Melioidosis Causing Critical Illness: A Review of 24 Years of Experience From the Royal Darwin Hospital ICU.

OBJECTIVES: Melioidosis is increasing in incidence with newly recognized foci of melioidosis in the Americas, Africa, and elsewhere. This review describes the demographics, management, and outcomes of a large cohort of critically ill patients with melioidosis. DESIGN: Data were extracted from two prospective databases-the Menzies School of Health Research Melioidosis Database (1989-2013) and the Royal Darwin Hospital ICU Melioidosis Database (2001-2013). SETTING AND PATIENTS: The Royal Darwin Hospital ICU is the only ICU in the tropical Top End of Northern Territory of Australia, an endemic area for melioidosis. The study included all patients with melioidosis admitted to Royal Darwin Hospital ICU from 1989 to 2013. MEASUREMENTS AND MAIN RESULTS: From 1989 to 2013, 207 patients with melioidosis required admission to ICU. Mortality reduced from 92% (1989-1997) to 26% (1998-2013) (p < 0.001). The reduced mortality coincided with the introduction of an intensivist-led service, meropenem, and adjuvant granulocyte colony-stimulating factor for confirmed melioidosis sepsis in 1998. Pneumonia was the presenting illness in 155 of 207 (75%). ICU melioidosis patients (2001-2013) had an Acute Physiology and Chronic Health Evaluation II score of 23, median length of stay in the ICU of 7 days, and median ventilation hours of 130 and one third required renal replacement therapy. CONCLUSIONS: The mortality for critically ill patients with melioidosis in the Top End of the Northern Territory of Australia has substantially reduced over the past 24 years. The reduction in mortality coincided with the introduction of an intensivist-led model of care, the empiric use of meropenem, and adjunctive treatment with granulocyte colony-stimulating factor in 1998.

Clinical presentation and medical management of melioidosis in children: a 24-year prospective study in the Northern Territory of Australia and review of the literature.

BACKGROUND: Melioidosis is less common in children than adults. The clinical spectrum of disease varies greatly between the 2 groups. Treatment guidelines are currently based on adult studies, and revision of existing guidelines is necessary to instruct specific pediatric management. METHODS: Culture-confirmed cases of melioidosis in the Northern Territory between 1989 and 2013 were identified from the Prospective Melioidosis Study. The epidemiology and clinical spectrum of disease for children aged ≤ 16 years were analyzed and compared with the adult data. RESULTS: Forty-five pediatric patients were identified, representing 5% of the total 820 melioidosis cases over 24 years. Most children (84%) had no recognized risk factors for melioidosis, and 80% presented during the wet season. Primary cutaneous melioidosis was the commonest presentation in children (60% vs 13%; P < .001), whereas pneumonia predominated in adults (54% vs 20%; P < .001). Bacteremia was less common in children than in adults (16% vs 59%; P < .001). Brainstem encephalitis occurred in 3 children without risk factors. Children were more likely to report an inoculating event (42%; P < .001). There was no difference in mortality between the groups (P = .178), with 3 children dying (7%); all had identifiable risk factors. Four children with cutaneous melioidosis were successfully treated with oral therapy alone, while 2 had skin lesions that resolved spontaneously. CONCLUSIONS: Pediatric melioidosis commonly manifests as localized cutaneous disease in immunocompetent hosts. The disease can be fatal, especially in individuals with risk factors for disease. Melioidosis with encephalomyelitis can result in severe residual disability. Prompt diagnosis requires a high index of clinical suspicion in endemic areas.

Melioidosis at Royal Darwin Hospital in the big 2009-2010 wet season: comparison with the preceding 20 years.

