Professor Richard J Maude

Research Area: Global Health
Technology Exchange: Bioinformatics, Computational biology, In vivo imaging, Medical statistics, SNP typing and Statistical genetics
Scientific Themes: Tropical Medicine & Global Health and Clinical Trials & Epidemiology
Keywords: malaria, epidemiology, modelling, pathogenesis, GIS, artemisinin, elimination and clinical trial
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Professor Maude is Head of Epidemiology at Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand and Associate Professor in Tropical Medicine at the University of Oxford, Honorary Consultant Physician at the John Radcliffe Hospital in Oxford and a Visiting Scientist at Harvard TH Chan School of Public Health, Harvard University, Boston, USA. He has worked at Mahidol-Oxford Tropical Medicine Research Unit since 2007.

His research combines clinical studies, descriptive epidemiology and mathematical modelling of communicable diseases in South and Southeast Asia. His areas of interest include spatiotemporal epidemiology, GIS mapping and population movement, malaria parasite genetics, population dynamic mathematical modelling of artemisinin resistance and malaria elimination, and clinical studies on severe malaria pathogenesis and treatment, malaria diagnosis and antimalarial drug resistance.

Name Department Institution Country
Professor Caroline Buckee Center for Communicable Disease Dynamics, Epidemiology Harvard School of Public Health United States
Professor Nicholas Anstey International Health Division, Menzies School of Health Research Australia
Dr Nicholas AV Beare Ophthalmology University of Liverpool United Kingdom
Professor Baljean Dhillon Clinical Ophthalmology University of Edinburgh United Kingdom
Professor M Abul Faiz FRCP Medicine Sir Salimullah Medical College Bangladesh
Professor Md. Amir Hossain Department of Medicine Chittagong Medical College Bangladesh
Professor Dominic Kwiatkowski Wellcome Trust Centre for Human Genetics Oxford University, Henry Wellcome Building of Genomic Medicine United Kingdom
Professor Sanjib Mohanty Ispat General Hospital India
Dr Chea Nguon National Centre for Parasitology, Entomology and Malaria Control Cambodia
Dr Po Ly Teng National Centre for Parasitology, Entomology and Malaria Control Cambodia
Dr Jetsumon Sattabongkot Prachumsri Mahidol Vivax Research Unit Thailand
Professor Olivo Miotto Tropical Medicine Oxford University, Bangkok Thailand
Professor Lisa J White Tropical Medicine Oxford University, Bangkok Thailand
Stefan Jaeger Lister Hill Institute National Library of Medicine/National Institutes of Health United States
Dr Ricardo J Aguas Tropical Medicine Oxford University, Bangkok Thailand
Professor Philippe J Guerin Tropical Medicine Oxford University, NDM Research Building United Kingdom
Professor Peter Gething Big Data Institute Oxford University, Henry Wellcome Building of Genomic Medicine United Kingdom
Professor Joel Tarning Tropical Medicine Oxford University, Bangkok Thailand
Dr Sasithon Pukritayakamee Tropical Medicine Oxford University, Bangkok Thailand
Dr Kesinee Chotivanich Tropical Medicine Oxford University, Bangkok Thailand
Dr Caterina A Fanello Tropical Medicine Oxford University, Kinshasa Congo DR
Dr Mehul Dhorda Tropical Medicine Oxford University, Bangkok Thailand
Tripura R, Peto TJ, Veugen CC, Nguon C, Davoeung C, James N, Dhorda M, Maude RJ, Duanguppama J, Patumrat K et al. 2017. Submicroscopic Plasmodium prevalence in relation to malaria incidence in 20 villages in western Cambodia. Malar J, 16 (1), pp. 56. | Show Abstract | Read more

BACKGROUND: Cambodia has seen a marked reduction in the incidence of Plasmodium falciparum over the past decade without a corresponding decline in Plasmodium vivax incidence. It is unknown to what extent local transmission is sustained by a chain of clinical and sub-clinical infections or by continued re-introduction via migration. Using an ultrasensitive molecular technique, 20 villages in western Cambodia were surveyed to detect the low season prevalence of P. falciparum and P. vivax and local treatment records were reviewed. METHODS: During March to May 2015 cross-sectional surveys were conducted in 20 villages in Battambang, western Cambodia. Demographic and epidemiological data and venous blood samples were collected from 50 randomly selected adult volunteers in each village. Blood was tested for Plasmodium infections by rapid diagnostic test (RDT), microscopy and high volume (0.5 ml packed red blood cell) quantitative polymerase chain reaction (uPCR). Positive samples were analysed by nested PCR to determine the Plasmodium species. Malaria case records were collected from the Provincial Health Department and village malaria workers to determine incidence and migration status. RESULTS: Among the 1000 participants, 91 (9.1%) were positive for any Plasmodium infection by uPCR, seven (0.7%) by microscopy, and two (0.2%) by RDT. uPCR P. vivax prevalence was 6.6%, P. falciparum 0.7%, and undetermined Plasmodium species 1.8%. Being male (adjusted OR 2.0; 95% CI 1.2-3.4); being a young adult <30 years (aOR 2.1; 95% CI 1.3-3.4); recent forest travel (aOR 2.8; 95% CI 1.6-4.8); and, a history of malaria (aOR 5.2; 95% CI 2.5-10.7) were independent risk factors for parasitaemia. Of the clinical malaria cases diagnosed by village malaria workers, 43.9% (297/634) and 38.4% (201/523) were among migrants in 2013 and in 2014, respectively. Plasmodium vivax prevalence determined by uPCR significantly correlated with vivax malaria incidences in both 2014 and 2015 (p = 0.001 and 0.002, respectively), whereas no relationship was observed in falciparum malaria (p = 0.36 and p = 0.59, respectively). DISCUSSION: There was heterogeneity in the malaria parasite reservoir between villages, and Plasmodium prevalence correlated with subsequent malaria incidence. The association was attributable chiefly to P. vivax infections, which were nine-fold more prevalent than P. falciparum infections. In the absence of a radical cure with 8-aminoquinolines, P. vivax transmission will continue even as P. falciparum prevalence declines. Migration was associated with over a third of incident cases of clinical malaria. Trial registration clinicaltrials.gov (NCT01872702). Registered 4 June 2013.

Brady OJ, Slater HC, Pemberton-Ross P, Wenger E, Maude RJ, Ghani AC, Penny MA, Gerardin J, White LJ, Chitnis N et al. 2017. Model citizen - Authors' reply. Lancet Glob Health, 5 (10), pp. e974. | Read more

Brady OJ, Slater HC, Pemberton-Ross P, Wenger E, Maude RJ, Ghani AC, Penny MA, Gerardin J, White LJ, Chitnis N et al. 2017. Role of mass drug administration in elimination of Plasmodium falciparum malaria: a consensus modelling study. Lancet Glob Health, 5 (7), pp. e680-e687. | Show Abstract | Read more

BACKGROUND: Mass drug administration for elimination of Plasmodium falciparum malaria is recommended by WHO in some settings. We used consensus modelling to understand how to optimise the effects of mass drug administration in areas with low malaria transmission. METHODS: We collaborated with researchers doing field trials to establish a standard intervention scenario and standard transmission setting, and we input these parameters into four previously published models. We then varied the number of rounds of mass drug administration, coverage, duration, timing, importation of infection, and pre-administration transmission levels. The outcome of interest was the percentage reduction in annual mean prevalence of P falciparum parasite rate as measured by PCR in the third year after the final round of mass drug administration. FINDINGS: The models predicted differing magnitude of the effects of mass drug administration, but consensus answers were reached for several factors. Mass drug administration was predicted to reduce transmission over a longer timescale than accounted for by the prophylactic effect alone. Percentage reduction in transmission was predicted to be higher and last longer at lower baseline transmission levels. Reduction in transmission resulting from mass drug administration was predicted to be temporary, and in the absence of scale-up of other interventions, such as vector control, transmission would return to pre-administration levels. The proportion of the population treated in a year was a key determinant of simulated effectiveness, irrespective of whether people are treated through high coverage in a single round or new individuals are reached by implementation of several rounds. Mass drug administration was predicted to be more effective if continued over 2 years rather than 1 year, and if done at the time of year when transmission is lowest. INTERPRETATION: Mass drug administration has the potential to reduce transmission for a limited time, but is not an effective replacement for existing vector control. Unless elimination is achieved, mass drug administration has to be repeated regularly for sustained effect. FUNDING: Bill & Melinda Gates Foundation.

Plewes K, Kingston HWF, Ghose A, Maude RJ, Herdman MT, Leopold SJ, Ishioka H, Hasan MMU, Haider MS, Alam S et al. 2017. Cell-free hemoglobin mediated oxidative stress is associated with acute kidney injury and renal replacement therapy in severe falciparum malaria: an observational study. BMC Infect Dis, 17 (1), pp. 313. | Show Abstract | Read more

BACKGROUND: Intravascular hemolysis is an intrinsic feature of severe malaria pathophysiology but the pathogenic role of cell-free hemoglobin-mediated oxidative stress in severe malaria associated acute kidney injury (AKI) is unknown. METHODS: As part of a prospective observational study, enrolment plasma cell-free hemoglobin (CFH), lipid peroxidation markers (F2-isoprostanes (F2-IsoPs) and isofurans (IsoFs)), red cell deformability, and serum creatinine were quantified in Bangladeshi patients with severe falciparum malaria (n = 107), uncomplicated malaria (n = 80) and sepsis (n = 28). The relationships between these indices and kidney function and clinical outcomes were examined. RESULTS: AKI was diagnosed at enrolment in 58% (62/107) of consecutive patients with severe malaria, defined by an increase in creatinine ≥1.5 times expected baseline. Severe malaria patients with AKI had significantly higher plasma cell-free hemoglobin (geometric mean CFH: 8.8 μM; 95% CI, 6.2-12.3 μM), F2-isoprostane (56.7 pg/ml; 95% CI, 45.3-71.0 pg/ml) and isofuran (109.2 pg/ml; 95% CI, 85.1-140.1 pg/ml) concentrations on enrolment compared to those without AKI (CFH: 5.1 μM; 95% CI, 4.0-6.6 μM; P = 0.018; F2-IsoPs: 27.8 pg/ml; 95% CI, 23.7-32.7 pg/ml; P < 0.001; IsoFs: 41.7 pg/ml; 95% CI, 30.2-57.6 pg/ml; P < 0.001). Cell-free hemoglobin correlated with markers of hemolysis, parasite burden (P. falciparum histidine rich protein 2 (PfHRP2)), and F2-IsoPs. Plasma F2-IsoPs and IsoFs inversely correlated with pH, positively correlated with creatinine, PfHRP2 and fractional excretion of sodium, and were higher in patients later requiring hemodialysis. Plasma F2-IsoP concentrations also inversely correlated with red cell deformability and were higher in fatal cases. Mixed effects modeling including an interaction term for CFH and time showed that F2-IsoPs, IsoFs, PfHRP2, CFH, and red cell rigidity were independently associated with increasing creatinine over 72 h. Multivariable logistic regression showed that admission F2-IsoPs, IsoFs and red cell deformability were associated with the need for subsequent hemodialysis. CONCLUSIONS: Cell-free hemoglobin and lipid peroxidation are associated with acute kidney injury and disease severity in falciparum malaria, suggesting a pathophysiological role in renal tubular injury. Evaluation of adjunctive therapies targeting cell-free hemoglobin-mediated oxidative stress is warranted.

Mercado CE, Ekapirat N, Dondorp AM, Maude RJ. 2017. An assessment of national surveillance systems for malaria elimination in the Asia Pacific. Malar J, 16 (1), pp. 127. | Show Abstract | Read more

BACKGROUND: Heads of Government from Asia and the Pacific have committed to a malaria-free region by 2030. In 2015, the total number of confirmed cases reported to the World Health Organization by 22 Asia Pacific countries was 2,461,025. However, this was likely a gross underestimate due in part to incidence data not being available from the wide variety of known sources. There is a recognized need for an accurate picture of malaria over time and space to support the goal of elimination. A survey was conducted to gain a deeper understanding of the collection of malaria incidence data for surveillance by National Malaria Control Programmes in 22 countries identified by the Asia Pacific Leaders Malaria Alliance. METHODS: In 2015-2016, a short questionnaire on malaria surveillance was distributed to 22 country National Malaria Control Programmes (NMCP) in the Asia Pacific. It collected country-specific information about the extent of inclusion of the range of possible sources of malaria incidence data and the role of the private sector in malaria treatment. The findings were used to produce recommendations for the regional heads of government on improving malaria surveillance to inform regional efforts towards malaria elimination. RESULTS: A survey response was received from all 22 target countries. Most of the malaria incidence data collected by NMCPs originated from government health facilities, while many did not collect comprehensive data from mobile and migrant populations, the private sector or the military. All data from village health workers were included by 10/20 countries and some by 5/20. Other sources of data included by some countries were plantations, police and other security forces, sentinel surveillance sites, research or academic institutions, private laboratories and other government ministries. Malaria was treated in private health facilities in 19/21 countries, while anti-malarials were available in private pharmacies in 16/21 and private shops in 6/21. Most countries use primarily paper-based reporting. CONCLUSIONS: Most collected malaria incidence data in the Asia Pacific is from government health facilities while data from a wide variety of other known sources are often not included in national surveillance databases. In particular, there needs to be a concerted regional effort to support inclusion of data on mobile and migrant populations and the private sector. There should also be an emphasis on electronic reporting and data harmonization across organizations. This will provide a more accurate and up to date picture of the true burden and distribution of malaria and will be of great assistance in helping realize the goal of malaria elimination in the Asia Pacific by 2030.

