Now showing 1 - 10 of 90
  • Publication
    Journal Article
    The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria: A systematic review and a pooled multicentre individual-patient meta-analysis.
    (2020-10-19)
    Mousa A
    ;
    Al-Taiar A
    ;
    ;
    Badaut C
    ;
    Barber BE
    ;
    Bassat Q
    ;
    Challenger JD
    ;
    Cunnington AJ
    ;
    Datta D
    ;
    Drakeley CJ
    ;
    Ghani AC
    ;
    Gordeuk VR
    ;
    Grigg MJ
    ;
    Hugo P
    ;
    John CC
    ;
    Mayor A
    ;
    Migot-Nabias F
    ;
    Opoka RO
    ;
    Pasvol G
    ;
    Rees C
    ;
    Reyburn H
    ;
    Riley EM
    ;
    Shah BN
    ;
    Sitoe A
    ;
    Sutherland CJ
    ;
    Thuma PE
    ;
    Unger SA
    ;
    Viwami F
    ;
    Walther M
    ;
    Whitty CJM
    ;
    William T
    ;
    Okell LC
    BACKGROUND: Delay in receiving treatment for uncomplicated malaria (UM) is often reported to increase the risk of developing severe malaria (SM), but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as 'test-and-treat' policies administered by community health workers (CHWs). We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with SM. METHODS AND FINDINGS: A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe Plasmodium falciparum malaria that included information on treatment delay, such as fever duration (inception to 22nd September 2017). Studies identified included 5 case-control and 8 other observational clinical studies of SM and UM cases. Risk of bias was assessed using the Newcastle-Ottawa scale, and all studies were ranked as 'Good', scoring ≥7/10. Individual-patient data (IPD) were pooled from 13 studies of 3,989 (94.1% aged <15 years) SM patients and 5,780 (79.6% aged <15 years) UM cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen, and Zambia. Definitions of SM were standardised across studies to compare treatment delay in patients with UM and different SM phenotypes using age-adjusted mixed-effects regression. The odds of any SM phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (odds ratio [OR] = 1.33, 95% CI: 1.07-1.64 for a delay of >24 hours versus ≤24 hours; p = 0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children, with an OR of 2.79 (95% CI:1.92-4.06; p < 0.001) for a delay of 2-3 days and 5.46 (95% CI: 3.49-8.53; p < 0.001) for a delay of >7 days, compared with receiving treatment within 24 hours from symptom onset. We estimate that 42.8% of childhood SMA cases and 48.5% of adult SMA cases in the study areas would have been averted if all individuals were able to access treatment within the first day of symptom onset, if the association is fully causal. In studies specifically recording onset of nonsevere symptoms, long treatment delay was moderately associated with other SM phenotypes (OR [95% CI] >3 to ≤4 days versus ≤24 hours: cerebral malaria [CM] = 2.42 [1.24-4.72], p = 0.01; respiratory distress syndrome [RDS] = 4.09 [1.70-9.82], p = 0.002). In addition to unmeasured confounding, which is commonly present in observational studies, a key limitation is that many severe cases and deaths occur outside healthcare facilities in endemic countries, where the effect of delayed or no treatment is difficult to quantify. CONCLUSIONS: Our results quantify the relationship between rapid access to treatment and reduced risk of severe disease, which was particularly strong for SMA. There was some evidence to suggest that progression to other severe phenotypes may also be prevented by prompt treatment, though the association was not as strong, which may be explained by potential selection bias, sample size issues, or a difference in underlying pathology. These findings may help assess the impact of interventions that improve access to treatment.
      1300
  • Publication
    Journal Article
    Severe Disseminated Gonococcal Infection with Polyarticular Gout: Two Cases in Older Travelers.