OBJECTIVE: To compare the unprecedented 91 cases of melioidosis in the Top End of the Northern Territory of Australia from 1 October 2009 to 30 September 2010 with the 540 cases in the preceding 20 years and postulate reasons for this year of very high melioidosis incidence. DESIGN, SETTING AND PARTICIPANTS: Review of prospectively collected data on all patients with culture-confirmed melioidosis at Royal Darwin Hospital, the Top End's tertiary referral centre, since 1 October 1989. MAIN OUTCOME MEASURES: Population-based annual incidence of melioidosis; differences in epidemiology, clinical presentations and outcomes for 2009-2010 compared with the preceding 20 years. RESULTS: In 2009-2010, the estimated population-based incidence of melioidosis was 50.2 cases per 100 000 in the Top End population overall, and 102.4 cases per 100 000 in the Top End Indigenous population. The proportion of patients acquiring melioidosis in the Darwin urban area increased from 49% in 1989-2009 to 65% in 2009-2010 (OR, 1.96; 95% CI, 1.20-3.19). Among the 49 Indigenous Australian patients with melioidosis in 2009-2010, 63% acquired the infection in Darwin, compared with 35% of Indigenous patients in the previous 20 years (OR, 3.17; 95% CI, 1.62-6.24). CONCLUSIONS: In 2009-2010, the Top End had the highest annual incidence of melioidosis documented from anywhere to date. The prominent increase in cases in Darwin was associated with above average rainfall in Darwin during December 2009 to February 2010. The increase in the proportion of Indigenous Australians who acquired melioidosis in Darwin may reflect movement of some Indigenous people into Darwin from remote communities.

The Darwin Prospective Melioidosis Study: a 30-year prospective, observational investigation.

BACKGROUND: The global distribution of melioidosis is under considerable scrutiny, with both unmasking of endemic disease in African and Pacific nations and evidence of more recent dispersal in the Americas. Because of the high incidence of disease in tropical northern Australia, The Darwin Prospective Melioidosis Study commenced in October, 1989. We present epidemiology, clinical features, outcomes, and bacterial genomics from this 30-year study, highlighting changes in the past decade. METHODS: The present study was a prospective analysis of epidemiological, clinical, and laboratory data for all culture-confirmed melioidosis cases from the tropical Northern Territory of Australia from Oct 1, 1989, until Sept 30, 2019. Cases were identified on the basis of culture-confirmed melioidosis, a laboratory-notifiable disease in the Northern Territory of Australia. Patients who were culture-positive were included in the study. Multivariable analysis determined predictors of clinical presentations and outcome. Incidence, survival, and cluster analyses were facilitated by population and rainfall data and genotyping of Burkholderia pseudomallei, including multilocus sequence typing and whole-genome sequencing. FINDINGS: There were 1148 individuals with culture-confirmed melioidosis, of whom 133 (12%) died. Median age was 50 years (IQR 38-60), 48 (4%) study participants were children younger than 15 years of age, 721 (63%) were male individuals, and 600 (52%) Indigenous Australians. All but 186 (16%) had clinical risk factors, 513 (45%) had diabetes, and 455 (40%) hazardous alcohol use. Only three (2%) of 133 fatalities had no identified risk. Pneumonia was the most common presentation occurring in 595 (52%) patients. Bacteraemia occurred in 633 (56%) of 1135 patients, septic shock in 240 (21%) patients, and 180 (16%) patients required mechanical ventilation. Cases correlated with rainfall, with 80% of infections occurring during the wet season (November to April). Median annual incidence was 20·5 cases per 100 000 people; the highest annual incidence in Indigenous Australians was 103·6 per 100 000 in 2011-12. Over the 30 years, annual incidences increased, as did the proportion of patients with diabetes, although mortality decreased to 17 (6%) of 278 patients over the past 5 years. Genotyping of B pseudomallei confirmed case clusters linked to environmental sources and defined evolving and new sequence types. INTERPRETATION: Melioidosis is an opportunistic infection with a diverse spectrum of clinical presentations and severity. With early diagnosis, specific antimicrobial therapy, and state-of-the-art intensive care, mortality can be reduced to less than 10%. However, mortality remains much higher in the many endemic regions where health resources remain scarce. Genotyping of B pseudomallei informs evolving local and global epidemiology. FUNDING: The Australian National Health and Medical Research Council.

Quad bike injuries at an Australian regional hospital: a trauma registry review.