Jeeyapant A, Kingston HW, Plewes K, Maude RJ, Hanson J, Herdman MT, Leopold SJ, Ngernseng T, Charunwatthana P, Phu NH et al. 2017. Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria. PLoS One, 12 (1), pp. e0169307. | Show Abstract | Read more

BACKGROUND: Clinical trials in severe falciparum malaria require a large sample size to detect clinically meaningful differences in mortality. This means few interventions can be evaluated at any time. Using a validated surrogate endpoint for mortality would provide a useful alternative allowing a smaller sample size. Here we evaluate changes in coma score and plasma lactate as surrogate endpoints for mortality in severe falciparum malaria. METHODS: Three datasets of clinical studies in severe malaria were re-evaluated: studies from Chittagong, Bangladesh (adults), the African 'AQUAMAT' trial comparing artesunate and quinine (children), and the Vietnamese 'AQ' study (adults) comparing artemether with quinine. The absolute change, relative change, slope of the normalization over time, and time to normalization were derived from sequential measurements of plasma lactate and coma score, and validated for their use as surrogate endpoint, including the proportion of treatment effect on mortality explained (PTE) by these surrogate measures. RESULTS: Improvements in lactate concentration or coma scores over the first 24 hours of admission, were strongly prognostic for survival in all datasets. In hyperlactataemic patients in the AQ study (n = 173), lower mortality with artemether compared to quinine closely correlated with faster reduction in plasma lactate concentration, with a high PTE of the relative change in plasma lactate at 8 and 12 hours of 0.81 and 0.75, respectively. In paediatric patients enrolled in the 'AQUAMAT' study with cerebral malaria (n = 785), mortality was lower with artesunate compared to quinine, but this was not associated with faster coma recovery. CONCLUSIONS: The relative changes in plasma lactate concentration assessed at 8 or 12 hours after admission are valid surrogate endpoints for severe malaria studies on antimalarial drugs or adjuvant treatments aiming at improving the microcirculation. Measures of coma recovery are not valid surrogate endpoints for mortality.

Parker DM, Landier J, von Seidlein L, Dondorp A, White L, Hanboonkunupakarn B, Maude RJ, Nosten FH. 2016. Limitations of malaria reactive case detection in an area of low and unstable transmission on the Myanmar-Thailand border. Malar J, 15 (1), pp. 571. | Show Abstract | Read more

BACKGROUND: Reactive case detection is an approach that has been proposed as a tool for malaria elimination in low-transmission settings. It is an intuitively justified approach based on the concept of space-time clustering of malaria cases. When an index malaria clinical case is detected, it triggers reactive screening and treatment in the index house and neighbouring houses. However, the efficacy of this approach at varying screening radii and malaria prevalence remains ill defined. METHODS: Data were obtained from a detailed demographic and geographic surveillance study in four villages on the Myanmar-Thailand border. Clinical cases were recorded at village malaria clinics and were linked back to patients' residencies. These data were used to simulate the efficacy of reactive case detection for clinical cases using rapid diagnostic tests (RDT). Simulations took clinical cases in a given month and tabulated the number of cases that would have been detected in the following month at varying screening radii around the index houses. Simulations were run independently for both falciparum and vivax malaria. Each simulation of a reactive case detection effort was run in comparison with a strategy using random selection of houses for screening. RESULTS: In approximately half of the screenings for falciparum and 10% for vivax it would have been impossible to detect any malaria cases regardless of the screening strategy because the screening would have occurred during times when there were no cases. When geographically linked cases were present in the simulation, reactive case detection would have only been successful at detecting most malaria cases using larger screening radii (150-m radius and above). At this screening radius and above, reactive case detection does not perform better than random screening of an equal number of houses in the village. Screening within very small radii detects only a very small proportion of cases, but despite this low performance is better than random screening with the same sample size. CONCLUSIONS: The results of these simulations indicate that reactive case detection for clinical cases using RDTs has limited ability in halting transmission in regions of low and unstable transmission. This is linked to high spatial heterogeneity of cases, acquisition of malaria infections outside the village, as well missing asymptomatic infections. When cases are few and sporadic, reactive case detection would result in major time and budgetary losses.

Grist EP, Flegg JA, Humphreys G, Mas IS, Anderson TJ, Ashley EA, Day NP, Dhorda M, Dondorp AM, Faiz MA et al. 2016. Optimal health and disease management using spatial uncertainty: a geographic characterization of emergent artemisinin-resistant Plasmodium falciparum distributions in Southeast Asia. Int J Health Geogr, 15 (1), pp. 37. | Show Abstract | Read more

BACKGROUND: Artemisinin-resistant Plasmodium falciparum malaria parasites are now present across much of mainland Southeast Asia, where ongoing surveys are measuring and mapping their spatial distribution. These efforts require substantial resources. Here we propose a generic 'smart surveillance' methodology to identify optimal candidate sites for future sampling and thus map the distribution of artemisinin resistance most efficiently. METHODS: The approach uses the 'uncertainty' map generated iteratively by a geostatistical model to determine optimal locations for subsequent sampling. RESULTS: The methodology is illustrated using recent data on the prevalence of the K13-propeller polymorphism (a genetic marker of artemisinin resistance) in the Greater Mekong Subregion. CONCLUSION: This methodology, which has broader application to geostatistical mapping in general, could improve the quality and efficiency of drug resistance mapping and thereby guide practical operations to eliminate malaria in affected areas.

Maude RR, Ghose A, Samad R, de Jong HK, Fukushima M, Wijedoru L, Hassan MU, Hossain MA, Karim MR, Sayeed AA et al. 2016. A prospective study of the importance of enteric fever as a cause of non-malarial febrile illness in patients admitted to Chittagong Medical College Hospital, Bangladesh. BMC Infect Dis, 16 (1), pp. 567. | Show Abstract | Read more

BACKGROUND: Fever is a common cause of hospital admission in Bangladesh but causative agents, other than malaria, are not routinely investigated. Enteric fever is thought to be common. METHODS: Adults and children admitted to Chittagong Medical College Hospital with a temperature of ≥38.0 °C were investigated using a blood smear for malaria, a blood culture, real-time PCR to detect Salmonella Typhi, S. Paratyphi A and other pathogens in blood and CSF and an NS1 antigen dengue ELISA. RESULTS: We enrolled 300 febrile patients with a negative malaria smear between January and June 2012: 156 children (aged ≤15 years) and 144 adults with a median (interquartile range) age of 13 (5-31) years and median (IQR) illness duration before admission of five (2-8) days. Clinical enteric fever was diagnosed in 52 patients (17.3 %), lower respiratory tract infection in 48 (16.0 %), non-specific febrile illness in 48 (16.0 %), a CNS infection in 37 patients (12.3 %), urinary sepsis in 23 patients (7.7 %), an upper respiratory tract infection in 21 patients (7.0 %), and diarrhea or dysentery in 21 patients (7.0 %). Malaria was still suspected in seven patients despite a negative microscopy test. S. Typhi was detected in blood by culture or PCR in 34 (11.3 %) of patients. Of note Rickettsia typhi and Orientia tsutsugamushi were detected by PCR in two and one patient respectively. Twenty-nine (9 %) patients died during their hospital admission (15/160 (9.4 %) of children and 14/144 (9.7 %) adults). Two of 52 (3.8 %) patients with enteric fever, 5/48 (10.4 %) patients with lower respiratory tract infections, and 12/37 (32.4 %) patients with CNS infection died. CONCLUSION: Enteric fever was confirmed in 11.3 % of patients admitted to this hospital in Bangladesh with non-malaria fever. Lower respiratory tract and CNS infections were also common. CNS infections in this location merit more detailed study due to the high mortality.

Govindasamy G, Barber BE, Ghani SA, William T, Grigg MJ, Borooah S, Dhillon B, Dondorp AM, Yeo TW, Anstey NM, Maude RJ. 2016. Retinal Changes in Uncomplicated and Severe Plasmodium knowlesi Malaria. J Infect Dis, 213 (9), pp. 1476-1482. | Show Abstract | Read more

BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

Ishioka H, Ghose A, Charunwatthana P, Maude R, Plewes K, Kingston H, Intharabut B, Woodrow C, Chotivanich K, Sayeed AA et al. 2016. Sequestration and Red Cell Deformability as Determinants of Hyperlactatemia in Falciparum Malaria. J Infect Dis, 213 (5), pp. 788-793. | Show Abstract | Read more

BACKGROUND: Hyperlactatemia is a strong predictor of mortality in severe falciparum malaria. Sequestered parasitized erythrocytes and reduced uninfected red blood cell deformability (RCD) compromise microcirculatory flow, leading to anaerobic glycolysis. METHODS: In a cohort of patients with falciparum malaria hospitalized in Chittagong, Bangladesh, bulk RCD was measured using a laser diffraction technique, and parasite biomass was estimated from plasma concentrations of Plasmodium falciparum histidine-rich protein 2 (PfHRP2). A multiple linear regression model was constructed to examine their associations with plasma lactate concentrations. RESULTS: A total of 286 patients with falciparum malaria were studied, of whom 224 had severe malaria, and 70 died. Hyperlactatemia (lactate level, ≥ 4 mmol/L) was present in 111 cases. RCD at shear stresses of 1.7 Pa and 30 Pa was reduced significantly in patients who died, compared with survivors, individuals with uncomplicated malaria, or healthy individuals (P < .05, for all comparisons). Multiple linear regression analysis showed that the plasma PfHRP2 level, parasitemia level, total bilirubin level, and RCD at a shear stress of 1.7 Pa were each independently correlated with plasma lactate concentrations (n = 278; R(2) = 0.35). CONCLUSIONS: Sequestration of parasitized red blood cells and reduced RCD both contribute to decreased microcirculatory flow in severe disease.

Herdman MT, Maude RJ, Chowdhury MS, Kingston HW, Jeeyapant A, Samad R, Karim R, Dondorp AM, Hossain MA. 2016. The Relationship between Poverty and Healthcare Seeking among Patients Hospitalized with Acute Febrile Illnesses in Chittagong, Bangladesh. PLoS One, 11 (4), pp. e0152965. | Show Abstract | Read more

Delays in seeking appropriate healthcare can increase the case fatality of acute febrile illnesses, and circuitous routes of care-seeking can have a catastrophic financial impact upon patients in low-income settings. To investigate the relationship between poverty and pre-hospital delays for patients with acute febrile illnesses, we recruited a cross-sectional, convenience sample of 527 acutely ill adults and children aged over 6 months, with a documented fever ≥38.0 °C and symptoms of up to 14 days' duration, presenting to a tertiary referral hospital in Chittagong, Bangladesh, over the course of one year from September 2011 to September 2012. Participants were classified according to the socioeconomic status of their households, defined by the Oxford Poverty and Human Development Initiative's multidimensional poverty index (MPI). 51% of participants were classified as multidimensionally poor (MPI>0.33). Median time from onset of any symptoms to arrival at hospital was 22 hours longer for MPI poor adults compared to non-poor adults (123 vs. 101 hours) rising to a difference of 26 hours with adjustment in a multivariate regression model (95% confidence interval 7 to 46 hours; P = 0.009). There was no difference in delays for children from poor and non-poor households (97 vs. 119 hours; P = 0.394). Case fatality was 5.9% vs. 0.8% in poor and non-poor individuals respectively (P = 0.001)-5.1% vs. 0.0% for poor and non-poor adults (P = 0.010) and 6.4% vs. 1.8% for poor and non-poor children (P = 0.083). Deaths were attributed to central nervous system infection (11), malaria (3), urinary tract infection (2), gastrointestinal infection (1) and undifferentiated sepsis (1). Both poor and non-poor households relied predominantly upon the (often informal) private sector for medical advice before reaching the referral hospital, but MPI poor participants were less likely to have consulted a qualified doctor. Poor participants were more likely to attribute delays in decision-making and travel to a lack of money (P<0.001), and more likely to face catastrophic expenditure of more than 25% of monthly household income (P<0.001). We conclude that multidimensional poverty is associated with greater pre-hospital delays and expenditure in this setting. Closer links between health and development agendas could address these consequences of poverty and streamline access to adequate healthcare.

