Infectious Diseases - Research Publications

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    Cytomegalovirus DNAemia and disease: current-era epidemiology, clinical characteristics and outcomes in cancer patients other than allogeneic haemopoietic transplantation
    Tay, KH ; Slavin, MA ; Thursky, KA ; Coussement, J ; Worth, LJ ; Teh, BW ; Khot, A ; Tam, CS ; Yong, MK (WILEY, 2022-10)
    BACKGROUND: High-intensity chemotherapy and advances in novel immunotherapies have seen the emergence of cytomegalovirus (CMV) infections in cancer patients other than allogeneic haemopoietic cell transplantation (HCT). Aim To evaluate the epidemiology, clinical characteristics and outcomes of CMV infection in this population. METHODS: A retrospective review of cancer patients other than allogeneic HCT who had CMV DNAemia and/or disease from July 2013 till May 2020 at a quaternary cancer centre was performed. RESULTS: Of 11 485 cancer patients who underwent treatment during this period, 953 patients had CMV DNA testing performed and 238 of them had CMV DNAemia. After excluding patients with allogeneic HCT, 62 patients with CMV DNAemia were identified, of whom 10 had concurrent CMV disease. The most frequent underlying malignancies were B-cell lymphoproliferative disease (LPD) (31%; 19/62), T-cell LPD (21%; 13/62), chronic lymphocytic leukaemia (11%; 7/62) and multiple myeloma (10%; 6/62). Most patients had lymphopenia (77%; 48/62), multiple cancer therapies (63%; 39/62 received ≥2 previous therapies), co-infection (56%; 35/62 had ≥1 co-infection) and corticosteroid therapy (48%; 30/62) within 1 month before CMV diagnosis. CMV DNAemia and disease were observed in patients receiving novel immunotherapies, including bispecific antibody therapy, chimeric-antigen receptor T-cell therapy and immune checkpoint inhibitors. CONCLUSION: Patients with haematological malignancy, particularly B-cell LPD, T-cell LPD, chronic lymphocytic leukaemia and multiple myeloma, were frequently identified to have CMV DNAemia and disease. Lymphopenia, multiple cancer therapies, co-infection and recent receipt of systemic corticosteroids were also commonly observed. Future studies are necessary to determine optimal identification and management of CMV in these patients.
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    Prevalence and predictors of poor outcome in children with febrile neutropaenia presenting to the emergency department
    Long, E ; Babl, FE ; Phillips, N ; Craig, S ; Zhang, M ; Kochar, A ; McCaskill, M ; Borland, ML ; Slavin, MA ; Phillips, R ; Lourenco, RDA ; Michinaud, F ; Thursky, KA ; Haeusler, G (WILEY, 2022-10)
    OBJECTIVE: Children with acquired neutropaenia due to cancer chemotherapy are at high risk of severe infection. The present study aims to describe the prevalence and predictors of poor outcomes in children with febrile neutropaenia (FN). METHODS: This is a multicentre, prospective observational study in tertiary Australian EDs. Cancer patients with FN were included. Fever was defined as a single temperature ≥38°C, and neutropaenia was defined as an absolute neutrophil count <1000/mm3 . The primary outcome was the ICU admission for organ support therapy (inotropic support, mechanical ventilation, renal replacement therapy, extracorporeal life support). Secondary outcomes were: ICU admission, ICU length of stay (LOS) ≥3 days, proven or probable bacterial infection, hospital LOS ≥7 days and 28-day mortality. Initial vital signs, biomarkers (including lactate) and clinical sepsis scores, including Systemic Inflammatory Response Syndrome, quick Sequential Organ Failure Assessment and quick Paediatric Logistic Organ Dysfunction-2 were evaluated as predictors of poor outcomes. RESULTS: Between December 2016 and January 2018, 2124 episodes of fever in children with cancer were screened, 547 episodes in 334 children met inclusion criteria. Four episodes resulted in ICU admission for organ support therapy, nine episodes required ICU admission, ICU LOS was ≥3 days in four, hospital LOS was ≥7 days in 153 and two patients died within 28 days. Vital signs, blood tests and clinical sepsis scores, including Systemic Inflammatory Response Syndrome, quick Sequential Organ Failure Assessment and quick Paediatric Logistic Organ Dysfunction-2, performed poorly as predictors of these outcomes (area under the receiver operating characteristic curve <0.6). CONCLUSIONS: Very few patients with FN required ICU-level care. Vital signs, biomarkers and clinical sepsis scores for the prediction of poor outcomes are of limited utility in children with FN.