BACKGROUND: Quad bikes are a prominent cause of morbidity and mortality in Australia in both agriculture and recreation. This study describes the clinical and epidemiological characteristics of quad bike injuries at the Royal Darwin Hospital (RDH). METHODS: A retrospective review of the RDH Trauma Registry for all quad bike mechanism of injury from 1 January 2006 to 31 December 2015 was conducted. We analysed patient demographics, remoteness of injury, injury circumstances, patterns and severity of injury, surgical intervention, length of stay and outcome. RESULTS: In total, 186 persons were injured, of whom 81% (n = 150) were male. There was an increase in quad bike incidents during the 10-year study period, and the greatest increase was seen in the 16-30 years age group. When helmet use was recorded, it was low at 36% (n = 47). Alcohol involvement was 40% (n = 74). Cases with alcohol involvement were 10 times less likely to have worn a helmet than those cases without alcohol involvement (95% confidence interval 3.8-29). The median Injury Severity Score was 8 (interquartile range 4-10). The median hospital length of hospital stay was 4 days (interquartile range 3-7). The majority, 57% (n = 106), did not require surgical intervention. The fatality rate was <5%. CONCLUSION: Quad bike incidents presenting to RDH are increasing. This likely corresponds to the increased number of quad bikes in circulation, and has resulted in an increased demand on health care. Alcohol use and a lack of safety equipment continue to be potentially correctable factors.

Burkholderia pseudomallei Lipopolysaccharide Genotype Does Not Correlate With Severity or Outcome in Melioidosis: Host Risk Factors Remain the Critical Determinant.

BACKGROUND: The causative agent of melioidosis is the Gram-negative bacterium Burkholderia pseudomallei. Clinical presentations of melioidosis are notably diverse, with host risk factors considered central to progression from infection to disease and clinical outcome. Ubiquitous and variably present virulence determinants have been described for B pseudomallei, with several variably present minority genotypes associated with specific disease presentations. The lipopolysaccharide (LPS) O-antigen of B pseudomallei is highly diverse with 3 types described. In vitro data suggest differential virulence between LPS types, but it remains unclear whether this LPS O-antigen diversity influences clinical presentation, severity, and outcomes in patients with melioidosis. METHODS: Whole-genome sequencing was performed to assign an LPS type to 1005 consecutive B pseudomallei strains, each corresponding to a melioidosis patient enrolled in the 28-year Darwin Prospective Melioidosis study. Correlations of LPS genotype with clinical parameters was then undertaken. RESULTS: Bivariate analysis demonstrated that mortality and the rates of bacteremia and septic shock were the same for patients with the 2 predominant B pseudomallei LPS genotypes A (87% of cases) and B (12% of all cases). Mortality was 12% and 12%, bacteremia was 57% and 53%, and septic shock was 22% and 18% for LPS A and LPS B, respectively. CONCLUSIONS: Lipopolysaccharide genotype was not associated with melioidosis severity or outcome. These findings suggest that in vitro differential virulence between B pseudomallei LPS genotypes does not translate to clinical significance, and this supports the primary role of host risk factors in determining disease severity and outcomes in melioidosis.

Tracing the environmental footprint of the Burkholderia pseudomallei lipopolysaccharide genotypes in the tropical "Top End" of the Northern Territory, Australia.

The Tier 1 select agent Burkholderia pseudomallei is an environmental bacterium that causes melioidosis, a high mortality disease. Variably present genetic markers used to elucidate strain origin, relatedness and virulence in B. pseudomallei include the Burkholderia intracellular motility factor A (bimA) and filamentous hemagglutinin 3 (fhaB3) gene variants. Three lipopolysaccharide (LPS) O-antigen types in B. pseudomallei have been described, which vary in proportion between Australian and Asian isolates. However, it remains unknown if these LPS types can be used as genetic markers for geospatial analysis within a contiguous melioidosis-endemic region. Using a combination of whole-genome sequencing (WGS), statistical analysis and geographical mapping, we examined if the LPS types can be used as geographical markers in the Northern Territory, Australia. The clinical isolates revealed that LPS A prevalence was highest in the Darwin and surrounds (n = 660; 96% being LPS A and 4% LPS B) and LPS B in the Katherine and Katherine remote and East Arnhem regions (n = 79; 60% being LPS A and 40% LPS B). Bivariate logistics regression of 999 clinical B. pseudomallei isolates revealed that the odds of getting a clinical isolate with LPS B was highest in East Arnhem in comparison to Darwin and surrounds (OR 19.5, 95% CI 9.1-42.0; p<0.001). This geospatial correlation was subsequently confirmed by geographically mapping the LPS type from 340 environmental Top End strains. We also found that in the Top End, the minority bimA genotype bimABm has a similar remote region geographical footprint to that of LPS B. In addition, correlation of LPS type with multi-locus sequence typing (MLST) was strong, and where multiple LPS types were identified within a single sequence type, WGS confirmed homoplasy of the MLST loci. The clinical, sero-diagnostic and vaccine implications of geographically-based B. pseudomallei LPS types, and their relationships to regional and global dispersal of melioidosis, require global collaborations with further analysis of larger clinically and geospatially-linked datasets.