Tripura R, Peto TJ, Chalk J, Lee SJ, Sirithiranont P, Nguon C, Dhorda M, von Seidlein L, Maude RJ, Day NP et al. 2016. Persistent Plasmodium falciparum and Plasmodium vivax infections in a western Cambodian population: implications for prevention, treatment and elimination strategies. Malar J, 15 (1), pp. 181. | Show Abstract | Read more

BACKGROUND: Subclinical Plasmodium parasitaemia is an important reservoir for the transmission and persistence of malaria, particularly in low transmission areas. METHODS: Using ultrasensitive quantitative PCR (uPCR) for the detection of parasitaemia, the entire population of three Cambodian villages in Pailin province were followed for 1 year at three-monthly intervals. A cohort of adult participants found initially to have asymptomatic malaria parasitaemia was followed monthly over the same period. RESULTS: The initial cross sectional survey in June 2013 (M0) of 1447 asymptomatic residents found that 32 (2.2%) had Plasmodium falciparum, 48 (3.3%) had P. vivax, 4 (0.3%) had mixed infections and in 142/1447 (9.8%) malaria was detected but there was insufficient DNA to identify the species (Plasmodium. species). Polymorphisms in the 'K13-propeller' associated with reduced susceptibility to artemisinin derivatives (C580Y) were found in 17/32 (51%) P. falciparum strains. Monthly follow-up without treatment of 24 adult participants with asymptomatic mono or mixed P. falciparum infections found that 3/24 (13%) remained parasitaemic for 2-4 months, whereas the remaining 21/24 (87%) participants had cleared their parasitaemia after 1 month. In contrast, 12/34 (35%) adult participants with P. vivax mono-infection at M0 had malaria parasites (P. vivax or P. sp.) during four or more of the following 11 monthly surveys. CONCLUSIONS: This longitudinal survey in a low transmission setting shows limited duration of P. falciparum carriage, but prolonged carriage of P. vivax infections. Radical treatment of P. vivax infections by 8-aminoquinoline regimens may be required to eliminate all malaria from Cambodia. Trial registration ClinicalTrials.gov NCT01872702.

Plewes K, Maude RJ, Ghose A, Dondorp AM. 2015. Severe falciparum malaria complicated by prolonged haemolysis and rhinomaxillary mucormycosis after parasite clearance: a case report. BMC Infect Dis, 15 (1), pp. 555. | Show Abstract | Read more

BACKGROUND: Severe falciparum malaria may be complicated by prolonged haemolysis and recurrent fever after parasite clearance. However, their respective etiologies are unclear and challenging to diagnose. We report the first case of severe falciparum malaria followed by prolonged haemolytic anaemia and rhinomaxillary mucormycosis in a previously healthy adult male. CASE PRESENTATION: A 30-year old Bangladeshi man was admitted with severe falciparum malaria complicated by hyperlactataemia and haemoglobinuria. Prior to admission he was treated with intravenous quinine and upon admission received intravenous artesunate and empiric ceftriaxone. Thirty hours later the peripheral parasitaemia cleared with resolution of fever and haemoglobinuria. Despite parasite clearance, on day 3 the patient developed recurrent fever and acute haemolytic anaemia requiring seven blood transfusions over six days with no improvement of his haemoglobin or haemoglobinuria. On day 10, he was treated with high-dose dexamethasone and meropenem with discontinuation of the ceftriaxone. Two days later the haemoglobinuria resolved. Ceftriaxone-induced haemolysis was the suspected final diagnosis. On day 16, the patient had progressively worsening right-sided facial pain and swelling; a necrotic ulceration of the hard palate was observed. Rhinomaxillary mucormycosis was diagnosed supported by microscopy findings. The patient initially responded to treatment with urgent surgical debridement, itraconazole, followed by two weeks of amphotericin B deoxycholate, however was subsequently lost to follow up. CONCLUSIONS: This case highlights the range of potential alternative aetiologies of acute, prolonged haemolysis and recurrent fever following parasite clearance in severe falciparum malaria. It emphasizes the importance of a high degree of suspicion for alternative causes of haemolysis in order to avoid unnecessary treatments, including blood transfusion and steroids. It is critical to consider and identify common invasive bacterial and rare opportunistic co-infections as a cause of fever in severe malaria patients remaining febrile after parasite clearance to promote antimicrobial stewardship and prompt emergency care.

MacCormick IJ, Maude RJ, Beare NA, Borooah S, Glover S, Parry D, Leach S, Molyneux ME, Dhillon B, Lewallen S, Harding SP. 2015. Grading fluorescein angiograms in malarial retinopathy. Malar J, 14 (1), pp. 367. | Show Abstract | Read more

BACKGROUND: Malarial retinopathy is an important finding in Plasmodium falciparum cerebral malaria, since it strengthens diagnostic accuracy, predicts clinical outcome and appears to parallel cerebral disease processes. Several angiographic features of malarial retinopathy have been described, but observations in different populations can only be reliably compared if consistent methodology is used to capture and grade retinal images. Currently no grading scheme exists for fluorescein angiographic features of malarial retinopathy. METHODS: A grading scheme for fluorescein angiographic images was devised based on consensus opinion of clinicians and researchers experienced in malarial retinopathy in children and adults. Dual grading were performed with adjudication of admission fluorescein images from a large cohort of children with cerebral malaria. RESULTS: A grading scheme is described and standard images are provided to facilitate future grading studies. Inter-grader agreement was >70 % for most variables. Intravascular filling defects are difficult to grade and tended to have lower inter-grader agreement (>57 %) compared to other features. CONCLUSIONS: This grading scheme provides a consistent way to describe retinal vascular damage in paediatric cerebral malaria, and can facilitate comparisons of angiographic features of malarial retinopathy between different patient groups, and analysis against clinical outcomes. Inter-grader agreement is reasonable for the majority of angiographic signs. Dual grading with expert adjudication should be used to maximize accuracy.

Herdman MT, Sriboonvorakul N, Leopold SJ, Douthwaite S, Mohanty S, Hassan MM, Maude RJ, Kingston HW, Plewes K, Charunwatthana P et al. 2015. Erratum to: the role of previously unmeasured organic acids in the pathogenesis of severe malaria. Crit Care, 19 (1), pp. 382. | Read more

Herdman MT, Sriboonvorakul N, Leopold SJ, Douthwaite S, Mohanty S, Hassan MM, Maude RJ, Kingston HW, Plewes K, Charunwatthana P et al. 2015. The role of previously unmeasured organic acids in the pathogenesis of severe malaria. Crit Care, 19 (1), pp. 317. | Show Abstract | Read more

INTRODUCTION: Severe falciparum malaria is commonly complicated by metabolic acidosis. Together with lactic acid (LA), other previously unmeasured acids have been implicated in the pathogenesis of falciparum malaria. METHODS: In this prospective study, we characterised organic acids in adults with severe falciparum malaria in India and Bangladesh. Liquid chromatography-mass spectrometry was used to measure organic acids in plasma and urine. Patients were followed until recovery or death. RESULTS: Patients with severe malaria (n=138), uncomplicated malaria (n=102), sepsis (n=32) and febrile encephalopathy (n=35) were included. Strong ion gap (mean ± SD) was elevated in severe malaria (8.2 mEq/L ± 4.5) and severe sepsis (8.6 mEq/L ± 7.7) compared with uncomplicated malaria (6.0 mEq/L ± 5.1) and encephalopathy (6.6 mEq/L ± 4.7). Compared with uncomplicated malaria, severe malaria was characterised by elevated plasma LA, hydroxyphenyllactic acid (HPLA), α-hydroxybutyric acid and β-hydroxybutyric acid (all P<0.05). In urine, concentrations of methylmalonic, ethylmalonic and α-ketoglutaric acids were also elevated. Multivariate logistic regression showed that plasma HPLA was a strong independent predictor of death (odds ratio [OR] 3.5, 95 % confidence interval [CI] 1.6-7.5, P=0.001), comparable to LA (OR 3.5, 95 % CI 1.5-7.8, P=0.003) (combined area under the receiver operating characteristic curve 0.81). CONCLUSIONS: Newly identified acids, in addition to LA, are elevated in patients with severe malaria and are highly predictive of fatal outcome. Further characterisation of their sources and metabolic pathways is now needed.

Maude RR, de Jong HK, Wijedoru L, Fukushima M, Ghose A, Samad R, Hossain MA, Karim MR, Faiz MA, Parry CM, CMCH Typhoid Study Group. 2015. The diagnostic accuracy of three rapid diagnostic tests for typhoid fever at Chittagong Medical College Hospital, Chittagong, Bangladesh. Trop Med Int Health, 20 (10), pp. 1376-1384. | Show Abstract | Read more

OBJECTIVE: To determine the diagnostic accuracy of three rapid diagnostic tests (RDTs) for typhoid fever in febrile hospitalised patients in Bangladesh. METHODS: Febrile adults and children admitted to Chittagong Medical College Hospital, Bangladesh, were investigated with Bact/Alert(®) blood cultures and real-time PCR to detect Salmonella enterica Typhi and Paratyphi A and assays for Rickettsia, leptospirosis and dengue fever. Acute serum samples were examined with the LifeAssay (LA) Test-it™ Typhoid IgM lateral flow assay detecting IgM antibodies against S. Typhi O antigen, CTKBiotech Onsite Typhoid IgG/IgM Combo Rapid-test cassette lateral flow assay detecting IgG and IgM antibodies against S. Typhi O and H antigens and SD Bioline line assay for IgG and IgM antibodies against S. Typhi proteins. RESULTS: In 300 malaria smear-negative febrile patients [median (IQR) age of 13.5 (5-31) years], 34 (11.3%) had confirmed typhoid fever: 19 positive by blood culture for S. Typhi (three blood PCR positive) and 15 blood culture negative but PCR positive for S. Typhi in blood. The respective sensitivity and specificity of the three RDTs in patients using a composite reference standard of blood culture and/or PCR-confirmed typhoid fever were 59% and 61% for LifeAssay, 59% and 74% for the CTK IgM and/or IgG, and 24% and 96% for the SD Bioline RDT IgM and/or IgG. The LifeAssay RDT had a sensitivity of 63% and a specificity of 91% when modified with a positive cut-off of ≥2+ and analysed using a Bayesian latent class model. CONCLUSIONS: These typhoid RDTs demonstrated moderate diagnostic accuracies, and better tests are needed.

Hanson J, Lee SJ, Hossain MA, Anstey NM, Charunwatthana P, Maude RJ, Kingston HW, Mishra SK, Mohanty S, Plewes K et al. 2015. Microvascular obstruction and endothelial activation are independently associated with the clinical manifestations of severe falciparum malaria in adults: an observational study. BMC Med, 13 (1), pp. 122. | Show Abstract | Read more

BACKGROUND: Microvascular obstruction and endothelial dysfunction have both been linked to tissue hypoperfusion in falciparum malaria, but their relative contributions to the disease's pathogenesis and outcome are unknown. METHODS: Microvascular blood flow was quantified in adults with severe falciparum malaria on their admission to hospital; plasma biomarkers of endothelial function were measured simultaneously. The relationship between these indices and the patients' clinical findings and in-hospital course was examined. RESULTS: Microvascular obstruction was observed in 119/142 (84 %) patients; a median (interquartile range (IQR)) of 14.9 % (6.6-34.9 %) of capillaries were obstructed in patients that died versus 8.3 % (1.7-26.6 %) in survivors (P = 0.039). The proportion of obstructed capillaries correlated with the estimated parasite biomass (rs = 0.25, P = 0.004) and with plasma lactate (rs = 0.38, P <0.0001), the strongest predictor of death in the series. Plasma angiopoietin-2 (Ang-2) concentrations were markedly elevated suggesting widespread endothelial activation; the median (IQR) Ang-2 concentration was 21.9 ng/mL (13.4-29.4 ng/mL) in patients that died versus 14.9 ng/mL (9.8-29.3 ng/mL) in survivors (P = 0.035). Ang-2 concentrations correlated with estimated parasite biomass (rs = 0.35, P <0.001) and plasma lactate (rs = 0.37, P <0.0001). Microvascular obstruction and Ang-2 concentrations were not significantly correlated with each other (rs = 0.17, P = 0.06), but were independently associated with plasma lactate (P <0.001 and P = 0.002, respectively). CONCLUSIONS: Microvascular obstruction and systemic endothelial activation are independently associated with plasma lactate, the strongest predictor of death in adults with falciparum malaria. This supports the hypothesis that the two processes make an independent contribution to the pathogenesis and clinical manifestations of the disease.