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    [18F]FDG-PET-CT compared with CT for persistent or recurrent neutropenic fever in high-risk patients (PIPPIN): a multicentre, open-label, phase 3, randomised, controlled trial
    Douglas, A ; Thursky, K ; Spelman, T ; Szer, J ; Bajel, A ; Harrison, S ; Tio, SY ; Bupha-Intr, O ; Tew, M ; Worth, L ; Teh, B ; Chee, L ; Ng, A ; Carney, D ; Khot, A ; Haeusler, G ; Yong, M ; Trubiano, J ; Chen, S ; Hicks, R ; Ritchie, D ; Slavin, M (ELSEVIER SCI LTD, 2022-08)
    BACKGROUND: Management of neutropenic fever in high-risk haematology patients is challenging; there are often few localising clinical features, and diagnostic tests have poor sensitivity and specificity. We aimed to compare how [18F]flurodeoxyglucose ([18F]FDG)-PET-CT scans and conventional CT scans affected the guidance of antimicrobial management and the outcomes of patients with persistent or recurrent neutropenic fever. METHODS: We did a multicentre, open-label, phase 3, randomised, controlled trial in two tertiary referral hospitals in Australia. We recruited adults aged 18 years or older who were receiving conditioning chemotherapy for haematopoietic stem-cell transplantation or chemotherapy for acute leukaemia and had persistent (>72 h) or recurrent (new fever beyond 72 h of initial onset interspersed with >48 h defervescence) neutropenic fever. Exclusion criteria were pregnancy, allergy to iodinated contrast, or estimated glomerular filtration rate of less than 30 mL/min. Patients were randomly assigned by computer-generated randomisation chart (1:1) to [18F]FDG-PET-CT or conventional CT. Masking was not possible because of the nature of the investigation. Scans were done within 3 days of random assignment. The primary endpoint was a composite of starting, stopping, or changing the spectrum (broadening or narrowing) of antimicrobial therapy-referred to here as antimicrobial rationalisation-within 96 h of the assigned scan, analysed per protocol. This trial is registered with clinicaltrials.gov, NCT03429387, and is complete. FINDINGS: Between Jan 8, 2018, and July 23, 2020, we assessed 316 patients for eligibility. 169 patients were excluded and 147 patients were randomly assigned to either [18F]FDG-PET-CT (n=73) or CT (n=74). Nine patients did not receive a scan per protocol, and two participants in each group were excluded for repeat entry into the study. 65 patients received [18F]FDG-PET-CT (38 [58%] male; 53 [82%] White) and 69 patients received CT (50 [72%] male; 58 [84%] White) per protocol. Median follow up was 6 months (IQR 6-6). Antimicrobial rationalisation occurred in 53 (82%) of 65 patients in the [18F]FDG-PET-CT group and 45 (65%) of 69 patients in the CT group (OR 2·36, 95% CI 1·06-5·24; p=0·033). The most frequent component of antimicrobial rationalisation was narrowing spectrum of therapy, in 28 (43%) of 65 patients in the [18F]FDG-PET-CT group compared with 17 (25%) of 69 patients in the CT group (OR 2·31, 95% CI 1·11-4·83; p=0·024). INTERPRETATION: [18F]FDG-PET-CT was associated with more frequent antimicrobial rationalisation than conventional CT. [18F]FDG-PET-CT can support decision making regarding antimicrobial cessation or de-escalation and should be considered in the management of patients with haematological diseases and persistent or recurrent high-risk neutropenic fever after chemotherapy or transplant conditioning. FUNDING: National Health and Medical Research Council Centre of Research Excellence (APP1116876), Melbourne Health foundation, Gilead Research Fellowship grants supported this study.
