Infectious Diseases - Research Publications

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    Blood transcriptomics identifies immune signatures indicative of infectious complications in childhood cancer patients with febrile neutropenia
    Haeusler, GM ; Garnham, AL ; Li-Wai-Suen, CS ; Clark, JE ; Babl, FE ; Allaway, Z ; Slavin, MA ; Mechinaud, F ; Smyth, GK ; Phillips, B ; Thursky, KA ; Pellegrini, M ; Doerflinger, M (WILEY, 2022-01-01)
    OBJECTIVES: Febrile neutropenia (FN) is a major cause of treatment disruption and unplanned hospitalization in childhood cancer patients. This study investigated the transcriptome of peripheral blood mononuclear cells (PBMCs) in children with cancer and FN to identify potential predictors of serious infection. METHODS: Whole-genome transcriptional profiling was conducted on PBMCs collected during episodes of FN in children with cancer at presentation to the hospital (Day 1; n = 73) and within 8-24 h (Day 2; n = 28) after admission. Differentially expressed genes as well as gene pathways that correlated with clinical outcomes were defined for different infectious outcomes. RESULTS: Global differences in gene expression associated with specific immune responses in children with FN and documented infection, compared to episodes without documented infection, were identified at admission. These differences resolved over the subsequent 8-24 h. Distinct gene signatures specific for bacteraemia were identified both at admission and on Day 2. Differences in gene signatures between episodes with bacteraemia and episodes with bacterial infection, viral infection and clinically defined infection were also observed. Only subtle differences in gene expression profiles between non-bloodstream bacterial and viral infections were identified. CONCLUSION: Blood transcriptome immune profiling analysis during FN episodes may inform monitoring and aid in defining adequate treatment for different infectious aetiologies in children with cancer.
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    Examining health-related quality of life in pediatric cancer patients with febrile neutropenia: Factors predicting poor recovery in children and their parents
    Crothers, A ; Haeusler, GM ; Slavin, MA ; Babl, FE ; Mechinaud, F ; Phillips, R ; Tapp, H ; Padhye, B ; Zeigler, D ; Clark, J ; Walwyn, T ; Super, L ; Alvaro, F ; Thursky, K ; Lourenco, RDA (ELSEVIER, 2021-10-25)
    BACKGROUND: The impact febrile neutropenia (FN) has on the health-related quality of life (HRQoL) of children with cancer and their families is poorly understood. We sought to characterize the course of child and parent HRQoL during and following FN episodes. METHOD: Data on HRQoL were collected in the multisite Australian Predicting Infectious ComplicatioNs in Children with Cancer (PICNICC) study. Participants were enrolled between November 2016 to January 2018. The Child Health Utility (CHU9D) was used to assess HRQoL in children (N = 167 FN events) and the Assessment of Quality of Life (AQoL-8D) was used to assess HRQoL parents (N = 218 FN events) at three time points: 0-3 days, 7-days and 30-days following the onset of FN. Group-based trajectory modeling (GBTM) was used to characterize the course of HRQoL. FINDINGS: For children, three distinct groups were identified: persistently low HRQoL over the 30-day course of follow-up (chronic: N = 78/167; 47%), increasing HRQoL after the onset of FN to 30 days follow-up (recovering: N = 36/167; 22%), and persistently high HRQoL at all three timepoints (resilient: N = 53/167; 32%). Applying these definitions, parents were classified into two distinct groups: chronic (N = 107/218, 49%) and resilient (N = 111/218, 51%). The child being male, having solid cancer, the presence of financial stress, and relationship difficulties between the parent and child were significant predictors of chronic group membership for both parents and children. Children classified as high-risk FN were significantly more likely to belong to the recovery group. Being female, having blood cancers and the absence of financial or relationship difficulties were predictive of both parents and children being in the resilient group. INTERPRETATION: Approximately half the children and parents had chronically low HRQoL scores, which did not improve following resolution of the FN episode. The child's sex, cancer type, and presence of financial and relationship stress were predictive of chronic group membership for both parents and children. These families may benefit from increased financial and psychosocial support during anti-cancer treatment. FUNDING: National Health and Medical Research Council Grant (APP1104527).