Prognostic value of lung sestamibi uptake in myocardial perfusion imaging of patients with known or suspected coronary artery disease.

OBJECTIVES: We sought to determine whether lung uptake of technetium-99m (99mTc)-based myocardial perfusion tracers predicts cardiac events. BACKGROUND: Increased lung uptake of thallium-201 during myocardial perfusion scintigraphy can predict important clinical outcomes. It is unclear whether lung uptake of 99mTc-based myocardial perfusion tracers can be used in a similar way. METHODS: Stress lung-to-heart ratio (sLHR) was determined in 718 patients undergoing 99mTc-sestamibi single-photon emission computed tomographic stress imaging. The primary outcome was acute myocardial infarction or death. RESULTS: During a mean follow-up of 5.6 years, a primary end point occurred in 114 patients (16%). The sLHR was significantly greater in those with an adverse outcome (p < 0.00001). The likelihood of an adverse outcome increased by a factor of 1.5 (95% confidence interval 1.2 to 1.7) for each standard deviation increase in sLHR after adjustment for all other variables. The sLHR provided a small but significant improvement in risk stratification when added to clinical, stress test, perfusion, and left ventricular volume information (global chi-square 168.6 vs. 150.7, p < 0.00001). CONCLUSIONS: Stress LHR is an adjunctive prognostic measure in patients with known or suspected coronary artery disease.

Prognostic value of automated quantification of 99mTc-sestamibi myocardial perfusion imaging.

UNLABELLED: Although human interpretation of (99m)Tc-sestamibi SPECT myocardial perfusion imaging has been repeatedly validated in the diagnostic and prognostic assessment of coronary artery disease, it remains unclear if automated computer-derived quantitative indices of perfusion have similar or independent prognostic information. METHODS: We studied 718 patients referred for (99m)Tc-sestamibi SPECT myocardial perfusion imaging who were followed for 5.6 +/- 1.1 y (mean +/- SD). The SPECT studies were initially interpreted visually without benefit of computer-based analysis and were then subjected to a blinded reprocessing to extract quantitative indices of perfusion. Follow-up was through the Manitoba Population Health Research Data Repository. Acute myocardial infarction or cardiac death occurred in 79 individuals (11.0% of the cohort). RESULTS: Visual and quantitative categorization of scan perfusion abnormalities showed similar prognostic value for predicting acute myocardial infarction or cardiac death. Discordance between the visual and quantitative categorizations defined a group at intermediate risk. There was a gradient of risk with increasing severity of the summed stress score (SSS) or summed difference score (SDS). The automated SSS and SDS provided incremental prognostic information over that obtained from visual interpretation. CONCLUSION: Automated quantification of (99m)Tc-sestamibi SPECT myocardial perfusion scans provides objective prognostic information and may complement the conventional visual image interpretation.

Ten years of trauma in the 'top end' of the Northern Territory, Australia: a retrospective analysis.

AIM: To examine characteristics of traumatic injury in adults and children at the Royal Darwin Hospital (RDH) over a 10 year period. METHOD: A retrospective review of the RDH Trauma Registry data from 1 January 2003 to 31 December 2012, with analysis of patient demographics, mechanism of injury, Injury Severity Score (ISS), and outcome. PARTICIPANTS: Two thousand seven hundred twenty-five patients with an ISS greater than or equal to 9 and met all other study inclusion criteria. RESULTS: Motor vehicle crashes, assaults and falls consistently remained the three most common mechanisms of injury throughout the 10 year period. Indigenous admissions showed a significant downward trend (p = 0.009). Upward trends were noted in presentations from patients aged greater than 44 (p = 0.002), all-terrain vehicle accidents (p <0.001), and hangings (p = 0.003). No other trends were noted to significant at a p <0.05 level. Admitted Indigenous patients were significantly more likely to be present due to assault (p <0.001) and female patients were more likely to present due to assault, falls and motor vehicle crashes (p <0.01) than their counterparts. CONCLUSION: Presentations for traumatic injury to Royal Darwin Hospital have remained in the most part, consistently stable for the period of 2003-2012. Though there were some increases/decreases in regard to specific demographics and mechanisms, few were found to be statistically significant at a p < 0.05 level.