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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)
    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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    Pilot study of a combined genomic and epidemiologic surveillance program for hospital-acquired multidrug-resistant pathogens across multiple hospital networks in Australia
    Sherry, NL ; Lee, RS ; Gorrie, CL ; Kwong, JC ; Stuart, RL ; Korman, TM ; Marshall, C ; Higgs, C ; Chan, HT ; Graham, M ; Johnson, PDR ; Leroi, MJ ; Reed, C ; Richards, MJ ; Slavin, MA ; Worth, LJ ; Howden, BP ; Grayson, ML (CAMBRIDGE UNIV PRESS, 2021-05)
    OBJECTIVES: To conduct a pilot study implementing combined genomic and epidemiologic surveillance for hospital-acquired multidrug-resistant organisms (MDROs) to predict transmission between patients and to estimate the local burden of MDRO transmission. DESIGN: Pilot prospective multicenter surveillance study. SETTING: The study was conducted in 8 university hospitals (2,800 beds total) in Melbourne, Australia (population 4.8 million), including 4 acute-care, 1 specialist cancer care, and 3 subacute-care hospitals. METHODS: All clinical and screening isolates from hospital inpatients (April 24 to June 18, 2017) were collected for 6 MDROs: vanA VRE, MRSA, ESBL Escherichia coli (ESBL-Ec) and Klebsiella pneumoniae (ESBL-Kp), and carbapenem-resistant Pseudomonas aeruginosa (CRPa) and Acinetobacter baumannii (CRAb). Isolates were analyzed and reported as routine by hospital laboratories, underwent whole-genome sequencing at the central laboratory, and were analyzed using open-source bioinformatic tools. MDRO burden and transmission were assessed using combined genomic and epidemiologic data. RESULTS: In total, 408 isolates were collected from 358 patients; 47.5% were screening isolates. ESBL-Ec was most common (52.5%), then MRSA (21.6%), vanA VRE (15.7%), and ESBL-Kp (7.6%). Most MDROs (88.3%) were isolated from patients with recent healthcare exposure.Combining genomics and epidemiology identified that at least 27.1% of MDROs were likely acquired in a hospital; most of these transmission events would not have been detected without genomics. The highest proportion of transmission occurred with vanA VRE (88.4% of patients). CONCLUSIONS: Genomic and epidemiologic data from multiple institutions can feasibly be combined prospectively, providing substantial insights into the burden and distribution of MDROs, including in-hospital transmission. This analysis enables infection control teams to target interventions more effectively.
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    Multi-site implementation of whole genome sequencing for hospital infection control: A prospective genomic epidemiological analysis
    Sherry, NL ; Gorrie, CL ; Kwong, JC ; Higgs, C ; Stuart, RL ; Marshall, C ; Ballard, SA ; Sait, M ; Korman, TM ; Slavin, MA ; Lee, RS ; Graham, M ; Leroi, M ; Worth, LJ ; Chan, HT ; Seemann, T ; Grayson, ML ; Howden, BP (ELSEVIER, 2022-06)
    BACKGROUND: Current microbiological methods lack the resolution to accurately identify multidrug-resistant organism (MDRO) transmission, however, whole genome sequencing can identify highly-related patient isolates providing opportunities for precision infection control interventions. We investigated the feasibility and potential impact of a prospective multi-centre genomics workflow for hospital infection control. METHODS: We conducted a prospective genomics implementation study across eight Australian hospitals over 15 months (2017,2018), collecting all clinical and screening isolates from inpatients with vanA VRE, MRSA, ESBL Escherichia coli (ESBL-Ec), or ESBL Klebsiella pneumoniae (ESBL-Kp). Genomic and epidemiologic data were integrated to assess MDRO transmission. FINDINGS: In total, 2275 isolates were included from 1970 patients, predominantly ESBL-Ec (40·8%) followed by MRSA (35·6%), vanA VRE (15·2%), and ESBL-Kp (8·3%).Overall, hospital and genomic epidemiology showed 607 patients (30·8%) acquired their MDRO in hospital, including the majority of vanA VRE (266 patients, 86·4%), with lower proportions of ESBL-Ec (186 patients, 23·0%), ESBL-Kp (42 patients, 26·3%), and MRSA (113 patients, 16·3%). Complex patient movements meant the majority of MDRO transmissions would remain undetected without genomic data.The genomics implementation had major impacts, identifying unexpected MDRO transmissions prompting new infection control interventions, and contributing to vanA VRE becoming a notifiable condition. We identified barriers to implementation and recommend strategies for mitigation. INTERPRETATION: Implementation of a multi-centre genomics-informed infection control workflow is feasible and identifies many unrecognised MDRO transmissions. This provides critical opportunities for interventions to improve patient safety in hospitals. FUNDING: Melbourne Genomics Health Alliance (supported by State Government of Victoria, Australia), and National Health and Medical Research Council (Australia).
