Doherty Institute - Research Publications

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    Hospitalisation, morbidity and outcomes associated with respiratory syncytial virus compared with influenza in adults of all ages
    Leaver, B ; Smith, B ; Irving, L ; Johnson, D ; Tong, S (WILEY, 2021-12-01)
    BACKGROUND: Respiratory syncytial virus (RSV) is understood to be a cause of significant disease in older adults and children. Further analysis of RSV in younger adults may reveal further insight into its role as an important pathogen in all age groups. METHODS: We identified, through laboratory data, adults who tested positive for either influenza or RSV between January 2017 and June 2019 at a single Australian hospital. We compared baseline demographics, testing patterns, hospitalisations and outcomes between these groups. RESULTS: Of 1128 influenza and 193 RSV patients, the RSV cohort was older (mean age 54.7 vs. 64.9, p < 0.001) and was more comorbid as determined by the Charlson Comorbidity Index (2.4 vs. 3.2, p < 0.001). For influenza hospitalisations, the majority admitted were aged under 65 which was not the case for RSV (61.8% vs. 45.6%, p < 0.001). Testing occurred later in RSV hospitalisations as measured by the proportion tested in the emergency department (ED) (80.3% vs. 69.2%, p < 0.001), and this was strongly associated with differences in presenting phenotype (the presence of fever). RSV was the biggest predictor of 6-month representation, with age and comorbidities predicting this less strongly. CONCLUSION: RSV is a significant contributor to morbidity and hospitalisation, sometimes outweighing that of influenza, and is not limited to elderly cohorts. Understanding key differences in the clinical syndrome and consequent testing paradigms may allow better detection and potentially treatment of RSV to reduce individual morbidity and health system burden. This growing area of research helps quantify the need for directed therapies for RSV.
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    Point of care and oral fluid hepatitis B testing in remote Indigenous communities of northern Australia
    Sullivan, RP ; Davies, J ; Binks, P ; Dhurrkay, RG ; Gurruwiwi, GG ; Bukulatjpi, SM ; McKinnon, M ; Hosking, K ; Littlejohn, M ; Jackson, K ; Locarnini, S ; Davis, JS ; Tong, SYC (WILEY, 2019-12-22)
    Many Indigenous Australians in northern Australia living with chronic hepatitis B are unaware of their diagnosis due to low screening rates. A venous blood point of care test (POCT) or oral fluid laboratory test could improve testing uptake in this region. The purpose of this study was to assess the field performance of venous blood POCT and laboratory performance of an oral fluid hepatitis B surface antigen (HBsAg) test in Indigenous individuals living in remote northern Australian communities. The study was conducted with four very remote communities in the tropical north of Australia's Northern Territory. Community research workers collected venous blood and oral fluid samples. We performed the venous blood POCT for HBsAg in the field. We assessed the venous blood and oral fluid specimens for the presence of HBsAg using standard laboratory assays. We calculated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the POCT and oral fluid test, using serum laboratory detection of HBsAg as the gold standard. From 215 enrolled participants, 155 POCT and 197 oral fluid tests had corresponding serum HBsAg results. The POCT had a sensitivity of 91.7% and specificity of 100%. Based on a population prevalence of 6%, the PPV was 100% and NPV was 99.5%. The oral fluid test had a sensitivity of 56.8%, specificity of 98.1%, PPV of 97.3% and NPV of 65.9%. The venous blood POCT has excellent test characteristics and could be used to identify individuals with chronic HBV infection in high prevalence communities with limited access to health care. Oral fluid performance was suboptimal.