Bone density monitoring with the total hip site: time for a re-evaluation?

Serial measurement of bone density is important in the clinical management of osteoporosis because it helps to confirm therapeutic response and identify individuals who continue to lose bone density. The lumbar spine is often stated to be the preferred site for monitoring purposes, but much of the supporting information derives from the relatively poor precision of the femoral neck, which is known to be less reproducible than the total hip. The Manitoba Bone Density Program delivers clinical services to the Province of Manitoba, Canada and maintains a detailed quality assurance program. We compared lumbar spine and total hip reproducibility using a pencil-beam scanner (n = 82), a fan-beam scanner (n = 92), and a cross-calibration between the two scanners (n = 61). Each comparison showed significantly lower measurement error at the total hip than at the lumbar spine (p < 0.001). We assessed the likelihood that follow-up measurements would show an absolute difference exceeding the least significant change in routine clinical practice (n = 2412 paired examinations). The total hip measurement detected change more frequently than the lumbar spine in each of these comparisons. In summary, we believe that the total hip site has been undervalued for monitoring purposes and might actually be the preferred site in older individuals with a high prevalence of lumbar spine artifact.

Automated quantification of 99mTc sestamibi myocardial perfusion compared with visual analysis.

OBJECTIVES: The visual interpretation of 99mTc sestamibi single photon emission computed tomography (SPECT) myocardial perfusion images can be challenging due to the quantity of scan information generated, the large number of normal variants, attenuation artifacts and gender differences. The development of automated, computer derived, quantitative indices of perfusion can assist in this interpretation by providing an objective measure. It is important to verify that similar results can be obtained when the software is used in centres outside those where the algorithms were initially developed. Our objective was to assess the degree of concordance between the visual and automated diagnostic assessments of 99mTc sestamibi SPECT. METHODS: We studied 718 patients referred for 99mTc sestamibi SPECT myocardial perfusion imaging. The SPECT studies were initially interpreted visually without benefit of computer based analysis, and were then subjected to blinded reprocessing to extract quantitative indices of perfusion. RESULTS: There was very good agreement between the visual and quantitative diagnostic classifications. When a visual abnormality was taken to be the reference standard, the automated summed stress score (SSS) showed agreement (SSS>3) in 80% (kappa 0.60, P<0.0001). The area under the receiver operating characteristic (ROC) curve was 0.89 (95% confidence interval (CI), 0.86-0.91). Concordance was greater in those with previous myocardial infarction or severe perfusion defects, but was not affected by age, prior revascularization, stress procedure or heart rate. Concordance over the presence or absence of visual reversibility and the summed difference score (SDS) in abnormal scans was slightly lower (overall agreement 73% (kappa 0.36, P<0.00001) and ROC area 0.84 (95% CI, 0.77-0.90)). CONCLUSION: Automated quantification of 99mTc sestamibi SPECT myocardial perfusion with the SSS and SDS provides objective diagnostic information and concordance when compared with conventional visual image interpretation.

Variable virulence factors in Burkholderia pseudomallei (melioidosis) associated with human disease.