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    Impact of a hospital-wide sepsis pathway on improved quality of care and clinical outcomes in surgical patients at a comprehensive cancer centre
    Hiong, A ; Thursky, KA ; Venn, G ; Teh, BW ; Haeusler, GM ; Crane, M ; Slavin, MA ; Worth, LJ (WILEY, 2019-05-01)
    PURPOSE: Sepsis is a significant complication following cancer surgery. Although standardised care bundles improve sepsis outcomes in other populations, the benefits in cancer patients are unclear. The objectives of this study were to describe the epidemiology of sepsis in cancer patients post-surgery, and to evaluate the impact of a clinical sepsis pathway on management and clinical outcomes. METHODS: A standardised hospital-wide sepsis pathway was developed in 2013, and all cases of sepsis at the Peter MacCallum Cancer Centre in 2014 were retrospectively evaluated. Inclusion criteria were sepsis onset during the 100-day period following a surgical procedure for cancer diagnosis. Patients were identified using ICD-10-AM sepsis discharge codes, audit documentation and the hospital's antimicrobial approval system. Sepsis episodes were classified as managed on- or off-pathway. RESULTS: A total of 119 sepsis episodes were identified. Of these, 71 (59.7%) were managed on the sepsis pathway. Episodes managed on-pathway resulted more frequently in administration of appropriate antibiotics compared to those off-pathway (94.4% vs. 66.7%, p < 0.001), and had shorter time to first-dose antibiotics (median 85 vs. 315 min, p < 0.001). Pathway utilisation was associated with significant reductions in need for inotropes (7% vs. 13%, p = 0.023), ventilation (3% vs. 10%, p = 0.006) and length of hospitalisation (median 15 vs. 30 days, p = 0.008). The most frequent source of infection was organ-space surgical site infection (24.4% of instances). CONCLUSIONS: A dedicated hospital-wide sepsis pathway had significant impact on the quality of care and clinical outcomes of sepsis in cancer surgery patients. Cost-benefit analysis of sepsis pathways for cancer patients is required.
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    Procalcitonin and Interleukin-10 May Assist in Early Prediction of Bacteraemia in Children With Cancer and Febrile Neutropenia
    Doerflinger, M ; Haeusler, GM ; Li-Wai-Suen, CSN ; Clark, JE ; Slavin, M ; Babl, FE ; Allaway, Z ; Mechinaud, F ; Smyth, GK ; De Abreu Lourenco, R ; Phillips, B ; Pellegrini, M ; Thursky, KA (FRONTIERS MEDIA SA, 2021-05-20)
    OBJECTIVES: Febrile neutropenia (FN) causes treatment disruption and unplanned hospitalization in children with cancer. Serum biomarkers are infrequently used to stratify these patients into high or low risk for serious infection. This study investigated plasma abundance of cytokines in children with FN and their ability to predict bacteraemia. METHODS: Thirty-three plasma cytokines, C-reactive protein (CRP) and procalcitonin (PCT) were measured using ELISA assays in samples taken at FN presentation (n = 79) and within 8-24 h (Day 2; n = 31). Optimal thresholds for prediction of bacteraemia were identified and the predictive ability of biomarkers in addition to routinely available clinical variables was assessed. RESULTS: The median age of included FN episodes was 6.0 years and eight (10%) had a bacteraemia. On presentation, elevated PCT, IL-10 and Mip1-beta were significantly associated with bacteraemia, while CRP, IL-6 and IL-8 were not. The combination of PCT (≥0.425 ng/ml) and IL-10 (≥4.37 pg/ml) had a sensitivity of 100% (95% CI 68.8-100%) and specificity of 89% (95% CI 80.0-95.0%) for prediction of bacteraemia, correctly identifying all eight bacteraemia episodes and classifying 16 FN episodes as high-risk. There was limited additive benefit of incorporating clinical variables to this model. On Day 2, there was an 11-fold increase in PCT in episodes with a bacteraemia which was significantly higher than that observed in the non-bacteraemia episodes. CONCLUSION: Elevated PCT and IL-10 accurately identified all bacteraemia episodes in our FN cohort and may enhance the early risk stratification process in this population. Prospective validation and implementation is required to determine the impact on health service utilisation.