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    Integrated immune dynamics define correlates of COVID-19 severity and antibody responses
    Koutsakos, M ; Rowntree, LC ; Hensen, L ; Chua, BY ; van de Sandt, CE ; Habel, JR ; Zhang, W ; Jia, X ; Kedzierski, L ; Ashhurst, TM ; Putri, GH ; Marsh-Wakefield, F ; Read, MN ; Edwards, DN ; Clemens, EB ; Wong, CY ; Mordant, FL ; Juno, JA ; Amanat, F ; Audsley, J ; Holmes, NE ; Gordon, CL ; Smibert, OC ; Trubiano, JA ; Hughes, CM ; Catton, M ; Denholm, JT ; Tong, SYC ; Doolan, DL ; Kotsimbos, TC ; Jackson, DC ; Krammer, F ; Godfrey, D ; Chung, AW ; King, NJC ; Lewin, SR ; Wheatley, AK ; Kent, SJ ; Subbarao, K ; McMahon, J ; Thevarajan, I ; Thi, HON ; Cheng, AC ; Kedzierska, K (ELSEVIER, 2021-03-16)
    SARS-CoV-2 causes a spectrum of COVID-19 disease, the immunological basis of which remains ill defined. We analyzed 85 SARS-CoV-2-infected individuals at acute and/or convalescent time points, up to 102 days after symptom onset, quantifying 184 immunological parameters. Acute COVID-19 presented with high levels of IL-6, IL-18, and IL-10 and broad activation marked by the upregulation of CD38 on innate and adaptive lymphocytes and myeloid cells. Importantly, activated CXCR3+cTFH1 cells in acute COVID-19 significantly correlate with and predict antibody levels and their avidity at convalescence as well as acute neutralization activity. Strikingly, intensive care unit (ICU) patients with severe COVID-19 display higher levels of soluble IL-6, IL-6R, and IL-18, and hyperactivation of innate, adaptive, and myeloid compartments than patients with moderate disease. Our analyses provide a comprehensive map of longitudinal immunological responses in COVID-19 patients and integrate key cellular pathways of complex immune networks underpinning severe COVID-19, providing important insights into potential biomarkers and immunotherapies.
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    The Global Epidemiology of Impetigo: A Systematic Review of the Population Prevalence of Impetigo and Pyoderma
    Bowen, AC ; Mahe, A ; Hay, RJ ; Andrews, RM ; Steer, AC ; Tong, SYC ; Carapetis, JR ; Reid, SD (PUBLIC LIBRARY SCIENCE, 2015-08-28)
    OBJECTIVE: We conducted a comprehensive, systematic review of the global childhood population prevalence of impetigo and the broader condition pyoderma. METHODS: PubMed was systematically searched for impetigo or pyoderma studies published between January 1 1970 and September 30 2014. Two independent reviewers extracted data from each relevant article on the prevalence of impetigo. FINDINGS: Sixty-six articles relating to 89 studies met our inclusion criteria. Based on population surveillance, 82 studies included data on 145,028 children assessed for pyoderma or impetigo. Median childhood prevalence was 12·3% (IQR 4·2-19·4%). Fifty-eight (65%) studies were from low or low-middle income countries, where median childhood prevalences were 8·4% (IQR 4·2-16·1%) and 14·5% (IQR 8·3-20·9%), respectively. However, the highest burden was seen in underprivileged children from marginalised communities of high-income countries; median prevalence 19·4%, (IQR 3·9-43·3%). CONCLUSION: Based on data from studies published since 2000 from low and low-middle income countries, we estimate the global population of children suffering from impetigo at any one time to be in excess of 162 million, predominantly in tropical, resource-poor contexts. Impetigo is an under-recognised disease and in conjunction with scabies, comprises a major childhood dermatological condition with potential lifelong consequences if untreated.
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    Comparative M-protein analysis of Streptococcus pyogenes from pharyngitis and skin infections in New Zealand: Implications for vaccine development
    Williamson, DA ; Smeesters, PR ; Steer, AC ; Morgan, J ; Davies, M ; Carter, P ; Upton, A ; Tong, SYC ; Fraser, J ; Moreland, NJ (BIOMED CENTRAL LTD, 2016-10-12)
    BACKGROUND: Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are responsible for a significant disease burden amongst Māori and Pacific populations in New Zealand (NZ). However, contemporary data are lacking regarding circulating group A Streptococcal (GAS) strains in NZ. Such information is important in guiding vaccine development. METHODS: GAS isolates from April to June 2015 were recovered from skin and pharyngeal samples from children living in areas of high social deprivation in Auckland, NZ, a significant proportion of which are Māori or Pacific. These children are among the highest risk group for developing ARF. Isolates were compared to concurrently collected pharyngeal isolates from Dunedin, NZ, where both the proportion of Māori and Pacific children and risk of developing ARF is low. Emm typing, emm cluster typing and theoretical coverage of the 30-valent vaccine candidate were undertaken as previously described. RESULTS: A high diversity of emm types and a high proportion of emm-pattern D and cluster D4 isolates were detected amongst both skin and pharyngeal isolates in children at high risk of ARF. Pharyngeal isolates from children at low risk of ARF within the same country were significantly less diverse, less likely to be emm pattern D, and more likely to be theoretically covered by the 30-valent M protein vaccine. CONCLUSIONS: The high proportion of emm pattern D GAS strains amongst skin and pharyngeal isolates from children at high risk of ARF raises further questions about the role of skin infection in ARF pathogenesis. Emm types and emm clusters differed considerably between ARF endemic and non-endemic settings, even within the same country. This difference should be taken into account for vaccine development.
