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.

Malaria due to Plasmodium knowlesi is reported throughout South-East Asia, and is the commonest cause of it in Malaysia. P. knowlesi replicates every 24 h and can cause severe disease and death. Current 2010 WHO Malaria Treatment Guidelines have no recommendations for the optimal treatment of non-severe knowlesi malaria. Artemisinin-combination therapies (ACT) and chloroquine have each been successfully used to treat knowlesi malaria; however, the rapidity of parasite clearance has not been prospectively compared. Malaysia's national policy for malaria pre-elimination involves mandatory hospital admission for confirmed malaria cases with discharge only after two negative blood films; use of a more rapidly acting antimalarial agent would have health cost benefits. P. knowlesi is commonly microscopically misreported as P. malariae, P. falciparum or P. vivax, with a high proportion of the latter two species being chloroquine-resistant in Malaysia. A unified ACT-treatment protocol would provide effective blood stage malaria treatment for all Plasmodium species. ACT KNOW, the first randomised controlled trial ever performed in knowlesi malaria, is a two-arm open-label trial with enrolments over a 2-year period at three district sites in Sabah, powered to show a difference in proportion of patients negative for malaria by microscopy at 24 h between treatment arms (clinicaltrials.gov #NCT01708876). Enrolments started in December 2012, with completion expected by September 2014. A total sample size of 228 is required to give 90% power (α 0.05) to determine the primary end point using intention-to-treat analysis. Secondary end points include parasite clearance time, rates of recurrent infection/treatment failure to day 42, gametocyte carriage throughout follow-up and rates of anaemia at day 28, as determined by survival analysis. This study has been approved by relevant institutional ethics committees in Malaysia and Australia. Results will be disseminated to inform knowlesi malaria treatment policy in this region through peer-reviewed publications and academic presentations. NCT01708876.

Plasmodium vivax causes almost half of all malaria cases in Asia and is recognised as a significant cause of morbidity. In recent years it has been associated with severe and fatal disease. The extent to which P. vivax contributes to death is not known. To define the epidemiology of mortality attributable to vivax malaria in southern Papua, Indonesia, a retrospective clinical records-based audit was conducted of all deaths in patients with vivax malaria at a tertiary referral hospital. Between January 2004 and September 2009, hospital surveillance identified 3,495 inpatients with P. vivax monoinfection and 65 (1.9%) patients who subsequently died. Charts for 54 of these 65 patients could be reviewed, 40 (74%) of whom had pure P. vivax infections on cross-checking. Using pre-defined conservative criteria, vivax malaria was the primary cause of death in 6 cases, a major contributor in 17 cases and a minor contributor in a further 13 cases. Extreme anaemia was the most common primary cause of death. Malnutrition, sepsis with respiratory and gastrointestinal manifestations, and chronic diseases were the commonest attributed causes of death for patients in the latter two categories. There were an estimated 293,763 cases of pure P. vivax infection in the community during the study period giving an overall minimum case fatality of 0.12 per 1,000 infections. The corresponding case fatality in hospitalised patients was 10.3 per 1,000 infections. Although uncommonly directly fatal, vivax malaria is an important indirect cause of death in southern Papua in patients with malnutrition, sepsis syndrome and chronic diseases, including HIV infection.

To investigate the effect of early administration of granulocyte colony-stimulating factor (G-CSF) on hospital mortality in nonneutropenic patients with septic shock, excluding patients with melioidosis. A randomized, placebo-controlled, double-blinded clinical trial. Adult patients with septic shock admitted to the Royal Darwin Hospital Intensive Care Unit. Patients were randomized to receive G-CSF or placebo intravenously daily for 10 days, in addition to routine management of septic shock. Primary outcome was hospital mortality. Secondary outcomes included intensive care unit mortality, intensive care unit and hospital length of stay, ventilator hours, and time to resolution of shock. Patient comorbidities, baseline and daily physiology, and organ function were collected. Of 166 patients enrolled, 83 were allocated to receive G-CSF (81 included in analysis) and 83 were allocated to receive placebo. At baseline, 30% of patients had diabetes, 18% were known to have renal impairment or failure, and 38% had a history of hazardous alcohol use. The two groups had similar comorbidities at baseline and a similar severity of illness. The in-hospital mortality was 27% in the G-CSF group and 25% in the placebo group. Secondary end points were not different between groups. There was a higher rate of new organ failure in G-CSF-treated patients than placebo-treated patients (50% vs. 33%, p = .03), most of which was accounted for by new liver dysfunction (11% vs. 1%, p = .007). There was no significant difference in the proportion of patients with troponin I of >0.08 mg/L (78% vs. 66%, p = .09), and the prevalence of acute myocardial infarction (6% vs. 4%, p = .55) was not different during the study. The median peak troponin I level was higher in the G-CSF group (0.5 vs. 0.14 mg/L, p = .007), but baseline levels were not available. G-CSF does not improve outcomes in patients with septic shock, excluding melioidosis. Increased hepatic dysfunction and higher peak troponin levels in patients receiving G-CSF have not been reported in previous clinical trials and warrant further investigation.