Tun KM, Imwong M, Lwin KM, Win AA, Hlaing TM, Hlaing T, Lin K, Kyaw MP, Plewes K, Faiz MA et al. 2015. Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker. Lancet Infect Dis, 15 (4), pp. 415-421. | Show Abstract | Read more

BACKGROUND: Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global control of Plasmodium falciparum malaria. Discovery of the K13 marker has transformed approaches to the monitoring of artemisinin resistance, allowing introduction of molecular surveillance in remote areas through analysis of DNA. We aimed to assess the spread of artemisinin-resistant P falciparum in Myanmar by determining the relative prevalence of P falciparum parasites carrying K13-propeller mutations. METHODS: We did this cross-sectional survey at malaria treatment centres at 55 sites in ten administrative regions in Myanmar, and in relevant border regions in Thailand and Bangladesh, between January, 2013, and September, 2014. K13 sequences from P falciparum infections were obtained mainly by passive case detection. We entered data into two geostatistical models to produce predictive maps of the estimated prevalence of mutations of the K13 propeller region across Myanmar. FINDINGS: Overall, 371 (39%) of 940 samples carried a K13-propeller mutation. We recorded 26 different mutations, including nine mutations not described previously in southeast Asia. In seven (70%) of the ten administrative regions of Myanmar, the combined K13-mutation prevalence was more than 20%. Geospatial mapping showed that the overall prevalence of K13 mutations exceeded 10% in much of the east and north of the country. In Homalin, Sagaing Region, 25 km from the Indian border, 21 (47%) of 45 parasite samples carried K13-propeller mutations. INTERPRETATION: Artemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided. FUNDING: Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme and the Bill & Melinda Gates Foundation.

Hanson J, Phu NH, Hasan MU, Charunwatthana P, Plewes K, Maude RJ, Prapansilp P, Kingston HW, Mishra SK, Mohanty S et al. 2015. The clinical implications of thrombocytopenia in adults with severe falciparum malaria: a retrospective analysis. BMC Med, 13 (1), pp. 97. | Show Abstract | Read more

BACKGROUND: Thrombocytopenia is a common finding in adults with severe falciparum malaria, but its clinical and prognostic utility is incompletely defined. METHODS: Clinical and laboratory data from 647 adults with severe falciparum malaria were analysed retrospectively to determine the relationship between a patient's platelet count on admission to hospital and their subsequent clinical course. RESULTS: On admission, 614 patients (94.9%) were thrombocytopenic (platelet count <150 × 10(9)/L) and 328 (50.7%) had a platelet count <50 × 10(9)/L. The admission platelet count was inversely correlated with parasite biomass (estimated from plasma PfHRP2 concentrations, rs = -0.28, P = 0.003), the degree of microvascular sequestration (measured with orthogonal polarizing spectral imaging, rs = -0.31, P = 0.001) and disease severity (the number of World Health Organization severity criteria satisfied by the patient, rs = -0.21, P <0.001). Platelet counts were lower on admission in the patients who died (median: 30 (interquartile range 22 to 52) × 10(9)/L versus 50 (34 to 78) × 10(9)/L in survivors; P <0.001), but did not predict outcome independently from other established laboratory and clinical prognostic indices. The 39 patients (6%) with profound thrombocytopenia (platelet count <20 × 10(9)/L) were more likely to die (odds ratio: 5.00, 95% confidence interval: 2.56 to 9.75) than patients with higher platelet counts, but these high-risk patients could be identified more rapidly with simple bedside clinical assessment. The admission platelet count did not reliably identify the 50 patients (7.7%) with major bleeding during the study. CONCLUSIONS: Thrombocytopenia is a marker of disease severity in adults with falciparum malaria, but has limited utility in prognostication, triage and management.

Maude RJ, Nguon C, Ly P, Bunkea T, Ngor P, Canavati de la Torre SE, White NJ, Dondorp AM, Day NP, White LJ, Chuor CM. 2014. Spatial and temporal epidemiology of clinical malaria in Cambodia 2004-2013. Malar J, 13 (1), pp. 385. | Show Abstract | Read more

BACKGROUND: Artemisinin-resistant Plasmodium falciparum malaria has recently been identified on the Thailand-Cambodia border and more recently in parts of Thailand, Myanmar and Vietnam. There is concern that if this resistance were to spread, it would severely hamper malaria control and elimination efforts worldwide. Efforts are currently underway to intensify malaria control activities and ultimately eliminate malaria from Cambodia. To support these efforts, it is crucial to have a detailed picture of disease burden and its major determinants over time. METHODS: An analysis of spatial and temporal data on clinical malaria in Cambodia collected by the National Centre for Parasitology, Entomology and Malaria Control (CNM) and the Department of Planning and Health Information, Ministry of Health Cambodia from 2004 to 2013 is presented. RESULTS: There has been a marked decrease of 81% in annual cases due to P. falciparum since 2009 coinciding with a rapid scale-up in village malaria workers (VMWs) and insecticide-treated bed nets (ITNs). Concurrently, the number of cases with Plasmodium vivax has greatly increased. It is estimated that there were around 112,000 total cases in 2012, 2.8 times greater than the WHO estimate for that year, and 68,000 in 2013 (an annual parasite incidence (API) of 4.6/1000). With the scale-up of VMWs, numbers of patients presenting to government facilities did not fall and it appears likely that those who saw VMWs had previously accessed healthcare in the private sector. Malaria mortality has decreased, particularly in areas with VMWs. There has been a marked decrease in cases in parts of western Cambodia, especially in Pailin and Battambang Provinces. In the northeast, the fall in malaria burden has been more modest, this area having the highest API in 2013. CONCLUSION: The clinical burden of falciparum malaria in most areas of Cambodia has greatly decreased from 2009 to 2013, associated with roll-out of ITNs and VMWs. Numbers of cases with P. vivax have increased. Possible reasons for these trends are discussed and areas requiring further study are highlighted. Although malaria surveillance data are prone to collection bias and tend to underestimate disease burden, the finding of similar trends in two independent datasets in this study greatly increased the robustness of the findings.

Nath P, Basher A, Harada M, Sarkar S, Selim S, Maude RJ, Noiri E, Faiz A. 2014. Immediate hypersensitivity reaction following liposomal amphotericin-B (AmBisome) infusion. Trop Doct, 44 (4), pp. 241-242. | Show Abstract | Read more

Liposomal amphotericin-B (AmBisome) is now becoming first choice for the treatment of visceral leishmaniasis (kala-azar) patients due to high efficacy and less toxicity. The reported incidence of hypersensitivity reactions to liposomal amphotericin-B (AmBisome), especially during therapy, is very rare. We report two patients with kala-azar: one developed breathing difficulties and hypotension followed by shock and the other had facial angioedema with chest tightness during treatment. Both patients were managed with immediate action of injection: adrenaline, diphenhydramine and hydrocortisone. In our experience, AmBisome can cause severe hypersensitivity reactions that warrant proper support and close supervision.

Maude RR, Maude RJ, Ghose A, Amin MR, Islam MB, Ali M, Bari MS, Majumder MI, Tanganuchitcharnchai A, Dondorp AM et al. 2014. Serosurveillance of Orientia tsutsugamushi and Rickettsia typhi in Bangladesh. Am J Trop Med Hyg, 91 (3), pp. 580-583. | Show Abstract | Read more

Scrub and murine typhus infections are under-diagnosed causes of febrile illness across the tropics, and it is not known how common they are in Bangladesh. We conducted a prospective seroepidemiologic survey across six major teaching hospitals in Bangladesh by using an IgM enzyme-linked immunosorbent assay. Results indicated recent exposure (287 of 1,209, 23.7% seropositive for Orientia tsutsugamushi and 805 of 1,209, 66.6% seropositive for Rickettsia typhi). Seropositive rates were different in each region. However, there was no geographic clustering of seropositive results for both organisms. There was no difference between those from rural or urban areas. Rickettsia typhi seroreactivity was positively correlated with age. Scrub typhus and murine typhus should be considered as possible causes of infection in Bangladesh.

Lubell Y, White L, Varadan S, Drake T, Yeung S, Cheah PY, Maude RJ, Dondorp A, Day NP, White NJ, Parker M. 2014. Ethics, economics, and the use of primaquine to reduce falciparum malaria transmission in asymptomatic populations. PLoS Med, 11 (8), pp. e1001704. | Show Abstract | Read more

Yoel Lubell and colleagues consider ethical and economic perspectives on mass drug administration of primaquine to limit transmission of P. falciparum malaria. Please see later in the article for the Editors' Summary.

Maude RJ, Kingston HW, Joshi S, Mohanty S, Mishra SK, White NJ, Dondorp AM. 2014. Reversibility of retinal microvascular changes in severe falciparum malaria. Am J Trop Med Hyg, 91 (3), pp. 493-495. | Show Abstract | Read more

Malarial retinopathy allows detailed study of central nervous system vascular pathology in living patients with severe malaria. An adult with cerebral malaria is described who had prominent retinal whitening with corresponding retinal microvascular obstruction, vessel dilatation, increased vascular tortuosity, and blood retinal barrier leakage with decreased visual acuity, all of which resolved on recovery. Additional study of these features and their potential role in elucidating the pathogenesis of cerebral malaria is warranted.

Maude RR, Amir Hossain M, Hassan MU, Osbourne S, Langan K, Sayeed A, Karim MR, Samad R, Borooah S, Dhillon B et al. 2014. Correction: Transorbital Sonographic Evaluation of Normal Optic Nerve Sheath Diameter in Healthy Volunteers in Bangladesh PLoS ONE, 9 (1), | Read more

Zaloumis SG, Tarning J, Krishna S, Price RN, White NJ, Davis TM, McCaw JM, Olliaro P, Maude RJ, Kremsner P et al. 2014. Population pharmacokinetics of intravenous artesunate: a pooled analysis of individual data from patients with severe malaria. CPT Pharmacometrics Syst Pharmacol, 3 (11), pp. e145. | Show Abstract | Read more

There are ~660,000 deaths from severe malaria each year. Intravenous artesunate (i.v. ARS) is the first-line treatment in adults and children. To optimize the dosing regimen of i.v. ARS, the largest pooled population pharmacokinetic study to date of the active metabolite dihydroartemisinin (DHA) was performed. The pooled dataset consisted of 71 adults and 195 children with severe malaria, with a mixture of sparse and rich sampling within the first 12 h after drug administration. A one-compartment model described the population pharmacokinetics of DHA adequately. Body weight had the greatest impact on DHA pharmacokinetics, resulting in lower DHA exposure for smaller children (6-10 kg) than adults. Post hoc estimates of DHA exposure were not significantly associated with parasitological outcomes. Comparable DHA exposure in smaller children and adults after i.v. ARS was achieved under a dose modification for intramuscular ARS proposed in a separate analysis of children.

Maude RJ, Nguon C, Dondorp AM, White LJ, White NJ. 2014. The diminishing returns of atovaquone-proguanil for elimination of Plasmodium falciparum malaria: modelling mass drug administration and treatment. Malar J, 13 (1), pp. 380. | Show Abstract | Read more

BACKGROUND: Artemisinin resistance is a major threat to current efforts to eliminate Plasmodium falciparum malaria which rely heavily on the continuing efficacy of artemisinin combination therapy (ACT). It has been suggested that ACT should not be used in mass drug administration (MDA) in areas where artemisinin-resistant P. falciparum is prevalent, and that atovaquone-proguanil (A-P) might be a preferable alternative. However, a single point mutation in the cytochrome b gene confers high level resistance to atovaquone, and such mutant parasites arise frequently during treatment making A-P a vulnerable tool for elimination. METHODS: A deterministic, population level, mathematical model was developed based on data from Cambodia to explore the possible effects of large-scale use of A-P compared to dihydroartemisinin-piperaquine ACT for mass drug administration and/or treatment of P. falciparum malaria, with and without adjunctive primaquine (PQ) and long-lasting insecticide-treated bed nets (LLIN). The aim was local elimination. RESULTS: The model showed the initial efficacy of ACT and A-P for MDA to be similar. However, each round of A-P MDA resulted in rapid acquisition and spread of atovaquone resistance. Even a single round of MDA could compromise efficacy sufficient to preclude its use for treatment or prophylaxis. A switch to A-P for treatment of symptomatic episodes resulted in a complete loss of efficacy in the population within four to five years of its introduction. The impact of MDA was temporary and a combination of maintained high coverage with ACT treatment for symptomatic individuals and LLIN was necessary for elimination. CONCLUSION: For malaria elimination, A-P for MDA or treatment of symptomatic cases should be avoided. A combined strategy of high coverage with ACT for treatment of symptomatic episodes, LLIN and ACT + P MDA would be preferable.