    (2018-11-19)
    Smith EL
    ;
    Hodgetts KE
    ;
    ;
    Two male travelers with histories of gout and hazardous alcohol consumption, presented with a triad of severe culture-positive disseminated gonococcal infection, crystal-positive polyarticular gout, and gonococcal soft tissue collections, following unprotected sexual contact in The Philippines. Both men initially attributed symptoms to gout, since their usual joints were affected, but clinical deterioration occurred with self-administration of anti-inflammatory agents alone. The clinical courses were severe and protracted, requiring aggressive management of infection with prolonged intravenous antimicrobials and repeated surgery, and prolonged anti-inflammatory agents for gout. Joint symptom onset in each case occurred within a week of sexual exposure in conjunction with hazardous alcohol ingestion. We speculate that acute dissemination of infection to previously damaged joints triggered polyarticular gout, with progressive infection, exacerbated by unopposed anti-inflammatory agents and delayed antibiotics. Disseminated gonococcal infection can occur with polyarticular gout and delays in recognition and treatment, including while traveling, can lead to severe disease from both.
      1285
  • Publication
    Journal Article
    Epidemiology of community-acquired and nosocomial bloodstream infections in tropical Australia: a 12-month prospective study.
    (2004-07)
    Douglas MW
    ;
    Lum G
    ;
    Roy J
    ;
    Fisher DA
    ;
    ;
    To define the relative incidence of organisms causing blood stream infections in a tropical setting with a very low prevalence of human immunodeficiency virus infection (<1%). A 12-month prospective study of blood stream infections in 2000 at Royal Darwin Hospital in the tropical north of Australia. Significant isolates were grown from 257 sets of blood cultures. Staphylococcus aureus was the most common isolate overall (28%); 26% of these were methicillin-resistant (MRSA). Escherichia coli was the most common cause of community-acquired bacteraemia. Burkholderia pseudomallei caused 32% of community acquired, bacteraemic pneumonia; 6% of bacteraemias overall. Vancomycin-resistant enterococci were not isolated. Crude mortality rates (13% overall; 9% attributable mortality) were lower than in most comparable studies. The major difference between these findings and surveys performed elsewhere is the presence of B. pseudomallei as a significant cause of bacteraemic community-acquired pneumonia. Our results demonstrate the effects of local environmental and patient characteristics on the range of organisms causing blood stream infections, and emphasize the important role of local microbiology laboratories in guiding empiric antibiotic therapy.
      1221
  • Publication
    Journal Article
    Age-Related Clinical Spectrum of Plasmodium knowlesi Malaria and Predictors of Severity.
    (2018-07-18)
    Grigg MJ
    ;
    William T
    ;
    Barber BE
    ;
    Rajahram GS
    ;
    Menon J
    ;
    Schimann E
    ;
    Piera K
    ;
    Wilkes CS
    ;
    Patel K
    ;
    Chandna A
    ;
    Drakeley CJ
    ;
    Yeo TW
    ;
    Plasmodium knowlesi is increasingly reported in Southeast Asia, but prospective studies of its clinical spectrum in children and comparison with autochthonous human-only Plasmodium species are lacking. Over 3.5 years, we prospectively assessed patients of any age with molecularly-confirmed Plasmodium monoinfection presenting to 3 district hospitals in Sabah, Malaysia. Of 481 knowlesi, 172 vivax, and 96 falciparum malaria cases enrolled, 44 (9%), 71 (41%), and 31 (32%) children aged ≤12 years. Median parasitemia was lower in knowlesi malaria (2480/μL [interquartile range, 538-8481/μL]) than in falciparum (9600/μL; P < .001) and vivax malaria. In P. knowlesi, World Health Organization-defined anemia was present in 82% (95% confidence interval [CI], 67%-92%) of children vs 36% (95% CI, 31%-41%) of adults. Severe knowlesi malaria occurred in 6.4% (95% CI, 3.9%-8.3%) of adults but not in children; the commenst severity criterion was acute kideny injury. No patient had coma. Age, parasitemia, schizont proportion, abdominal pain, and dyspnea were independently associated with severe knowlesi malaria, with parasitemia >15000/μL the best predictor (adjusted odds ratio, 16.1; negative predictive value, 98.5%; P < .001). Two knowlesi-related adult deaths occurred (fatality rate: 4.2/1000 adults). Age distribution and parasitemia differed markedly in knowlesi malaria compared to human-only species, with both uncomplicated and severe disease occurring at low parasitemia. Severe knowlesi malaria occurred only in adults; however, anemia was more common in children despite lower parasitemia. Parasitemia independently predicted knowlesi disease severity: Intravenous artesunate is warranted initially for those with parasitemia >15000/μL.