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    Impact of ethnicity and socio-economic status on Staphylococcus aureus bacteremia incidence and mortality: a heavy burden in Indigenous Australians
    Tong, SYC ; van Hal, SJ ; Einsiedel, L ; Currie, BJ ; Turnidge, JD (BMC, 2012-10-09)
    BACKGROUND: Investigations of the impact of ethnicity and socio-economic status on incidence and outcomes of Staphylococcus aureus bacteraemia are limited. METHODS: We prospectively identified all S. aureus bacteraemia episodes in the Australian New Zealand Cooperative on Outcomes in Staphylococcal Sepsis cohort study between 2007 and 2010. We calculated population level incidence rates using regional postcodes and stratified the analysis by ethnicity, age and socio-economic status indexes. RESULTS: There were 7539 episodes of S. aureus bacteraemia with an annual incidence of 11·2 episodes per 100,000 population. The age-adjusted incidence in the Indigenous population was 62·5 per 100,000 population with an age standardized incidence rate ratio of 5·9 compared to the non-Indigenous population and an incidence rate ratio of 29.2 for community-associated methicillin-resistant S. aureus (MRSA). Populations in the lowest socio-economic status quintile had an increased S. aureus bacteraemia incidence compared to higher quintiles. However, there was a disparity between Indigenous and non-Indigenous populations across all socio-economic status quintiles. The lower 30-day mortality for Indigenous patients (7%) compared to non-Indigenous patients (17%) was explained by differences in age. CONCLUSIONS: Indigenous Australians suffer from a higher rate of S. aureus bacteraemia than non-Indigenous Australians, particularly for community-associated MRSA. Ethnicity and socio-economic status had little impact on subsequent mortality, with other host factors contributing more significantly.
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    Panton-Valentine Leukocidin Is Not the Primary Determinant of Outcome for Staphylococcus aureus Skin Infections: Evaluation from the CANVAS Studies
    Tong, A ; Tong, SYC ; Zhang, Y ; Lamlertthon, S ; Sharma-Kuinkel, BK ; Rude, T ; Ahn, SH ; Ruffin, F ; Llorens, L ; Tamarana, G ; Biek, D ; Critchley, I ; Fowler, VG ; de Lencastre, H (PUBLIC LIBRARY SCIENCE, 2012-05-18)
    The impact of Panton-Valentine leukocidin (PVL) on the severity of complicated skin and skin structure infections (cSSSI) caused by Staphylococcus aureus is controversial. We evaluated potential associations between clinical outcome and PVL presence in both methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) isolates from patients enrolled in two large, multinational phase three clinical trials assessing ceftaroline fosamil for the treatment of cSSSI (the CANVAS 1 and 2 programs). Isolates from all microbiologically evaluable patients with monomicrobial MRSA or MSSA infections (n = 473) were genotyped by PCR for pvl and underwent pulsed-field gel electrophoresis (PFGE). Genes encoding pvl were present in 266/473 (56.2%) isolates. Infections caused by pvl-positive S. aureus were associated with younger patient age, North American acquisition, and presence of major abscesses (P<0.001 for each). Cure rates of patients infected with pvl-positive and pvl-negative S. aureus were similar overall (93.6% versus 92.8%; P = 0.72), and within MRSA-infected (94.5% vs. 93.1%; P = 0.67) and MSSA-infected patients (92.2% vs. 92.7%; P = 1.00). This finding persisted after adjustment for multiple patient characteristics. Outcomes were also similar when USA300 PVL+ and non-USA300 PVL+ infections were compared. The results of this contemporary, international study suggest that pvl presence was not the primary determinant of outcome in patients with cSSSI due to either MRSA or MSSA.
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    A Novel Clinical Grading Scale to Guide the Management of Crusted Scabies
    Davis, JS ; McGloughlin, S ; Tong, SYC ; Walton, SF ; Currie, BJ ; Vinetz, JM (PUBLIC LIBRARY SCIENCE, 2013-09-01)
    BACKGROUND: Crusted scabies, or hyperinfestation with Sarcoptes scabiei, occurs in people with an inadequate immune response to the mite. In recent decades, data have emerged suggesting that treatment of crusted scabies with oral ivermectin combined with topical agents leads to lower mortality, but there are no generally accepted tools for describing disease severity. Here, we describe a clinical grading scale for crusted scabies and its utility in real world practice. METHODOLOGY/PRINCIPAL FINDINGS: In 2002, Royal Darwin Hospital (RDH), a hospital in tropical Australia developed and began using a clinical grading scale to guide the treatment of crusted scabies. We conducted a retrospective observational study including all episodes of admission to RDH for crusted scabies during the period October 2002-December 2010 inclusive. Patients who were managed according to the grading scale were compared with those in whom the scale was not used at the time of admission but was calculated retrospectively. There were 49 admissions in 30 patients during the study period, of which 49 (100%) were in Indigenous Australians, 29 (59%) were male and the median age was 44.1 years. According to the grading scale, 8 (16%) episodes were mild, 24 (49%) were moderate, and 17 (35%) were severe. Readmission within the study period was significantly more likely with increasing disease severity, with an odds ratio (95% CI) of 12.8 (1.3-130) for severe disease compared with mild. The patients managed according to the grading scale (29 episodes) did not differ from those who were not (20 episodes), but they received fewer doses of ivermectin and had a shorter length of stay (11 vs. 16 days, p = 0.02). Despite this the outcomes were no different, with no deaths in either group and a similar readmission rate. CONCLUSIONS/SIGNIFICANCE: Our grading scale is a useful tool for the assessment and management of crusted scabies.