Maude RJ, Ahmed BU, Rahman AH, Rahman R, Majumder MI, Menezes DB, Abu Sayeed A, Hughes L, MacGillivray TJ, Borooah S et al. 2014. Retinal changes in visceral leishmaniasis by retinal photography. BMC Infect Dis, 14 (1), pp. 527. | Show Abstract | Read more

BACKGROUND: In visceral leishmaniasis (VL), retinal changes have previously been noted but not described in detail and their clinical and pathological significance are unknown. A prospective observational study was undertaken in Mymensingh, Bangladesh aiming to describe in detail visible changes in the retina in unselected patients with VL. METHODS: Patients underwent assessment of visual function, indirect and direct ophthalmoscopy and portable retinal photography. The photographs were assessed by masked observers including assessment for vessel tortuosity using a semi-automated system. RESULTS: 30 patients with VL were enrolled, of whom 6 (20%) had abnormalities. These included 5 with focal retinal whitening, 2 with cotton wool spots, 2 with haemorrhages, as well as increased vessel tortuosity. Visual function was preserved. CONCLUSIONS: These changes suggest a previously unrecognized retinal vasculopathy. An inflammatory aetiology is plausible such as a subclinical retinal vasculitis, possibly with altered local microvascular autoregulation, and warrants further investigation.

Maude RJ, Barkhof F, Hassan MU, Ghose A, Hossain A, Abul Faiz M, Choudhury E, Rashid R, Abu Sayeed A, Charunwatthana P et al. 2014. Magnetic resonance imaging of the brain in adults with severe falciparum malaria. Malar J, 13 (1), pp. 177. | Show Abstract | Read more

BACKGROUND: Magnetic resonance imaging (MRI) allows detailed study of structural and functional changes in the brain in patients with cerebral malaria. METHODS: In a prospective observational study in adult Bangladeshi patients with severe falciparum malaria, MRI findings in the brain were correlated with clinical and laboratory parameters, retinal photography and optic nerve sheath diameter (ONSD) ultrasound (a marker of intracranial pressure). RESULTS: Of 43 enrolled patients, 31 (72%) had coma and 12 (28%) died. MRI abnormalities were present in 79% overall with mostly mild changes in a wide range of anatomical sites. There were no differences in MRI findings between patients with cerebral and non-cerebral or fatal and non-fatal disease. Subtle diffuse cerebral swelling was common (n = 22/43), but mostly without vasogenic oedema or raised intracranial pressure (ONSD). Also seen were focal extracellular oedema (n = 11/43), cytotoxic oedema (n = 8/23) and mildly raised brain lactate on magnetic resonance spectroscopy (n = 5/14). Abnormalities were much less prominent than previously described in Malawian children. Retinal whitening was present in 36/43 (84%) patients and was more common and severe in patients with coma. CONCLUSION: Cerebral swelling is mild and not specific to coma or death in adult severe falciparum malaria. This differs markedly from African children. Retinal whitening, reflecting heterogeneous obstruction of the central nervous system microcirculation by sequestered parasites resulting in small patches of ischemia, is associated with coma and this process is likely important in the pathogenesis.

Plewes K, Royakkers AA, Hanson J, Hasan MM, Alam S, Ghose A, Maude RJ, Stassen PM, Charunwatthana P, Lee SJ et al. 2014. Correlation of biomarkers for parasite burden and immune activation with acute kidney injury in severe falciparum malaria. Malar J, 13 (1), pp. 91. | Show Abstract | Read more

BACKGROUND: Acute kidney injury (AKI) complicating severe Plasmodium falciparum malaria occurs in up to 40% of adult patients. The case fatality rate reaches 75% in the absence of renal replacement therapy (RRT). The precise pathophysiology of AKI in falciparum malaria remains unclear. Histopathology shows acute tubular necrosis with localization of host monocytes and parasitized red blood cells in the microvasculature. This study explored the relationship of plasma soluble urokinase-type plasminogen activator receptor (suPAR), as a proxy-measure of mononuclear cell activation, and plasma P. falciparum histidine rich protein 2 (PfHRP2), as a measure of sequestered parasite burden, with AKI in severe malaria. METHODS: Admission plasma suPAR and PfHRP2 concentrations were assessed in Bangladeshi adults with severe falciparum malaria (n=137). Patients were stratified according to AKI severity based on admission creatinine clearance. RESULTS: A total of 106 (77%) patients had AKI; 32 (23%), 42 (31%) and 32 (23%) were classified into 'mild, 'moderate' and 'severe' AKI groups, respectively. Plasma suPAR and PfHRP2 concentrations increased with AKI severity (test-for-trend P <0.0001) and correlated with other markers of renal dysfunction. Admission plasma suPAR and PfHRP2 concentrations were higher in patients who later required RRT (P <0.0001 and P=0.0004, respectively). In a multivariate analysis, both increasing suPAR and PfHRP2 were independently associated with increasing urine neutrophil gelatinase-associated lipocalin concentration, a marker of acute tubular necrosis (β=16.54 (95% CI 6.36-26.71) and β=0.07 (0.02-0.11), respectively). CONCLUSIONS: Both sequestered parasite burden and immune activation contribute to the pathogenesis of AKI in severe falciparum malaria.

Hanson J, Lee SJ, Mohanty S, Faiz MA, Anstey NM, Price RN, Charunwatthana P, Yunus EB, Mishra SK, Tjitra E et al. 2014. Rapid clinical assessment to facilitate the triage of adults with falciparum malaria, a retrospective analysis. PLoS One, 9 (1), pp. e87020. | Show Abstract | Read more

BACKGROUND: Most adults dying from falciparum malaria will die within 48 hours of their hospitalisation. An essential component of early supportive care is the rapid identification of patients at greatest risk. In resource-poor settings, where most patients with falciparum malaria are managed, decisions regarding patient care must frequently be made using clinical evaluation alone. METHODS: We retrospectively analysed 4 studies of 1801 adults with severe falciparum malaria to determine whether the presence of simple clinical findings might assist patient triage. RESULTS: If present on admission, shock, oligo-anuria, hypo- or hyperglycaemia, an increased respiratory rate, a decreased Glasgow Coma Score and an absence of fever were independently predictive of death. The variables were used to construct a simple clinical algorithm. When applied to the 1801 patients, this algorithm's positive predictive value for survival to 48 hours was 99.4 (95% confidence interval (CI) 97.8-99.9) and for survival to discharge 96.9% (95% CI 94.3-98.5). In the 712 patients receiving artesunate, the algorithm's positive predictive value for survival to 48 hours was 100% (95% CI 97.3-100) and to discharge was 98.5% (95% CI 94.8-99.8). CONCLUSIONS: Simple clinical findings are closely linked to the pathophysiology of severe falciparum malaria in adults. A basic algorithm employing these indices can facilitate the triage of patients in settings where intensive care services are limited. Patients classified as low-risk by this algorithm can be safely managed initially on a general ward whilst awaiting senior clinical review and laboratory data.

Koh GC, Maude RJ. 2014. The case against exchange transfusion has yet to be proved. Clin Infect Dis, 58 (2), pp. 302. | Read more

Maude RJ, Silamut K, Plewes K, Charunwatthana P, Ho M, Abul Faiz M, Rahman R, Hossain MA, Hassan MU, Bin Yunus E et al. 2014. Randomized controlled trial of levamisole hydrochloride as adjunctive therapy in severe falciparum malaria with high parasitemia. J Infect Dis, 209 (1), pp. 120-129. | Show Abstract | Read more

BACKGROUND: Cytoadherence and sequestration of erythrocytes containing mature stages of Plasmodium falciparum are central to the pathogenesis of severe malaria. The oral anthelminthic drug levamisole inhibits cytoadherence in vitro and reduces sequestration of late-stage parasites in uncomplicated falciparum malaria treated with quinine. METHODS: Fifty-six adult patients with severe malaria and high parasitemia admitted to a referral hospital in Bangladesh were randomized to receive a single dose of levamisole hydrochloride (150 mg) or no adjuvant to antimalarial treatment with intravenous artesunate. RESULTS: Circulating late-stage parasites measured as the median area under the parasite clearance curves were 2150 (interquartile range [IQR], 0-28 025) parasites/µL × hour in patients treated with levamisole and 5489 (IQR, 192-25 848) parasites/µL × hour in controls (P = .25). The "sequestration ratios" at 6 and 12 hours for all parasite stages and changes in microvascular blood flow did not differ between treatment groups (all P > .40). The median time to normalization of plasma lactate (<2 mmol/L) was 24 (IQR, 12-30) hours with levamisole vs 28 (IQR, 12-36) hours without levamisole (P = .15). CONCLUSIONS: There was no benefit of a single-dose of levamisole hydrochloride as adjuvant to intravenous artesunate in the treatment of adults with severe falciparum malaria. Rapid parasite killing by intravenous artesunate might obscure the effects of levamisole.

Vink JP, Laubscher M, Vlutters R, Silamut K, Maude RJ, Hasan MU, DE Haan G. 2013. An automatic vision-based malaria diagnosis system. J Microsc, 250 (3), pp. 166-178. | Show Abstract | Read more

Malaria is a worldwide health problem with 225 million infections each year. A fast and easy-to-use method, with high performance is required to differentiate malaria from non-malarial fevers. Manual examination of blood smears is currently the gold standard, but it is time-consuming, labour-intensive, requires skilled microscopists and the sensitivity of the method depends heavily on the skills of the microscopist. We propose an easy-to-use, quantitative cartridge-scanner system for vision-based malaria diagnosis, focusing on low malaria parasite densities. We have used special finger-prick cartridges filled with acridine orange to obtain a thin blood film and a dedicated scanner to image the cartridge. Using supervised learning, we have built a Plasmodium falciparum detector. A two-step approach was used to first segment potentially interesting areas, which are then analysed in more detail. The performance of the detector was validated using 5,420 manually annotated parasite images from malaria parasite culture in medium, as well as using 40 cartridges of 11,780 images containing healthy blood. From finger prick to result, the prototype cartridge-scanner system gave a quantitative diagnosis in 16 min, of which only 1 min required manual interaction of basic operations. It does not require a wet lab or a skilled operator and provides parasite images for manual review and quality control. In healthy samples, the image analysis part of the system achieved an overall specificity of 99.999978% at the level of (infected) red blood cells, resulting in at most seven false positives per microlitre. Furthermore, the system showed a sensitivity of 75% at the cell level, enabling the detection of low parasite densities in a fast and easy-to-use manner. A field trial in Chittagong (Bangladesh) indicated that future work should primarily focus on improving the filling process of the cartridge and the focus control part of the scanner.

Maude RR, Hossain MA, Hassan MU, Osbourne S, Sayeed KL, Karim MR, Samad R, Borooah S, Dhillon B, Day NP et al. 2013. Transorbital sonographic evaluation of normal optic nerve sheath diameter in healthy volunteers in Bangladesh. PLoS One, 8 (12), pp. e81013. | Show Abstract | Read more

INTRODUCTION: Measurement of optic nerve sheath diameter (ONSD) by ultrasound is increasingly used as a marker to detect raised intracranial pressure (ICP). ONSD varies with age and there is no clear consensus between studies for an upper limit of normal. Knowledge of normal ONSD in a healthy population is essential to interpret this measurement. METHODS: In a prospective observational study, ONSD was measured using a 15 MHz ultrasound probe in healthy volunteers in Chittagong, Bangladesh. The aims were to determine the normal range of ONSD in healthy Bangladeshi adults and children, compare measurements in males and females, horizontal and vertical beam orientations and left and right eyes in the same individual and to determine whether ONSD varies with head circumference independent of age. RESULTS: 136 subjects were enrolled, 12.5% of whom were age 16 or under. Median ONSD was 4.41 mm with 95% of subjects in the range 4.25-4.75 mm. ONSD was bimodally distributed. There was no relationship between ONSD and age (≥4 years), gender, head circumference, and no difference in left vs right eye or horizontal vs vertical beam. CONCLUSIONS: Ultrasonographic ONSD in Bangladeshi healthy volunteers has a narrow bimodal distribution independent of age (≥4 years), gender and head circumference. ONSD >4.75 mm in this population should be considered abnormal.