      1351
  • Publication
    Journal Article
    A cluster of melioidosis cases from an endemic region is clonal and is linked to the water supply using molecular typing of Burkholderia pseudomallei isolates.
    (2001-09) ;
    Mayo MJ
    ;
    ;
    Donohoe P
    ;
    Haase A
    ;
    Kemp DJ
    Nine cases of melioidosis with four deaths occurred over a 28-month period in members of a small remote Aboriginal community in the top end of the Northern Territory of Australia. Typing by pulsed-field gel electrophoresis showed isolates of Burkholderia pseudomallei from six of the cases to be clonal and also identical to an isolate from the community water supply, but not to soil isolates. The clonality of the isolates found in this cluster contrasts with the marked genetic diversity of human and environmental isolates found in this region which is hyperendemic for B. pseudomallei. It is possible that the clonal bacteria persisted and were propagated in biofilm in the water supply system. While the exact mode of transmission to humans and the reasons for cessation of the outbreak remain uncertain, contamination of the unchlorinated community water supply is a likely explanation.
      2847
  • Publication
    Journal Article
    A 16-year prospective study of community-onset bacteremic Acinetobacter pneumonia: low mortality with appropriate initial empirical antibiotic protocols.
    (2014-10)
    Davis JS
    ;
    McMillan M
    ;
    Swaminathan A
    ;
    Kelly JA
    ;
    Piera KE
    ;
    ; ;
    The genus Acinetobacter, well known as a nosocomial pathogen, can also cause severe community-onset pneumonia. Previous small case series have suggested fulminant disease and a pooled hospital mortality of > 60%. We conducted a prospective observational study of all episodes of bacteremic, community-onset, and radiologically confirmed pneumonia due to Acinetobacter species at a tertiary referral hospital in tropical Australia from 1997 to 2012 following the introduction of routine empirical treatment protocols covering Acinetobacter. Demographic, clinical, microbiologic, and outcome data were collected. There were 41 episodes of bacteremic community-onset Acinetobacter pneumonia, of which 36 had no indicators suggesting health-care-associated infection. Of these, 38 (93%) were Indigenous Australians, one-half were men, the average age was 44.1 years, and 36 episodes (88%) occurred during the rainy season. All patients had at least one risk factor, with hazardous alcohol intake in 82%. Of the 37 isolates available for molecular speciation, 35 were Acinetobacter baumannii and two were Acinetobacter nosocomialis. All isolates were susceptible in vitro to gentamicin, meropenem, and ciprofloxacin, but only one was fully susceptible to ceftriaxone. ICU admission was required in 80%. All 41 patients received appropriate antibiotics within the first 24 h of admission, and 28- and 90-day mortality were both low at 11%. Community-acquired Acinetobacter pneumonia is a severe disease, with the majority of patients requiring ICU admission. Most patients have risk factors, particularly hazardous alcohol use. Despite this severity, correct initial empirical antibiotic therapy in all patients was associated with low mortality.
      16535
  • Publication
    Journal Article
    Factors that are associated with the risk of acquiring Plasmodium knowlesi malaria in Sabah, Malaysia: a case-control study protocol.
    (2014-08-22)
    Grigg MJ
    ;
    William T
    ;
    Drakeley CJ
    ;
    Jelip J
    ;
    von Seidlein L
    ;
    Barber BE
    ;
    Fornace KM
    ;
    ;
    Yeo TW
    ;
    Cox J
    Plasmodium knowlesi has long been present in Malaysia, and is now an emerging cause of zoonotic human malaria. Cases have been confirmed throughout South-East Asia where the ranges of its natural macaque hosts and Anopheles leucosphyrus group vectors overlap. The majority of cases are from Eastern Malaysia, with increasing total public health notifications despite a concurrent reduction in Plasmodium falciparum and P. vivax malaria. The public health implications are concerning given P. knowlesi has the highest risk of severe and fatal disease of all Plasmodium spp in Malaysia. Current patterns of risk and disease vary based on vector type and competence, with individual exposure risks related to forest and forest-edge activities still poorly defined. Clustering of cases has not yet been systematically evaluated despite reports of peri-domestic transmission and known vector competence for human-to-human transmission. A population-based case-control study will be conducted over a 2-year period at two adjacent districts in north-west Sabah, Malaysia. Confirmed malaria cases presenting to the district hospital sites meeting relevant inclusion criteria will be requested to enrol. Three community controls matched to the same village as the case will be selected randomly. Study procedures will include blood sampling and administration of household and individual questionnaires to evaluate potential exposure risks associated with acquisition of P. knowlesi malaria. Secondary outcomes will include differences in exposure variables between P. knowlesi and other Plasmodium spp, risk of severe P. knowlesi malaria, and evaluation of P. knowlesi case clustering. Primary analysis will be per protocol, with adjusted ORs for exposure risks between cases and controls calculated using conditional multiple logistic regression models. This study has been approved by the human research ethics committees of Malaysia, the Menzies School of Health Research, Australia, and the London School of Hygiene and Tropical Medicine, UK.