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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)
    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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    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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    The role of 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG PET/CT) in assessment of complex invasive fungal disease and opportunistic co-infections in patients with acute leukemia prior to allogeneic hematopoietic cell transplant
    Anthony, L ; Ramin, A ; Amit, K ; Ashish, B ; Phillip, A ; Monica, S ; Karin, T (WILEY, 2021-06)
    INTRODUCTION: Individuals diagnosed with acute lymphoid and myeloid malignancies are at significant risk of invasive fungal and bacterial infections secondary to their marked immunocompromised states with a significant high risk of mortality. The role of metabolic imaging with 18F-Fluorodeoxyglucose (FDG) Positron Emission Tomography/Computed Tomography (PET/CT) has been increasingly recognized in optimizing the diagnosis of invasive infection, monitoring the response to therapy and guiding the duration of antimicrobial therapy or need to escalate to surgical intervention. METHODS: Two distinct cases of pulmonary co-infection of rare fungal and bacterial pathogens are explored in severely immunocompromised individuals where FDG PET/CT aided both patients to make a full recovery and transition to HCT. The first case explores mixed Scedosporium apiospermum and Rhizomucor pulmonary infection on a background of T cell/myeloid mixed phenotype acute leukemia ultimately warranting long-term antifungal therapy and lobectomy prior to HCT. The second case explores Fusarium and Nocardia pulmonary infection on a background of relapsed AML also warranting surgical resection with lobectomy and long-term antimicrobials prior to transition to HCT. DISCUSSION: The cases highlight the utility of FDG PET/CT to support the diagnosis of infections, including the presence or absence of disseminated infection, and to provide highly sensitive monitoring of the infection over time. FDG PET/CT played a key role in directing therapy duration decisions and prompted the necessity for surgical intervention. Ultimately, the use of FDG PET/CT allowed for a successful transition to HCT highlighting its value in this clinical setting. CONCLUSION: FDG PET/CT has an emerging role in the diagnostic and monitoring pathway for complex infections in high-risk immunocompromised patients.
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    Very late-onset cytomegalovirus disease with ganciclovir resistance >15 years following renal transplantation
    Khan, SF ; Yong, MK ; Slavin, MA ; Hughes, P ; Sasadeusz, J (WILEY, 2021-02)
    Cytomegalovirus (CMV) infection is a significant cause of morbidity and mortality after solid organ transplantation. There has been a significant shift in disease epidemiology with the introduction of antiviral prophylaxis, with CMV disease occurring later and clinical presentations more atypical. We describe two cases of very late-onset CMV disease where first disease occurred 15 and 18 years post-renal transplantation, with both cases complicated by antiviral drug resistance. We subsequently review the published cases and literature of very late-onset CMV disease (onset > 10 years post-solid organ transplantation) as an increasingly recognized phenomenon which is emerging as an important aspect in improving long-term patient outcomes in the current era of renal transplantation.