Vaid N, Langan KM, Maude RJ. 2013. Post-exposure prophylaxis in resource-poor settings: review and recommendations for pre-departure risk assessment and planning for expatriate healthcare workers. Trop Med Int Health, 18 (5), pp. 588-595. | Show Abstract | Read more

It is estimated that more than 3 million healthcare workers worldwide suffer needlestick and splash injuries whilst at work resulting in the potential transmission of blood-borne pathogens via exposure to bodily fluids. Under-reporting and the subsequent management of occupational injuries is a problem both in the United Kingdom and abroad. Many expatriate health care workers will work in low resource settings where the risk of transmission is greatest but in contrast to wealthier countries such as the United Kingdom, there is often a lack of effective systems for its safe management. This article provides important information about this risk and how to minimise it. The reasons for an increased risk in transmission, its subsequent management and pre-departure planning are discussed, together with the evidence for initiation of post-exposure prophylaxis; current National and International guidelines as well as the urgent need for International standardisation of these is also discussed.

Kolyva C, Kingston H, Tachtsidis I, Mohanty S, Mishra S, Patnaik R, Maude RJ, Dondorp AM, Elwell CE. 2013. Oscillations in cerebral haemodynamics in patients with falciparum malaria. Adv Exp Med Biol, 765 pp. 101-107. | Show Abstract | Read more

Spontaneous oscillations in cerebral haemodynamics studied with near-infrared spectroscopy (NIRS), become impaired in several pathological conditions. We assessed the spectral characteristics of these oscillations in 20 patients with falciparum malaria admitted to Ispat General Hospital, Rourkela, India. Monitoring included continuous frontal lobe NIRS recordings within 24 h of admission (Day 0), together with single measurements of a number of clinical and chemical markers recorded on admission. Seven patients returned for follow-up measurements on recovery (FU). A 2,048 sampling-point segment of oxygenated haemoglobin concentration ([ΔHbO(2)]) data was subjected to Fourier analysis per patient, and power spectral density was derived over the very low frequency (VLF: 0.02-0.04 Hz), low frequency (LF: 0.04-0.15 Hz) and high frequency (HF: 0.15-0.4 Hz) bands. At Day 0, VLF spectral power was 21.1 ± 16.4, LF power 7.2 ± 4.6 and HF power 2.6 ± 5.0, with VLF power being statistically significantly higher than LF and HF (P < 0.005). VLF power tended to decrease in the severely ill patients and correlated negatively with heart rate (r = 0.57, P < 0.01), while LF power correlated positively with aural body temperature (r = 0.49, P < 0.05). In all but one of the patients who returned for FU measurements, VLF power increased after recovery. This may be related to autonomic dysfunction in severe malaria, a topic of little research to date. The present study demonstrated that application of NIRS in a resource-poor setting is feasible and has potential as a research tool.

Maude RJ, Hasan MU, Hossain MA, Sayeed AA, Kanti Paul S, Rahman W, Maude RR, Vaid N, Ghose A, Amin R et al. 2012. Temporal trends in severe malaria in Chittagong, Bangladesh. Malar J, 11 (1), pp. 323. | Show Abstract | Read more

BACKGROUND: Epidemiological data on malaria in Bangladesh are sparse, particularly on severe and fatal malaria. This hampers the allocation of healthcare provision in this resource-poor setting. Over 85% of the estimated 150,000-250,000 annual malaria cases in Bangladesh occur in Chittagong Division with 80% in the Chittagong Hill Tracts (CHT). Chittagong Medical College Hospital (CMCH) is the major tertiary referral hospital for severe malaria in Chittagong Division. METHODS: Malaria screening data from 22,785 inpatients in CMCH from 1999-2011 were analysed to investigate the patterns of referral, temporal trends and geographical distribution of severe malaria in Chittagong Division, Bangladesh. RESULTS: From 1999 till 2011, 2,394 malaria cases were admitted, of which 96% harboured Plasmodium falciparum and 4% Plasmodium vivax. Infection was commonest in males (67%) between 15 and 34 years of age. Seasonality of malaria incidence was marked with a single peak in P. falciparum transmission from June to August coinciding with peak rainfall, whereas P. vivax showed an additional peak in February-March possibly representing relapse infections. Since 2007 there has been a substantial decrease in the absolute number of admitted malaria cases. Case fatality in severe malaria was 18% from 2008-2011, remaining steady during this period.A travel history obtained in 226 malaria patients revealed only 33% had been to the CHT in the preceding three weeks. Of all admitted malaria patients, only 9% lived in the CHT, and none in the more remote malaria endemic regions near the Indian border. CONCLUSIONS: The overall decline in admitted malaria cases to CMCH suggests recent control measures are successful. However, there are no reliable data on the incidence of severe malaria in the CHT, the most endemic area of Bangladesh, and most of these patients do not reach tertiary health facilities. Improvement of early treatment and simple supportive care for severe malaria in remote areas and implementation of a referral system for cases requiring additional supportive care could be important contributors to further reducing malaria-attributable disease and death in Bangladesh.

Joshi VS, Maude RJ, Reinhardt JM, Tang L, Garvin MK, Abu Sayeed A, Ghose A, Hassan MU, Abràmoff MD. 2012. Automated detection of malarial retinopathy-associated retinal hemorrhages. Invest Ophthalmol Vis Sci, 53 (10), pp. 6582-6588. | Show Abstract | Read more

PURPOSE: To develop an automated method for the detection of retinal hemorrhages on color fundus images to characterize malarial retinopathy, which may help in the assessment of patients with cerebral malaria. METHODS: A fundus image dataset from 14 patients (200 fundus images, with an average of 14 images per patient) previously diagnosed with malarial retinopathy was examined. We developed a pattern recognition-based algorithm, which extracted features from image watershed regions called splats (tobogganing). A reference standard was obtained by manual segmentation of hemorrhages, which assigned a label to each splat. The splat features with the associated splat label were used to train a linear k-nearest neighbor classifier that learnt the color properties of hemorrhages and identified the splats belonging to hemorrhages in a test dataset. In a crossover design experiment, data from 12 patients were used for training and data from two patients were used for testing, with 14 different permutations; and the derived sensitivity and specificity values were averaged. RESULTS: The experiment resulted in hemorrhage detection sensitivities in terms of splats as 80.83%, and in terms of lesions as 84.84%. The splat-based specificity was 96.67%, whereas for the lesion-based analysis, an average of three false positives was obtained per image. The area under the receiver operating characteristic curve was reported as 0.9148 for splat-based, and as 0.9030 for lesion-based analysis. CONCLUSIONS: The method provides an automated means of detecting retinal hemorrhages associated with malarial retinopathy. The results matched well with the reference standard. With further development, this technique may provide automated assistance for screening and quantification of malarial retinopathy.

Maude RR, Maude RJ, Ghose A, Amin MR, Islam MB, Ali M, Bari MS, Majumder MI, Wuthiekanan V, Dondorp AM et al. 2012. Seroepidemiological surveillance of Burkholderia pseudomallei in Bangladesh. Trans R Soc Trop Med Hyg, 106 (9), pp. 576-578. | Show Abstract | Read more

Melioidosis (Burkholderia pseudomallei infection) has yet to be demonstrated systematically in Bangladesh. A prospective, cross-sectional serological survey was conducted in 2010 at six Bangladeshi hospitals. Age, gender, occupation and residential address were recorded. Of 1244 patients, 359 (28.9%) were positive for B. pseudomallei by indirect haemagglutination assay. Farmers had an increased risk of seropositivity (risk ratio=1.4, 95% CI 1.0-1.8; p=0.03). There was no clear geographic clustering of seropositives. Melioidosis should be considered as a possible cause of febrile illness in Bangladesh. Further studies are needed to establish the incidence of clinical disease and distribution of environmental risk.

Maude RR, Vatcharapreechasakul T, Ariyaprasert P, Maude RJ, Hongsuwan M, Yuentrakul P, Limmathurotsakul D, Koh GC, Chaowagul W, Day NP, Peacock SJ. 2012. Prospective observational study of the frequency and features of intra-abdominal abscesses in patients with melioidosis in northeast Thailand. Trans R Soc Trop Med Hyg, 106 (10), pp. 629-631. | Show Abstract | Read more

Retrospective case series from Thailand have reported the presence of intra-abdominal abscesses in around half of patients with melioidosis, a much higher rate than our clinical experience would suggest. We performed a prospective, observational study of 230 adult patients with culture-confirmed melioidosis in which all patients underwent abdominal ultrasound. One or more abscesses were detected in the liver and/or spleen in 77 (33%) cases. These were often multiple (70%, 31/44 in hepatic abscesses and 88%, 50/57 in splenic abscesses) and clinically silent (27% of cases with abscesses presenting with abdominal pain). The mortality rate at 4 weeks post-discharge was lower in patients who were abscess-positive vs abscess-negative (10%, 8/77 vs 20%, 31/153).

Dondorp AM, Maude RJ, Hendriksen IC, Day NP, White NJ. 2012. Artesunate dosing in severe falciparum malaria. J Infect Dis, 206 (4), pp. 618-619. | Read more

Hanson J, Lam SW, Mahanta KC, Pattnaik R, Alam S, Mohanty S, Hasan MU, Hossain A, Charunwatthana P, Chotivanich K et al. 2012. Relative contributions of macrovascular and microvascular dysfunction to disease severity in falciparum malaria. J Infect Dis, 206 (4), pp. 571-579. | Show Abstract | Read more

BACKGROUND: Sequestration of parasitized erythrocytes in the microcirculation is considered the central pathophysiological process in severe falciparum malaria. Hypovolemia with reduced oxygen delivery and microvascular obstruction have different implications for patient management; however, their relative contributions to disease severity are uncertain. METHODS: Adult patients (n = 28) with severe Plasmodium falciparum malaria were enrolled in a prospective hemodynamic study. Volume status and oxygen delivery were assessed using transpulmonary thermodilution. Microvascular sequestration was measured using orthogonal polarized spectroscopy. FINDINGS: Duration of therapy before study enrollment was correlated with the amount of directly visualized and quantitated microvascular sequestration (P = .03). The amount of sequestration correlated with plasma lactate (r(s )= 0.55; P = .003) and disease severity (r(s )= 0.41; P = .04). In patients who had received artesunate for <10 hours, sequestration was higher in fatal cases than in survivors: median (range) 45% (32-50) vs 15% (0-40); P = .03). Parasite biomass estimated from plasma P. falciparum histidine-rich protein 2 correlated positively with disease severity (r(s )= 0.48; P = .01) and was significantly higher in patients who died (P = .046). There was no relationship between oxygen delivery and disease severity (P = .64) or outcome (P = .74). INTERPRETATION: Vital organ dysfunction in severe malaria results primarily from sequestration of parasitized erythrocytes in the microvasculature rather than reduction in circulating blood volume and oxygen delivery.

Abedin MJ, Sayeed AA, Basher A, Maude RJ, Hoque G, Faiz MA. 2012. Open-label randomized clinical trial of atropine bolus injection versus incremental boluses plus infusion for organophosphate poisoning in Bangladesh. J Med Toxicol, 8 (2), pp. 108-117. | Show Abstract | Read more

Severe organophosphate compound (OPC) poisoning is an important clinical problem in many countries of the world. Unfortunately, little clinical research has been performed and little evidence exists with which to determine the best therapy. A study was therefore undertaken to determine the optimal dosing regimen for atropine in the treatment of OPC poisoning. An open-label randomized clinical trial was conducted in Chittagong Medical College Hospital, Chittagong, Bangladesh, on 156 hospitalized individuals with OPC poisoning from June to September 2006. The aim was to compare the efficacy and safety of conventional bolus doses with individualized incremental doses of atropine for atropinization followed by continuous atropine infusion for management of OPC poisoning. Inclusion criteria were patients with a clear history of OPC poisoning with clear clinical signs of toxicity, i.e. features of cholinergic crisis. The patients were observed for at least 96 h. Immediate outcome and complications were recorded. Out of 156 patients, 81 patients received conventional bolus dose atropine (group A) and 75 patients received rapidly incremental doses of atropine followed by infusion (group B). The mortality in group 'A' was 22.5% (18/80) and in group 'B' 8% (6/75) (p < 0.05). The mean duration of atropinization in group 'A' was 151.74 min compared to 23.90 min for group 'B' (p < 0.001). More patients in group A experienced atropine toxicity than in group 'B' (28.4% versus 12.0%, p < 0.05); intermediate syndrome was more common in group 'A' than in group 'B' (13.6% versus 4%, p < 0.05), and respiratory support was required more often for patients in group 'A' than in group 'B' (24.7% versus 8%, p < 0.05). Rapid incremental dose atropinization followed by atropine infusion reduces mortality and morbidity from OPC poisoning and shortens the length of hospital stay and recovery. Incremental atropine and infusion should become the treatment of choice for OPC poisoning. Given the paucity of existing evidence, further clinical studies should be performed to determine the optimal dosing regimen of atropine that most rapidly and safely achieves atropinization in these patients.