      1260
  • Publication
    Journal Article
    The risk of adverse clinical outcomes following treatment of Plasmodium vivax malaria with and without primaquine in Papua, Indonesia.
    (2020-11-11)
    Thriemer K
    ;
    Poespoprodjo J-R
    ;
    Kenangalem E
    ;
    Douglas NM
    ;
    Sugiarto P
    ;
    ;
    Simpson JA
    ;
    The widespread use of primaquine (PQ) radical cure for P. vivax, is constrained by concerns over its safety. We used routinely collected patient data to compare the overall morbidity and mortality in patients treated with and without PQ without prior testing of Glucose-6-Phosphate-Dehydrogenase (G6PD) deficiency in Papua, Indonesia, where there is a low prevalence of G6PD deficiency. Records were collated from patients older than 1 year, with P. vivax infection, who were treated with an artemisinin combination therapy (ACT). The risks of re-presentation, hospitalization, major fall in haemoglobin and death within 30 days were quantified and compared between patients treated with and without PQ using a Cox regression model. In total 26,216 patients with P. vivax malaria presented to the hospital with malaria during the study period. Overall 27.56% (95% Confidence Interval (95%CI): 26.96-28.16) of 21,344 patients treated with PQ re-presented with any illness within 30 days and 1.69% (1.51-1.88) required admission to hospital. The corresponding risks were higher in the 4,872 patients not treated with PQ; Adjusted Hazard Ratio (AHR) = 0.84 (0.79-0.91; p<0.001) and 0.54 (0.41-0.70; p<0.001) respectively. By day 30, 14.15% (12.45-16.05) of patients who had received PQ had a fall in haemoglobin (Hb) below 7g/dl compared to 20.43% (16.67-24.89) of patients treated without PQ; AHR = 0.66 (0.45-0.97; p = 0.033). A total of 75 (0.3%) patients died within 30 days of treatment with a mortality risk of 0.27% (0.21-0.35) in patients treated with PQ, compared to 0.38% (0.24-0.60) without PQ; AHR = 0.79 (0.43-1.45; p = 0.448). In Papua, Indonesia routine administration of PQ radical cure without prior G6PD testing, was associated with lower risk of all cause hospitalization and other serious adverse clinical outcomes. In areas where G6PD testing is not available or cannot be delivered reliably, the risks of drug induced haemolysis should be balanced against the potential benefits of reducing recurrent P. vivax malaria and its associated morbidity and mortality.
      1029
  • Publication
    Journal Article
    Severe malarial thrombocytopenia: a risk factor for mortality in Papua, Indonesia.
    (2015-02-15)
    Lampah DA
    ;
    Yeo TW
    ;
    Malloy M
    ;
    Kenangalem E
    ;
    Douglas NM
    ;
    Ronaldo D
    ;
    Sugiarto P
    ;
    Simpson JA
    ;
    Poespoprodjo JR
    ;
    ;
    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.
      1321
  • Publication
    Journal Article
    Randomized, double-blind, placebo-controlled trial of granulocyte colony-stimulating factor in patients with septic shock.
    (2008-02)
    Stephens DP
    ;
    ;
    Higgins A
    ;
    Bailey M
    ;
    ; ;
    Cheng AC
    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.
      1207