The significance of thrombocytopenia to the morbidity and mortality of malaria is poorly defined. We compared the platelet counts and clinical correlates of patients with and those without malaria in southern Papua, Indonesia. Data were collated on patients presenting to a referral hospital between April 2004 and December 2012. Platelet measurements were available in 215 479 patients (23.4%), 66 421 (30.8%) of whom had clinical malaria. Patients with Plasmodium falciparum monoinfection had the lowest platelet counts and greatest risk of severe thrombocytopenia (platelet count, <50,000 platelets/µL), compared with those without malaria (adjusted odds ratio [OR], 6.03; 95% confidence interval [CI], 5.77-6.30]). The corresponding risks were 5.4 (95% CI, 5.02-5.80) for mixed infections, 3.73 (95% CI, 3.51-3.97) for Plasmodium vivax infection, and 2.16 (95% CI, 1.78-2.63) for Plasmodium malariae infection (P<.001). In total, 1.3% of patients (2701 of 215 479) died. Patients with severe malarial anemia alone (hemoglobin level, <5 g/dL) had an adjusted OR for death of 4.93 (95% CI, 3.79-6.42), those with severe malarial thrombocytopenia alone had an adjusted OR of 2.77 (95% CI, 2.20-3.48), and those with both risk factors had an adjusted OR of 13.76 (95% CI, 10.22-18.54; P<.001). Severe thrombocytopenia identifies both children and adults at increased risk of death from falciparum or vivax malaria, particularly in those with concurrent severe anemia.

Plasmodium knowlesi causes severe malaria, but its pathogenesis is poorly understood. Retinal changes provide insights into falciparum malaria pathogenesis but have not been studied in knowlesi malaria. An observational study was conducted in Malaysian adults hospitalized with severe (n = 20) and nonsevere (n = 24) knowlesi malaria using indirect ophthalmoscopy (n = 44) and fundus photography (n = 29). The patients' median age was 44 years (range, 18-74 years). No coma or deaths occurred. Photography detected retinal changes in 11 of 12 patients (92%) with severe and 14 of 17 (82%) with nonsevere knowlesi malaria. Nonspecific retinal whitening occurred in 3 (35%) and 5 (29%) patients with severe and nonsevere disease, respectively; hemorrhages in 2 (17%) and 3 (18%); loss of retinal pigment epithelium in 1 (8%) and 4 (24%); and drusen in 9 (71%) and 12 (75%). All changes were mild, with no significant differences between severe and nonsevere disease. Patients with retinal hemorrhages had lower platelet counts than those without (median, 22 vs 43 × 10(9)/L; P= .04). The paucity of specific retinal findings associated with disease severity in knowlesi malaria contrasts with the retinopathy of severe adult falciparum malaria with and without coma, suggesting that falciparum-like microvascular sequestration in the brain is not a major component in severe knowlesi malaria pathogenesis.

To describe the clinical and epidemiological features of sepsis and severe sepsis in the population of the tropical Top End of the Northern Territory of Australia and compare these with published estimates for temperate Australia, the United States and Europe. Prospective cohort study in the major hospital for tropical NT, a region where 27% of the population are Indigenous. We screened all adult (≥ 15 years) acute hospital admissions over a 12-month period (6 May 2007-5 May 2008) for sepsis by standard criteria, and collected standardised clinical data. Population-based incidence of community-onset sepsis and severe sepsis requiring intensive care unit (ICU) admission; 28-day mortality rate and microbial epidemiology. There were 1191 hospital admissions for sepsis in 1090 patients, of which 604 (50.7%) were Indigenous people; the average age was 46.7 years. The age-adjusted annual population-based incidence of sepsis was 11.8 admissions per 1000 (mortality rate, 5.4%), but for Indigenous people it was 40.8 per 1000 (mortality rate, 5.7%). For severe sepsis requiring ICU admission, the incidence was 1.3 per 1000 per year (mortality rate, 21.5%), with an Indigenous rate of 4.7 per 1000 (mortality rate, 19.3%). The incidence of sepsis in the tropical NT is substantially higher than that for temperate Australia, the United States and Europe, and these differences are mainly accounted for by the high rates of sepsis in Indigenous people. The findings support strategies to improve housing and access to health services, and reduce comorbidities, alcohol and tobacco use in Indigenous Australians. The burden of sepsis in indigenous populations worldwide requires further study to guide appropriate resourcing of health care and preventive strategies.