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    Staphylococcus aureus infections following knee and hip prosthesis insertion procedures
    Arduino, JM ; Kaye, KS ; Reed, SD ; Peter, SA ; Sexton, DJ ; Chen, LF ; Hardy, NC ; Tong, SYC ; Smugar, SS ; Fowler, VG ; Anderson, DJ (BIOMED CENTRAL LTD, 2015-12-21)
    BACKGROUND: Staphylococcus aureus is the most common and most important pathogen following knee and hip arthroplasty procedures. Understanding the epidemiology of invasive S. aureus infections is important to quantify this serious complication. METHODS: This nested retrospective cohort analysis included adult patients who had undergone insertion of knee or hip prostheses with clean or clean-contaminated wound class at 11 hospitals between 2003-2006. Invasive S. aureus infections, non-superficial incisional surgical site infections (SSIs) and blood stream infections (BSIs), were prospectively identified following each procedure. Prevalence rates, per 100 procedures, were estimated. RESULTS: 13,719 prosthetic knee (62%) and hip (38%) insertion procedures were performed. Of 92 invasive S. aureus infections identified, SSIs were more common (80%) than SSI and BSI (10%) or BSI alone (10%). The rate of invasive S. aureus infection/100 procedures was 0.57 [95% CI: 0.43-0.73] for knee insertion and 0.83 [95% CI: 0.61-1.08] for hip insertion. More than half (53%) were methicillin-resistant. Median time-to-onset of infection was 34 and 26 days for knee and hip insertion, respectively. Infection was associated with higher National Healthcare Safety Network risk index (p ≤ 0.0001). CONCLUSIONS: Post-operative invasive S. aureus infections were rare, but difficult-to-treat methicillin-resistant infections were relatively common. Optimizing preventative efforts may greatly reduce the healthcare burden associated with S. aureus infections.
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    Single-molecule sequencing reveals the molecular basis of multidrug-resistance in ST772 methicillin-resistant Staphylococcus aureus
    Steinig, EJ ; Andersson, P ; Harris, SR ; Sarovich, DS ; Manoharan, A ; Coupland, P ; Holden, MTG ; Parkhill, J ; Bentley, SD ; Robinson, DA ; Tong, SYC (BMC, 2015-05-16)
    BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of hospital-associated infection, but there is growing awareness of the emergence of multidrug-resistant lineages in community settings around the world. One such lineage is ST772-MRSA-V, which has disseminated globally and is increasingly prevalent in India. Here, we present the complete genome sequence of DAR4145, a strain of the ST772-MRSA-V lineage from India, and investigate its genomic characteristics in regards to antibiotic resistance and virulence factors. RESULTS: Sequencing using single-molecule real-time technology resulted in the assembly of a single continuous chromosomal sequence, which was error-corrected, annotated and compared to nine draft genome assemblies of ST772-MRSA-V from Australia, Malaysia and India. We discovered numerous and redundant resistance genes associated with mobile genetic elements (MGEs) and known core genome mutations that explain the highly antibiotic resistant phenotype of DAR4145. Staphylococcal toxins and superantigens, including the leukotoxin Panton-Valentinin Leukocidin, were predominantly associated with genomic islands and the phage φ-IND772PVL. Some of these mobile resistance and virulence factors were variably present in other strains of the ST772-MRSA-V lineage. CONCLUSIONS: The genomic characteristics presented here emphasize the contribution of MGEs to the emergence of multidrug-resistant and highly virulent strains of community-associated MRSA. Antibiotic resistance was further augmented by chromosomal mutations and redundancy of resistance genes. The complete genome of DAR4145 provides a valuable resource for future investigations into the global dissemination and phylogeography of ST772-MRSA-V.