factors to cal-culate a clinical risk score [2]. The negative predic-tive value of scores and prediction rules is high, whereas the positive predictive value is much lower, ranging from 10 to 60% [3]. Thus, using these rules to initiate antifungal therapy will still result in the treatment of many patients unneces-sarily. Current research efforts are investigating incorporating Candida biomarkers to trigger treatment in a high-risk population identified by risk prediction rules.

Candida biomarkers have a good positive pre-dictive values for infection, but lack sensitivity and are not able to identify all cases of IC. However, when used in a high-risk group their performance improves. Tissot et al. examined the utility of the fungal cell wall polysaccharide (1→3)-β-d-glucan (BDG) in serum for early diagnosis in high-risk surgical patients in Switzerland [4]. Patients had recurrent perforation, pancreatitis or burns, and most were colonized with Candida. BDG was tested in multiple blood samples over 21 days in 106 patients. BDG values were significantly higher in the patients with IC than the colonized patients, in the candidemic patients compared with noncandidemic IC patients, and in IC with severe sepsis/septic shock compared with sepsis. For the US FDA-approved BDG cutoff (≥80 pg/ml), sensitivity was 97% and specificity 20%. Two consecutive BDG results ≥150 pg/ml had the best diagnostic yield (sensitivity 73% and specificity 78%) and preceded start of anti fungal therapy based on the colonization index by 2 days and confirmed infection by 5 days [4].

Posteraro et al. compared the performance of BDG, Candida score and colonization index at admission in 95 patients admitted to the intensive care unit with sepsis who had an intensive care unit stay of more than 5 days [5]. In this group of patients, 14 were diagnosed with IC, and the

Gabrielle M Haeusler and Monica A Slavin*Department of Infectious Diseases, Peter MacCallum Cancer Centre and the Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, Victoria, Australia*Author for correspondence: Tel.: +61 396 561 707 Fax: +61 396 561 185 monica.slavin@petermac.org

The Australasian Society for Infectious Diseases Annual Scientific Meeting Fremantle, WA, Australia, 21–25 March 2012

The subtitle of the Australasian Society for Infectious Diseases Annual Scientific Meeting was ‘Sailing into the Future’, and speakers from both adult and pediatric infectious diseases explored this theme in relation to the management of sepsis. The future will entail better risk prediction tools for patients at risk for sepsis. Such risk prediction tools are likely to incorporate genetic profiling of the host to identify the groups at highest risk for disease and death. Focused diagnostic testing in these patients will include molecular diagnostics for early detection of infection.

Complications of sepsis: the role of risk prediction rules, biomarkers and host geneticsExpert Rev. Anti Infect. Ther. 10(7), 733–735 (2012)

Keywords: aspergillosis • candidiasis • febrile neutropenia • risk prediction

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Complications of sepsis: the role of risk prediction rules, biomarkers & host genetics

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BDG was positive in all patients 1–3 days prior to positive blood cultures. BDG performed the best in terms of positive and negative predictive values of the three methods and, thus, in selecting patients for early treatment [5]. However, in order to improve the performance of these tests more information may be required in the algorithm for selecting patients for early treatment. Professor Calandra concluded that future studies should evaluate the utility of combining genetic susceptibility factors, clinical risk prediction and possibly a combination of diagnostic tests, such as BDG with Candida PCR [6], and mannan and antimannan antibodies [3]. This is clearly an area for future research.

Invasive aspergillosis in hematology patientsDr Thomas Walsh discussed the need for early diagnosis and treatment to improve the outcome of invasive fungal infec-tions, most commonly invasive aspergillosis (IA), in hematology patients. Despite newer antifungal agents, mortality still remains at 35–85% [7]. New fungal diagnostic tools were discussed, includ-ing Aspergillus galactomannan (GM)-ELISA, a test widely used on serum in Europe and an accepted microbiological component of the European Organisation for Research and Treatment in Cancer (EORTC)/Mycoses Study Group (MSC) definitions for IA [8]. Another new diagnostic test, the Aspergillus PCR, is undergoing standardization in a European collaboration to develop a repro-ducible performance [9]. These tests are also useful when applied to bronchoalveolar lavage fluid [10]. Dr Orla Morrissey presented the results of a randomized Australian multicenter study in high-risk hematology patients (undergoing treatment for leukemia or allogeneic stem cell transplantation) comparing surveillance with twice-weekly GM-ELISA and Aspergillus PCR on blood to guide the performance of CT scans and antifungal usage (the pre-emptive arm) versus the standard approach of fever-driven investigation and empiric antifungal therapy [7,11]. Patients were followed for 26 weeks or until death. The primary end point was the proportion that received empiric antifungal therapy as assessed by an independent data review. Although patients in the pre-emptive arm received significantly less empiric therapy, significantly more probable IA was diagnosed, as would be expected in patients undergoing routine sur-veillance with Aspergillus GM-ELISA and PCR. However, despite more IA diagnoses, there was no difference between the arms in overall or IA-related deaths, or in overall duration and cost of anti-fungal therapy. This study suggests that a pre-emptive approach using GM-ELISA and PCR twice weekly is safe compared with empiric antifungal therapy and has the potential advantage of earlier diagnosis of IA. Subgroup analyses of patients who received fluco-nazole, itraconazole, voriconazole and posaconazole prophylaxis will be performed to determine how baseline antifungal prophylaxis impacts on the performance of pre-emptive therapy [11].