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    Managing low-risk febrile neutropenia in children in the time of COVID-19: What matters to parents and clinicians
    Haeusler, GM ; De Abreu Lourenco, R ; Bakos, C ; O'Brien, T ; Slavin, MA ; Clark, JE ; McMullan, B ; Borland, ML ; Babl, FE ; Krishnasamy, M ; Vanevski, M ; Thursky, KA ; Hall, L (WILEY, 2021-02-03)
    AIM: The Australian 'There is no place like home' project is implementing a paediatric low-risk febrile neutropenia (FN) programme across eight paediatric hospitals. We sought to identify the impact of the coronavirus disease 2019 (COVID-19) pandemic on programme implementation. METHODS: Paediatric oncology, infectious diseases and emergency medicine health-care workers and parent/carers were surveyed to explore the impact of the COVID-19 pandemic on home-based FN care. Online surveys were distributed nationally to health-care workers involved in care of children with FN and to parents or carers of children with cancer. RESULTS: Surveys were completed by 78 health-care workers and 32 parents/carers. Overall, 95% of health-care workers had confidence in the safety of home-based FN care, with 35% reporting changes at their own hospitals in response to the pandemic that made them more comfortable with this model. Compared to pre-pandemic, >50% of parent/carers were now more worried about attending the hospital with their child and >80% were interested in receiving home-based FN care. Among both groups, increased telehealth access and acceptance of home-based care, improved patient quality of life and reduced risk of nosocomial infection were identified as programme enablers, while re-direction of resources due to COVID-19 and challenges in implementing change during a crisis were potential barriers. CONCLUSION: There is strong clinician and parent/carer support for home-based management of low-risk FN across Australia. Changes made to the delivery of cancer care in response to the pandemic have generally increased acceptance for home-based treatments and opportunities exist to leverage these to refine the low-risk FN programme.
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    Predicting Infectious ComplicatioNs in Children with Cancer: an external validation study
    Haeusler, GM ; Thursky, KA ; Mechinaud, F ; Babl, FE ; Lourenco, RDA ; Slavin, MA ; Phillips, R (NATURE PUBLISHING GROUP, 2017-07-11)
    BACKGROUND: The aim of this study was to validate the 'Predicting Infectious ComplicatioNs in Children with Cancer' (PICNICC) clinical decision rule (CDR) that predicts microbiologically documented infection (MDI) in children with cancer and fever and neutropenia (FN). We also investigated costs associated with current FN management strategies in Australia. METHODS: Demographic, episode, outcome and cost data were retrospectively collected on 650 episodes of FN. We assessed the discrimination, calibration, sensitivity and specificity of the PICNICC CDR in our cohort compared with the derivation data set. RESULTS: Using the original variable coefficients, the CDR performed poorly. After recalibration the PICNICC CDR had an area under the receiver operating characteristic (AUC-ROC) curve of 0.638 (95% CI 0.590-0.685) and calibration slope of 0.24. The sensitivity, specificity, positive predictive value and negative predictive value of the PICNICC CDR at presentation was 78.4%, 39.8%, 28.6% and 85.7%, respectively. For bacteraemia, the sensitivity improved to 85.2% and AUC-ROC to 0.71. Application at day 2, taking into consideration the proportion of MDI known (43%), further improved the sensitivity to 87.7%. Length of stay is the main contributor to cost of FN treatment, with an average cost per day of AUD 2183 in the low-risk group. CONCLUSIONS: For prediction of any MDI, the PICNICC rule did not perform as well at presentation in our cohort as compared with the derivation study. However, for bacteraemia, the predictive ability was similar to that of the derivation study, highlighting the importance of recalibration using local data. Performance also improved after an overnight period of observation. Implementation of a low-risk pathway, using the PICNICC CDR after a short period of inpatient observation, is likely to be safe and has the potential to reduce health-care expenditure.