White LJ, Newton PN, Maude RJ, Pan-ngum W, Fried JR, Mayxay M, Maude RR, Day NP. 2012. Defining disease heterogeneity to guide the empirical treatment of febrile illness in resource poor settings. PLoS One, 7 (9), pp. e44545. | Show Abstract | Read more

BACKGROUND: Malaria incidence is in decline in many parts of SE Asia leading to a decreasing proportion of febrile illness that is attributable to malaria. However in the absence of rapid, affordable and accurate diagnostic tests, the non-malaria causes of these illnesses cannot be reliably identified. Studies on the aetiology of febrile illness have indicated that the causes are likely to vary by geographical location within countries (i.e. be spatially heterogeneous) and that national empirical treatment policies based on the aetiology measured in a single location could lead to inappropriate treatment. METHODS: Using data from Vientiane as a reference for the incidence of major febrile illnesses in the Lao People's Democratic Republic (Laos) and estimated incidences, plausible incidence in other Lao provinces were generated using a mathematical model for a range of national and local scale variations. For a range of treatment protocols, the mean number of appropriate treatments was predicted and the potential impact of a spatially explicit national empirical treatment protocol assessed. FINDINGS: The model predicted a negative correlation between number of appropriate treatments and the level of spatial heterogeneity. A spatially explicit national treatment protocol was predicted to increase the number of appropriate treatments by 50% for intermediate levels of spatial heterogeneity. CONCLUSIONS: The results suggest that given even only moderate spatial variation, a spatially explicit treatment algorithm will result in a significant improvement in the outcome of undifferentiated fevers in Laos and other similar resource poor settings.

Maude RR, Vatcharapreechasakul T, Ariyaprasert P, Maude RJ, Hongsuwan M, Yuentrakul P, Limmathurotsakul D, Koh GCKW, Chaowagul W, Day NPJ, Peacock SJ. 2012. Prospective observational study of the frequency and features of intra-abdominal abscesses in patients with melioidosis in northeast Thailand Transactions of the Royal Society of Tropical Medicine and Hygiene, 106 (10), pp. 629-631. | Show Abstract | Read more

Retrospective case series from Thailand have reported the presence of intra-abdominal abscesses in around half of patients with melioidosis, a much higher rate than our clinical experience would suggest. We performed a prospective, observational study of 230 adult patients with culture-confirmed melioidosis in which all patients underwent abdominal ultrasound. One or more abscesses were detected in the liver and/or spleen in 77 (33%) cases. These were often multiple (70%, 31/44 in hepatic abscesses and 88%, 50/57 in splenic abscesses) and clinically silent (27% of cases with abscesses presenting with abdominal pain). The mortality rate at 4 weeks post-discharge was lower in patients who were abscess-positive vs abscess-negative (10%, 8/77 vs 20%, 31/153). © 2012 Royal Society of Tropical Medicine and Hygiene.

Maude RR, Maude RJ, Ghose A, Amin MR, Islam MB, Ali M, Bari MS, Majumder MI, Wuthiekanan V, Dondorp AM et al. 2012. Seroepidemiological surveillance of Burkholderia pseudomallei in Bangladesh Transactions of the Royal Society of Tropical Medicine and Hygiene, 106 (9), pp. 576-578. | Show Abstract | Read more

Melioidosis (. Burkholderia pseudomallei infection) has yet to be demonstrated systematically in Bangladesh. A prospective, cross-sectional serological survey was conducted in 2010 at six Bangladeshi hospitals. Age, gender, occupation and residential address were recorded. Of 1244 patients, 359 (28.9%) were positive for . B. pseudomallei by indirect haemagglutination assay. Farmers had an increased risk of seropositivity (risk ratio. =. 1.4, 95% CI 1.0-1.8; p. =. 0.03). There was no clear geographic clustering of seropositives. Melioidosis should be considered as a possible cause of febrile illness in Bangladesh. Further studies are needed to establish the incidence of clinical disease and distribution of environmental risk. © 2012 Royal Society of Tropical Medicine and Hygiene.

Abedin MJ, Sayeed AA, Basher A, Maude RJ, Hoque G, Faiz MA. 2012. Open-Label Randomized Clinical Trial of Atropine Bolus Injection Versus Incremental Boluses Plus Infusion for Organophosphate Poisoning in Bangladesh Journal of Medical Toxicology, 8 (2), pp. 108-117. | Show Abstract | Read more

Severe organophosphate compound (OPC) poisoning is an important clinical problem in many countries of the world. Unfortunately, little clinical research has been performed and little evidence exists with which to determine the best therapy. A study was therefore undertaken to determine the optimal dosing regimen for atropine in the treatment of OPC poisoning. An open-label randomized clinical trial was conducted in Chittagong Medical College Hospital, Chittagong, Bangladesh, on 156 hospitalized individuals with OPC poisoning from June to September 2006. The aim was to compare the efficacy and safety of conventional bolus doses with individualized incremental doses of atropine for atropinization followed by continuous atropine infusion for management of OPC poisoning. Inclusion criteria were patients with a clear history of OPC poisoning with clear clinical signs of toxicity, i. e. features of cholinergic crisis. The patients were observed for at least 96 h. Immediate outcome and complications were recorded. Out of 156 patients, 81 patients received conventional bolus dose atropine (group A) and 75 patients received rapidly incremental doses of atropine followed by infusion (group B). The mortality in group 'A' was 22. 5% (18/80) and in group 'B' 8% (6/75) (p < 0. 05). The mean duration of atropinization in group 'A' was 151. 74 min compared to 23. 90 min for group 'B' (p < 0. 001). More patients in group A experienced atropine toxicity than in group 'B' (28. 4% versus 12. 0%, p < 0. 05); intermediate syndrome was more common in group 'A' than in group 'B' (13. 6% versus 4%, p < 0. 05), and respiratory support was required more often for patients in group 'A' than in group 'B' (24. 7% versus 8%, p < 0. 05). Rapid incremental dose atropinization followed by atropine infusion reduces mortality and morbidity from OPC poisoning and shortens the length of hospital stay and recovery. Incremental atropine and infusion should become the treatment of choice for OPC poisoning. Given the paucity of existing evidence, further clinical studies should be performed to determine the optimal dosing regimen of atropine that most rapidly and safely achieves atropinization in these patients. © 2012 American College of Medical Toxicology.

Maude RJ, Socheat D, Nguon C, Saroth P, Dara P, Li G, Song J, Yeung S, Dondorp AM, Day NP et al. 2012. Optimising strategies for Plasmodium falciparum malaria elimination in Cambodia: primaquine, mass drug administration and artemisinin resistance. PLoS One, 7 (5), pp. e37166. | Show Abstract | Read more

BACKGROUND: Malaria elimination requires a variety of approaches individually optimized for different transmission settings. A recent field study in an area of low seasonal transmission in South West Cambodia demonstrated dramatic reductions in malaria parasite prevalence following both mass drug administration (MDA) and high treatment coverage of symptomatic patients with artemisinin-piperaquine plus primaquine. This study employed multiple combined strategies and it was unclear what contribution each made to the reductions in malaria. METHOD AND FINDINGS: A mathematical model fitted to the trial results was used to assess the effects of the various components of these interventions, design optimal elimination strategies, and explore their interactions with artemisinin resistance, which has recently been discovered in Western Cambodia. The modelling indicated that most of the initial reduction of P. falciparum malaria resulted from MDA with artemisinin-piperaquine. The subsequent continued decline and near elimination resulted mainly from high coverage with artemisinin-piperaquine treatment. Both these strategies were more effective with the addition of primaquine. MDA with artemisinin combination therapy (ACT) increased the proportion of artemisinin resistant infections, although much less than treatment of symptomatic cases with ACT, and this increase was slowed by adding primaquine. Artemisinin resistance reduced the effectiveness of interventions using ACT when the prevalence of resistance was very high. The main results were robust to assumptions about primaquine action, and immunity. CONCLUSIONS: The key messages of these modelling results for policy makers were: high coverage with ACT treatment can produce a long-term reduction in malaria whereas the impact of MDA is generally only short-term; primaquine enhances the effect of ACT in eliminating malaria and reduces the increase in proportion of artemisinin resistant infections; parasite prevalence is a better surveillance measure for elimination programmes than numbers of symptomatic cases; combinations of interventions are most effective and sustained efforts are crucial for successful elimination.

Maude R, Hoque MG, Hasan MMU, Abu Sayeed M, Akter S, Samad R, Alam B, Bin Yunus E, Rahman MR, Rahman MW et al. 2011. TIMING OF ENTERAL FEEDING IN CEREBRAL MALARIA IN RESOURCE-POOR SETTINGS: A RANDOMIZED TRIALCATEGORY: SCIENTIFIC FREE PAPER JOURNAL OF INFECTION, 63 (6), pp. E101-E101.

Maude R, Abu Sayeed A, Beare N, Charunwatthana P, Faiz MA, Hossain A, Bin Yunus E, Hoque MG, Hasan MU, White N et al. 2011. MALARIAL RETINOPATHY IN ADULTS JOURNAL OF INFECTION, 63 (6), pp. 494-495. | Read more

Maude R, Socheat D, Nguon C, Yeung S, White L. 2011. OPTIMISING STRATEGIES FOR MALARIA ELIMINATION: PRIMAQUINE, MASS DRUG ADMINISTRATION AND ARTEMISININ RESISTANCECATEGORY: SCIENTIFIC FREE PAPER JOURNAL OF INFECTION, 63 (6), pp. E77-E77.

Hanson J, Hasan MM, Royakkers AA, Alam S, Charunwatthana P, Maude RJ, Douthwaite ST, Yunus EB, Mantha ML, Schultz MJ et al. 2011. Laboratory prediction of the requirement for renal replacement in acute falciparum malaria. Malar J, 10 (1), pp. 217. | Show Abstract | Read more

BACKGROUND: Acute renal failure is a common complication of severe malaria in adults, and without renal replacement therapy (RRT), it carries a poor prognosis. Even when RRT is available, delaying its initiation may increase mortality. Earlier identification of patients who will need RRT may improve outcomes. METHOD: Prospectively collected data from two intervention studies in adults with severe malaria were analysed focusing on laboratory features on presentation and their association with a later requirement for RRT. In particular, laboratory indices of acute tubular necrosis (ATN) and acute kidney injury (AKI) that are used in other settings were examined. RESULTS: Data from 163 patients were available for analysis. Whether or not the patients should have received RRT (a retrospective assessment determined by three independent reviewers) was used as the reference. Forty-three (26.4%) patients met criteria for dialysis, but only 19 (44.2%) were able to receive this intervention due to the limited availability of RRT. Patients with impaired renal function on admission (creatinine clearance < 60 ml/min) (n = 84) had their laboratory indices of ATN/AKI analysed. The plasma creatinine level had the greatest area under the ROC curve (AUC): 0.83 (95% confidence interval 0.74-0.92), significantly better than the AUCs for, urinary sodium level, the urea to creatinine ratio (UCR), the fractional excretion of urea (FeUN) and the urinary neutrophil gelatinase-associated lipocalcin (NGAL) level. The AUC for plasma creatinine was also greater than the AUC for blood urea nitrogen level, the fractional excretion of sodium (FeNa), the renal failure index (RFI), the urinary osmolality, the urine to plasma creatinine ratio (UPCR) and the creatinine clearance, although the difference for these variables did not reach statistical significance. CONCLUSIONS: In adult patients with severe malaria and impaired renal function on admission, none of the evaluated laboratory indices was superior to the plasma creatinine level when used to predict a later requirement for renal replacement therapy.

Maude RJ, Saralamba S, Lewis A, Sherwood D, White NJ, Day NP, Dondorp AM, White LJ. 2011. Modelling malaria elimination on the internet. Malar J, 10 (1), pp. 191. | Show Abstract | Read more

BACKGROUND: Unprecedented efforts are underway to eliminate malaria. Mathematical modelling can help to determine the optimal strategies for malaria elimination in different epidemiological settings. This is necessary as there is limited scope for expensive and time-consuming field studies and failure of planned elimination strategies is likely to discourage ongoing investment by funders. However, there has been very little modelling of malaria elimination and little direct involvement of policymakers in its development. There is thus an urgent need for user-friendly and accessible models purpose-designed in collaboration with policymakers to answer pertinent questions arising from the field. RESULTS: An internet site is presented with a simple mathematical modelling platform for population level models of malaria elimination. It is freely accessible to all and designed to be flexible so both the platform and models can be developed through interaction with users. The site is an accessible introduction to modelling for a non-mathematical audience, and lessons learned from the project will help inform future development of mathematical models and improve communication of modelling results. Currently it hosts a simple model of strategies for malaria elimination and this will be developed, and more models added, over time. The iterative process of feedback and development will result in an educational and planning tool for non-modellers to assist with malaria elimination efforts worldwide. CONCLUSIONS: By collaboration with end users, iterative development of mathematical models of malaria elimination through this internet platform will maximize its potential as an educational and public health policy planning tool. It will also assist with preliminary optimisation of local malaria elimination strategies before commitment of valuable resources.