Febrile neutropenia in children: identifying high- & low-risk patientsDr G Haeusler reviewed what is known about risk assessment for febrile neutropenia episodes in children. Similar to adults, children with chemotherapy-induced febrile neutropenia are a hetero geneous group with respect to their risk for severe bacterial infection and

medical complications. However, several important differences between adults and children with cancer exist, which preclude the applicability of adult-derived febrile neutropenia guidelines in the pediatric setting [12]. Recently, a number of reviews have been published, which summarize existing data for the management of low-risk pediatric febrile neutropenia and have identified key areas where evidence and guidelines are scant [13–16].

A reproducible clinical decision rule (CDR) that reliably predicts children with febrile neutropenia at low risk for bacterial infection and medical complications is lacking. In 2010, a comprehensive meta-analysis of pediatric risk stratification studies was published [13]. The authors identified 20 studies that described 16 different CDR in more than 8000 episodes of febrile neutropenia. However, due to differences in study methodologies, definitions and outcome measures, as well as a paucity of external validation studies, they were unable to conclude that any one CDR was more effective or reliable. Since this meta-analysis, additional pediatric risk stratifica-tion studies have been published, including one that attempts to externally validate six previously derived CDRs [17]. Results of this study further emphasize the problems associated with extrapolat-ing single-center or nonvalidated results to different populations.

Pooling of individual participant data is proposed as one way to overcome limitations of aggregate data meta-analysis [18]. A meta-analysis that combines the original raw data sets from numerous existing pediatric studies of febrile neutropenia is currently under-way [18]. The aim of this study is to identify a more accurate CDR that predicts children at low and high risk of adverse outcomes during an episode of febrile neutropenia. It is anticipated that the reanalysis of a much larger data set using a consistent approach will enable results to more robustly inform practice and future therapeutic trials.

A limited number of small studies have also investigated alter-natives to standard in-patient management of low-risk febrile neutro penia. Results of randomized trials suggest that outpatient management is more cost effective and may be a safe alternative in a carefully selected group of children [15]. Furthermore, some tri-als have shown success with oral antibiotics, although significant variability with time to randomization following in-patient par-enteral antibiotics exist [14]. There is uniform agreement between these studies on the need for a more reliable risk stratification tool before oral and/or ambulatory treatment options for pediatric febrile neutropenia can be safely recommended.

Host factors contributing to risk of infectionIn addressing genetic susceptibility to infection, Professor Robert C Read discussed host risk factors for the severity of meningococcal disease. Quantification of meningococcal plasma DNA by reverse transcriptase PCR has provided insights into the pathogenesis of the disease, with higher plasma loads being associated with more severe manifestations of disease (e.g., high levels seen with fulminant sepsis compared with moderate levels with bacteremia and meningitis, and lowest levels with meningitis alone). It is postulated that this correlates with the ability of the organisms to withstand killing. However, innate immunity also influences risk of death with increased complement activation, levels of cytokines and

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chemokines detected in those with a worse outcome, suggesting that this immune response is maladaptive [19]. In a macrophage exposed to meningococcus, approximately 200 genes are activated, although between individuals a 1000-fold difference in the level of TNF produced may be observed. Interesting observations on families of those with invasive meningococcal disease showed that family members of those who died produced significantly higher levels of TNF and IL-1 compared with family members of survivors [19]. A meta-analysis of genetic factors and death from meningococcal sepsis showed a consistent association between age, serogroup C, gene for interleukin production, plasminogen activation decrease and death [20]. The combination of age >65 years, serotype C and an interleukin increase predicted a 45% risk of death [20].

ConclusionThis meeting signposted new directions for the management of sepsis, particularly clinical risk prediction rules and mole cular diagnostics to guide early treatment and integration of host genetics into predictive and prognostic models.

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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16 Teuffel O, Sung L. Advances in management of low-risk febrile neutropenia. Curr. Opin. Pediatr. 24(1), 40–45 (2012).

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