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    Managing haematology and oncology patients during the COVID-19 pandemic: interim consensus guidance
    Weinkove, R ; McQuilten, ZK ; Adler, J ; Agar, MR ; Blyth, E ; Cheng, AC ; Conyers, R ; Haeusler, GM ; Hardie, C ; Jackson, C ; Lane, SW ; Middlemiss, T ; Mollee, P ; Mulligan, SP ; Ritchie, D ; Ruka, M ; Solomon, B ; Szer, J ; Thursky, KA ; Wood, EM ; Worth, LJ ; Yong, MK ; Slavin, MA ; Teh, BW (WILEY, 2020-05-13)
    INTRODUCTION: A pandemic coronavirus, SARS-CoV-2, causes COVID-19, a potentially life-threatening respiratory disease. Patients with cancer may have compromised immunity due to their malignancy and/or treatment, and may be at elevated risk of severe COVID-19. Community transmission of COVID-19 could overwhelm health care services, compromising delivery of cancer care. This interim consensus guidance provides advice for clinicians managing patients with cancer during the pandemic. MAIN RECOMMENDATIONS: During the COVID-19 pandemic: In patients with cancer with fever and/or respiratory symptoms, consider causes in addition to COVID-19, including other infections and therapy-related pneumonitis. For suspected or confirmed COVID-19, discuss temporary cessation of cancer therapy with a relevant specialist. Provide information on COVID-19 for patients and carers. Adopt measures within cancer centres to reduce risk of nosocomial SARS-CoV-2 acquisition; support population-wide social distancing; reduce demand on acute services; ensure adequate staffing; and provide culturally safe care. Measures should be equitable, transparent and proportionate to the COVID-19 threat. Consider the risks and benefits of modifying cancer therapies due to COVID-19. Communicate treatment modifications, and review once health service capacity allows. Consider potential impacts of COVID-19 on the blood supply and availability of stem cell donors. Discuss and document goals of care, and involve palliative care services in contingency planning. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: This interim consensus guidance provides a framework for clinicians managing patients with cancer during the COVID-19 pandemic. In view of the rapidly changing situation, clinicians must also monitor national, state, local and institutional policies, which will take precedence. ENDORSED BY: Australasian Leukaemia and Lymphoma Group; Australasian Lung Cancer Trials Group; Australian and New Zealand Children's Haematology/Oncology Group; Australia and New Zealand Society of Palliative Medicine; Australasian Society for Infectious Diseases; Bone Marrow Transplantation Society of Australia and New Zealand; Cancer Council Australia; Cancer Nurses Society of Australia; Cancer Society of New Zealand; Clinical Oncology Society of Australia; Haematology Society of Australia and New Zealand; National Centre for Infections in Cancer; New Zealand Cancer Control Agency; New Zealand Society for Oncology; and Palliative Care Australia.