Plasmodium malariae is a slow-growing parasite with a wide geographic distribution. Although generally regarded as a benign cause of malaria, it has been associated with nephrotic syndrome, particularly in young children, and can persist in the host for years. Morbidity associated with P. malariae infection has received relatively little attention, and the risk of P. malariae-associated nephrotic syndrome is unknown. We used data from a very large hospital-based surveillance system incorporating information on clinical diagnoses, blood cell parameters and treatment to describe the demographic distribution, morbidity and mortality associated with P. malariae infection in southern Papua, Indonesia. Between April 2004 and December 2013 there were 1,054,674 patient presentations to Mitra Masyarakat Hospital of which 196,380 (18.6%) were associated with malaria and 5,097 were with P. malariae infection (constituting 2.6% of all malaria cases). The proportion of malaria cases attributable to P. malariae increased with age from 0.9% for patients under one year old to 3.1% for patients older than 15 years. Overall, 8.5% of patients with P. malariae infection required admission to hospital and the median length of stay for these patients was 2.5 days (Interquartile Range: 2.0-4.0 days). Patients with P. malariae infection had a lower mean hemoglobin concentration (9.0 g/dL) than patients with P. falciparum (9.5 g/dL), P. vivax (9.6g/dL) and mixed species infections (9.3g/dL). There were four cases of nephrotic syndrome recorded in patients with P. malariae infection, three of which were in children younger than 5 years old, giving a risk in this age group of 0.47% (95% Confidence Interval; 0.10% to 1.4%). Overall, 2.4% (n = 16) of patients hospitalized with P. malariae infection subsequently died in hospital, similar to the proportions for the other endemic Plasmodium species (range: 0% for P. ovale to 1.6% for P. falciparum). Plasmodium malariae infection is relatively uncommon in Papua, Indonesia but is associated with significant morbidity from anemia and a similar risk of mortality to patients hospitalized with P. falciparum and P. vivax infection. In our large hospital database, one in 200 children under the age of 5 years with P. malariae infection were recorded as having nephrotic syndrome.

Endothelial nitric oxide (NO) bioavailability, microvascular function, and host oxygen consumption have not been assessed in pediatric malaria. We measured NO-dependent endothelial function by using peripheral artery tonometry to determine the reactive hyperemia index (RHI), and microvascular function and oxygen consumption (VO2) using near infrared resonance spectroscopy in 13 Indonesian children with severe falciparum malaria and 15 with moderately severe falciparum malaria. Compared with 19 controls, children with severe malaria and those with moderately severe malaria had lower RHIs (P = .03); 12% and 8% lower microvascular function, respectively (P = .03); and 29% and 25% higher VO2, respectively. RHIs correlated with microvascular function in all children with malaria (P < .001) and all with severe malaria (P < .001). Children with malaria have decreased endothelial and microvascular function and increased oxygen consumption, likely contributing to the pathogenesis of the disease.

Chloroquine (CQ)-resistant Plasmodium vivax is increasingly reported throughout southeast Asia. The efficacy of CQ and alternative artemisinin combination therapies (ACTs) for vivax malaria in Malaysia is unknown. A randomized, controlled trial of CQ vs artesunate-mefloquine (AS-MQ) for uncomplicated vivax malaria was conducted in 3 district hospitals in Sabah, Malaysia. Primaquine was administered on day 28. The primary outcome was the cumulative risk of treatment failure by day 28 by Kaplan-Meier analysis. From 2012 to 2014, 103 adults and children were enrolled. Treatment failure by day 28 was 61.1% (95% confidence interval [CI], 46.8-75.6) after CQ and 0% (95% CI, 0-.08) following AS-MQ (P < .001), of which 8.2% (95% CI, 2.5-9.6) were early treatment failures. All patients with treatment failure had therapeutic plasma CQ concentrations at day 7. Compared with CQ, AS-MQ was associated with faster parasite clearance (normalized clearance slope, 0.311 vs 0.127; P < .001) and fever clearance (mean, 19.0 vs 37.7 hours; P =001) and with lower risk of anemia at day 28 (odds ratio = 3.7; 95% CI, 1.5-9.3; P =005). Gametocytes were present at day 28 in 23.8% (10/42) of patients following CQ vs none with AS-MQ (P < .001). AS-MQ resulted in lower bed occupancy: 4037 vs 6510 days/1000 patients (incidence rate ratio 0.62; 95% CI, .60-.65; P < .001). One patient developed severe anemia not regarded as related to their AS-MQ treatment. High-grade CQ-resistant P. vivax is prevalent in eastern Malaysia. AS-MQ is an efficacious ACT for all malaria species. Wider CQ-efficacy surveillance is needed in vivax-endemic regions with earlier replacement with ACT when treatment failure is detected.Clinical Trials Registration NCT01708876.