Burkholderia pseudomallei is a Gram-negative environmental bacterium that causes melioidosis, a potentially life-threatening infectious disease affecting mammals, including humans. Melioidosis symptoms are both protean and diverse, ranging from mild, localized skin infections to more severe and often fatal presentations including pneumonia, septic shock with multiple internal abscesses and occasionally neurological involvement. Several ubiquitous virulence determinants in B. pseudomallei have already been discovered. However, the molecular basis for differential pathogenesis has, until now, remained elusive. Using clinical data from 556 Australian melioidosis cases spanning more than 20 years, we identified a Burkholderia mallei-like actin polymerization bimA(Bm) gene that is strongly associated with neurological disease. We also report that a filamentous hemagglutinin gene, fhaB3, is associated with positive blood cultures but is negatively correlated with localized skin lesions without sepsis. We show, for the first time, that variably present virulence factors play an important role in the pathogenesis of melioidosis. Collectively, our study provides a framework for assessing other non-ubiquitous bacterial virulence factors and their association with disease, such as candidate loci identified from large-scale microbial genome-wide association studies.

Severity scoring systems: are they internally valid, reliable and predictive of oxygen use in children with acute bronchiolitis?

BACKGROUND: Severity scores are commonly used in research and clinically to assess the severity of bronchiolitis. However, there are limitations as few have been validated. The aim of our study was to: (i) determine the validity and reliability of a bronchiolitis scoring system, and (ii) examine if the score predicted the need for oxygen at 12 and 24 hrs. Children aged <24 months presenting to Royal Darwin Hospital with a clinical diagnosis of bronchiolitis were eligible to participate. STUDY DESIGN: We reviewed published papers that used a bronchiolitis score and summarized the data in a table. We chose the Tal score that was easy to use and encompassed clinically important parameters. Three research nurses, trained to assess children, used two scoring systems (Tal and Modified-Tal; respiratory rate, accessory muscle use, wheezing, cyanosis, and oxygen saturation), blindly evaluated children within 15 min of each other. RESULTS: The children's (n = 115) median age was 5.4 months (IQR 2.9, 10.4); 65% were male and 64% were Indigenous. Internal consistency was excellent (Tal: Cronbach α = 0.66; Modified-Tal: α = 0.70). There was substantial inter-rater agreement; weighted kappa of 0.72 (95% CI: 0.63, 0.83) for Tal and 0.70 (95% CI: 0.63, 0.76) for Modified-Tal. For predicting requirement for oxygen at 12 and 24 hrs; area under receiver operating curve (aROC) was 0.69 (95% CI: 0.13, 1.0) and 0.75 (95% CI: 0.34, 1.0), respectively. CONCLUSION: The Tal and Modified-Tal scoring systems for bronchiolitis is repeatable and can reliably be used in research and clinical practice. Its utility for prediction of O2 requirement is limited.

Prognostic utility of sestamibi lung uptake does not require adjustment for stress-related variables: a retrospective cohort study.

BACKGROUND: Increased 99mTc-sestamibi stress lung-to-heart ratio (sLHR) has been shown to predict cardiac outcomes similar to pulmonary uptake of thallium. Peak heart rate and use of pharmacologic stress affect the interpretation of lung thallium uptake. The current study was performed to determine whether 99mTc-sestamibi sLHR measurements are affected by stress-related variables, and whether this in turn affects prognostic utility. METHODS: sLHR was determined in 718 patients undergoing 99mTc-sestamibi SPECT stress imaging. sLHR was assessed in relation to demographics, hemodynamic variables and outcomes (mean follow up 5.6 +/- 1.1 years). RESULTS: Mean sLHR was slightly greater in males than in females (P < 0.01) and also showed a weak negative correlation with age (P < 0.01) and systolic blood pressure (P < 0.01), but was unrelated to stress method or heart rate at the time of injection. In patients undergoing treadmill exercise, sLHR was also positively correlated with peak workload (P < 0.05) but inversely with double product (P < 0.05). The combined explanatory effect of sex, age and hemodynamic variables on sLHR was less than 10%. The risk of acute myocardial infarction (AMI) or death increased by a factor of 1.7-1.8 for each SD increase in unadjusted sLHR, and was unaffected by adjustment for sex, age and hemodynamic variables (hazard ratios 1.6-1.7). The area under the ROC curve for the unadjusted sLHR was 0.65 (95% CI 0.59-0.71, P < 0.0001) and was unchanged for the adjusted sLHR (0.65, 95% CI 0.61-0.72, P < 0.0001). CONCLUSION: Stress-related variables have only a weak effect on measured sLHR. Unadjusted and adjusted sLHR provide equivalent prognostic information for prediction of AMI or death.