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    Cost-effectiveness of home-based care of febrile neutropenia in children with cancer
    Tew, M ; Lourenco, RDA ; Gordon, JR ; Thursky, KA ; Slavin, MA ; Babl, FA ; Orme, L ; Bryant, PA ; Teh, BW ; Dalziel, K ; Haeusler, GM (WILEY, 2021-12-02)
    INTRODUCTION: Home-based treatment of febrile neutropenia (FN) in children with cancer with oral or intravenous antibiotics is safe and effective. There are limited data on the economic impact of this model of care. We evaluated the cost-effectiveness of implementing an FN programme, incorporating home-based intravenous antibiotics for carefully selected patients, in a tertiary paediatric hospital. METHODS: A decision analytic model was constructed to compare costs and outcomes of the home-based FN programme, with usual in-hospital treatment with intravenous antibiotics. The programme included a clinical decision rule to stratify patients by risk for severe infection and home-based eligibility criteria using disease, chemotherapy and patient-level factors. Health outcomes (quality of life) and probabilities of FN risk classification and home-based eligibility were based on prospectively collected data between 2017 and 2019. Patient-level costs were extracted from hospital administrative records. Cost-effectiveness was expressed as the incremental cost per quality-adjusted life year (QALY). FINDINGS: The mean health care cost of home-based FN treatment in low-risk patients was Australian dollars (A$) 7765 per patient compared to A$20,396 for in-hospital treatment (mean difference A$12,632 [95% CI: 12,496-12,767]). Overall, the home-based FN programme was the dominant strategy, being more effective (0.0011 QALY [95% CI: 0.0011-0.0012]) and less costly. Results of the model were most sensitive to proportion of children eligible for home-based care programme. CONCLUSION: Compared to in-hospital FN care, the home-based FN programme is cost-effective, with savings arising from cheaper cost of caring for children at home. These savings could increase as more patients eligible for home-based care are included in the programme.
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    Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, 2021
    Teh, BW ; Yeoh, DK ; Haeusler, GM ; Yannakou, CK ; Fleming, S ; Lindsay, J ; Slavin, MA (WILEY, 2021-11-01)
    Antifungal prophylaxis can reduce morbidity and mortality from invasive fungal disease (IFD). However, its use needs to be optimised and appropriately targeted to patients at highest risk to derive the most benefit. In addition to established risks for IFD, considerable recent progress in the treatment of malignancies has resulted in the development of new 'at-risk' groups. The changing epidemiology of IFD and emergence of drug resistance continue to impact choice of prophylaxis, highlighting the importance of active surveillance and knowledge of local epidemiology. These guidelines aim to highlight emerging risk groups and review the evidence and limitations around new formulations of established agents and new antifungal drugs. It provides recommendations around use and choice of antifungal prophylaxis, discusses the potential impact of the changing epidemiology of IFD and emergence of drug resistance, and future directions for risk stratification to assist optimal management of highly vulnerable patients.
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    Risk stratification in children with cancer and febrile neutropenia: A national, prospective, multicentre validation of nine clinical decision rules
    Haeusler, GM ; Thursky, KA ; Slavin, MA ; Babl, FE ; De Abreu Lourenco, R ; Allaway, Z ; Mechinaud, F ; Phillips, R ; Australian PICNICC study group and the PREDICT network, (Lancet, 2020-01)
    Background: Reduced intensity treatment of low-risk febrile neutropenia (FN) in children with cancer is safe and improves quality of life. Identifying children with low-risk FN using a validated risk stratification strategy is recommended. This study prospectively validated nine FN clinical decision rules (CDRs) designed to predict infection or adverse outcome. Methods: Data were collected on consecutive FN episodes in this multicentre, prospective validation study. The reproducibility and discriminatory ability of each CDR in the validation cohort was compared to the derivation dataset and details of missed outcomes were reported. Findings: There were 858 FN episodes in 462 patients from eight hospitals included. Bacteraemia occurred in 111 (12·9%) and a non-bacteraemia microbiological documented infection in 185 (21·6%). Eight CDRs exhibited reproducibility and sensitivity ranged from 64% to 96%. Rules that had >85% sensitivity in predicting outcomes classified few patients (<20%) as low risk. For three CDRs predicting a composite outcome of any bacterial or viral infection, the sensitivity and discriminatory ability improved for prediction of bacterial infection alone. Across all CDRs designed to be implemented at FN presentation, the sensitivity improved at day 2 assessment. Interpretation: While reproducibility was observed in eight out of the nine CDRs, no rule perfectly differentiated between children with FN at high or low risk of infection. This is in keeping with other validation studies and highlights the need for additional safeguards against missed infections or adverse outcomes before implementation can be considered.