Maude RJ, Plewes K, Dimock J, Dondorp AM. 2011. Low-cost portable fluorescein angiography. Br J Ophthalmol, 95 (9), pp. 1213-1215. | Show Abstract | Read more

Fundus fluorescein angiography has great potential as a unique non-invasive tool to investigate in vivo the microvascular pathogenesis of a wide variety of diseases affecting the central nervous system. However, because it requires a bulky and expensive tabletop retinal camera, it is normally limited to cooperative and alert seated patients in well-resourced settings. Recently completed and ongoing studies of the pathogenesis of severe malaria are using fluorescein angiography to examine in detail the postulated central role of microvascular obstruction. We describe a novel method of fluorescein angiography with a portable retinal camera that can be adapted at very low cost for use in sick patients at the bedside. This method greatly expands the scope of potential studies utilising fluorescein angiography.

Maude RJ, White NJ, White LJ. 2011. Feasibility of malaria elimination. Lancet, 377 (9766), pp. 638. | Read more

Maude RJ, Hoque G, Hasan MU, Sayeed A, Akter S, Samad R, Alam B, Yunus EB, Rahman R, Rahman W et al. 2011. Timing of enteral feeding in cerebral malaria in resource-poor settings: a randomized trial. PLoS One, 6 (11), pp. e27273. | Show Abstract | Read more

BACKGROUND: Early start of enteral feeding is an established treatment strategy in intubated patients in intensive care since it reduces invasive bacterial infections and length of hospital stay. There is equipoise whether early enteral feeding is also beneficial in non-intubated patients with cerebral malaria in resource poor settings. We hypothesized that the risk of aspiration pneumonia might outweigh the potential benefits of earlier recovery and prevention of hypoglycaemia. METHOD AND FINDINGS: A randomized trial of early (day of admission) versus late (after 60 hours in adults or 36 hours in children) start of enteral feeding was undertaken in patients with cerebral malaria in Chittagong, Bangladesh from May 2008 to August 2009. The primary outcome measures were incidence of aspiration pneumonia, hypoglycaemia and coma recovery time. The trial was terminated after inclusion of 56 patients because of a high incidence of aspiration pneumonia in the early feeding group (9/27 (33%)), compared to the late feeding group (0/29 (0%)), p = 0.001). One patient in the late feeding group, and none in the early group, had hypoglycaemia during admission. There was no significant difference in overall mortality (9/27 (33%) vs 6/29 (21%), p = 0.370), but mortality was 5/9 (56%) in patients with aspiration pneumonia. CONCLUSIONS: In conclusion, early start of enteral feeding is detrimental in non-intubated patients with cerebral malaria in many resource-poor settings. Evidence gathered in resource rich settings is not necessarily transferable to resource-poor settings. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN57488577.

Maude RJ, Plewes K, Dimock J, Ondorp AMD. 2011. Low-cost portable fluorescein angiography British Journal of Ophthalmology, 95 (9), pp. 1213-1215. | Show Abstract | Read more

Fundus fluorescein angiography has great potential as a unique non-invasive tool to investigate in vivo the microvascular pathogenesis of a wide variety of diseases affecting the central nervous system. However, because it requires a bulky and expensive tabletop retinal camera, it is normally limited to cooperative and alert seated patients in well-resourced settings. Recently completed and ongoing studies of the pathogenesis of severe malaria are using fluorescein angiography to examine in detail the postulated central role of microvascular obstruction. We describe a novel method of fluorescein angiography with a portable retinal camera that can be adapted at very low cost for use in sick patients at the bedside. This method greatly expands the scope of potential studies utilising fluorescein angiography.

Abu Sayeed A, Maude RJ, Hasan MU, Mohammed N, Hoque MG, Dondorp AM, Faiz MA. 2011. Malarial retinopathy in Bangladeshi adults. Am J Trop Med Hyg, 84 (1), pp. 141-147. | Show Abstract | Read more

To establish if assessment of malarial retinopathy in adult malaria using ophthalmoscopy by non-ophthalmologists has clinical and prognostic significance, 210 Bangladeshi adults were assessed by both direct and indirect ophthalmoscopy; 20 of 20 healthy subjects and 20 of 20 patients with vivax malaria showed no retinal changes, whereas in patients with falciparum malaria, indirect ophthalmoscopy revealed malarial retinopathy (predominantly retinal hemorrhages) in 18 of 21 (86%) fatal, 31 of 75 (41%) cerebral, 16 of 64 (25%) non-cerebral but severe, and 1 of 31 (3%) uncomplicated cases. Direct ophthalmoscopy missed retinopathy in one of these cases and found fewer retinal hemorrhages (mean difference = 3.09; 95% confidence interval = 1.50-4.68; P < 0.0001). Severity of retinopathy increased with severity of disease (P for trend < 0.0001), and renal failure, acidosis, and moderate/severe retinopathy were independent predictors of mortality by both ophthalmoscopic techniques. Direct ophthalmoscopy by non-ophthalmologists is an important clinical tool to aid diagnosis and prognosis in adults with severe malaria, and indirect ophthalmoscopy by non-ophthalmologists, although more sensitive, provides minimal additional prognostic information.

Saralamba S, Pan-Ngum W, Maude RJ, Lee SJ, Tarning J, Lindegårdh N, Chotivanich K, Nosten F, Day NP, Socheat D et al. 2011. Intrahost modeling of artemisinin resistance in Plasmodium falciparum. Proc Natl Acad Sci U S A, 108 (1), pp. 397-402. | Show Abstract | Read more

Artemisinin-resistant Plasmodium falciparum malaria has emerged in western Cambodia. Resistance is characterized by prolonged in vivo parasite clearance times (PCTs) following artesunate treatment. The biological basis is unclear. The hypothesis that delayed parasite clearance results from a stage-specific reduction in artemisinin sensitivity of the circulating young asexual parasite ring stages was examined. A mathematical model was developed, describing the intrahost parasite stage-specific pharmacokinetic-pharmacodynamic relationships. Model parameters were estimated using detailed pharmacokinetic and parasite clearance data from 39 patients with uncomplicated falciparum malaria treated with artesunate from Pailin (western Cambodia) where artemisinin resistance was evident and 40 patients from Wang Pha (northwestern Thailand) where efficacy was preserved. The mathematical model reproduced the observed parasite clearance for each patient with an accurate goodness of fit (rmsd: 0.03-0.67 in log(10) scale). The parameter sets that provided the best fits with the observed in vivo data consist of a highly conserved concentration-effect relationship for the trophozoite and schizont parasite stages, but a variable relationship for the ring stages. The model-derived assessment suggests that the efficacy of artesunate on ring stage parasites is reduced significantly in Pailin. This result supports the hypothesis that artemisinin resistance mainly reflects reduced ring-stage susceptibility and predicts that doubling the frequency of dosing will accelerate clearance of artemisinin-resistant parasites.

Glover SJ, Maude RJ, Taylor TE, Molyneux ME, Beare NA. 2010. Malarial retinopathy and fluorescein angiography findings in a Malawian child with cerebral malaria. Lancet Infect Dis, 10 (6), pp. 440. | Read more

Koh GC, Maude RJ, Paris DH, Newton PN, Blacksell SD. 2010. Diagnosis of scrub typhus. Am J Trop Med Hyg, 82 (3), pp. 368-370. | Show Abstract | Read more

Scrub typhus is transmitted by trombiculid mites and is endemic to East and Southeast Asia and Northern Australia. The clinical syndrome classically consists of a fever, rash, and eschar, but scrub typhus also commonly presents as an undifferentiated fever that requires laboratory confirmation of the diagnosis, usually by indirect fluorescent antibody (IFA) assay. We discuss the limitations of IFA, debate the value of other methods based on antigen detection and nucleic acid amplification, and outline recommendations for future study.

Maude RJ, Woodrow CJ, White LJ. 2010. Artemisinin Antimalarials: Preserving the "Magic Bullet" Drug Dev Res, 71 (1), pp. 12-19. | Show Abstract | Read more

The artemisinins are the most effective antimalarial drugs known. They possess a remarkably wide therapeutic index. These agents have been used in traditional Chinese herbal medicine for more than 2,000 years but were not subjected to scientific scrutiny until the 1970s. The first formal clinical trials of the artemisinins, and the development of methods for their industrial scale production, followed rapidly. A decade later, Chinese scientists shared their findings with the rest of the world; since then, a significant body of international trial evidence has confirmed these drugs to be far superior to any available alternatives. In particular, they have the ability to rapidly kill a broad range of asexual parasite stages at safe concentrations that are consistently achievable via standard dosing regimens. As their half-life is very short, there was also thought to be a low risk of resistance. These discoveries coincided with the appearance and spread of resistance to all the other major classes of antimalarials. As a result, the artemisinins now form an essential element of recommended first-line antimalarial treatment regimens worldwide. To minimize the risk of artemisinin resistance, they are recommended to be used to treat uncomplicated malaria in combination with other antimalarials as artemisinin combination therapies (ACTs). Their rollout has resulted in documented reductions in malaria prevalence in a number of African and Asian countries. Unfortunately, there are already worrisome early signs of artemisinin resistance appearing in western Cambodia. If this resistance were to spread, it would be disastrous for malaria control efforts worldwide. The enormous challenge for the international community is how to avert this catastrophe and preserve the effectiveness of this antimalarial "magic bullet". Drug Dev Res 71: 12-19, 2010. © 2009 Wiley-Liss, Inc.

Maude RJ, Hassan MU, Ghose A, Douthwaite ST, Faiz MA, Dondorp AM. 2010. Studies on severe malaria are still possible and essential. Clin Infect Dis, 50 (2), pp. 281-282. | Read more

Rahman W, Chotivanich K, Silamut K, Tanomsing N, Hossain A, Faiz MA, Dondorp AM, Maude RJ. 2010. Plasmodium malariae in Bangladesh. Trans R Soc Trop Med Hyg, 104 (1), pp. 78-80. | Show Abstract | Read more

We describe a 32-year-old Bangladeshi male presenting with severe malaria caused by a mono-infection with Plasmodium malariae. Rosetting of infected and uninfected erythrocytes, a putative virulence factor in falciparum malaria, was observed in the blood slide. Severe disease caused by P. malariae is extremely rare. The patient made a rapid recovery with intravenous quinine treatment.

Löwenberg EC, Charunwatthana P, Cohen S, van den Born BJ, Meijers JC, Yunus EB, Hassan MU, Hoque G, Maude RJ, Nuchsongsin F et al. 2010. Severe malaria is associated with a deficiency of von Willebrand factor cleaving protease, ADAMTS13. Thromb Haemost, 103 (1), pp. 181-187. | Show Abstract | Read more

Severe falciparum malaria remains a major killer in tropical countries. Central in the pathophysiology is mechanical obstruction in the microcirculation caused by cytoadherence and sequestration of parasitized erythrocytes. However, the pathogenesis of many features complicating severe malaria, including coma, renal failure and thrombocytopenia, remains incompletely understood. These disease manifestations are also key features of thrombotic thrombocytopenic purpura, a life-threatening disease strongly associated with a deficiency of the von Willebrand factor (VWF) cleaving protease, ADAMTS13. We measured plasma ADAMTS13 activity, VWF antigen and VWF propeptide levels in 30 patients with severe falciparum malaria, 12 patients with uncomplicated falciparum malaria and 14 healthy Bangladeshi controls. In patients with severe malaria ADAMTS13 activity levels were markedly decreased in comparison to normal controls (mean [95%CI]: 23% [20-26] vs. 64% [55-72]) and VWF antigen and propeptide concentrations were significantly elevated (VWF antigen: 439% [396-481] vs. 64% [46-83]; VWF propeptide: 576% [481-671] vs. 69% [59-78]). In uncomplicated malaria VWF levels were also increased compared to healthy controls but ADAMTS13 activity was normal. The results suggest that decreased ADAMTS13 activity in combination with increased VWF concentrations may contribute to the complications in severe malaria.

Cited:

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Scopus

Koh GCKW, Maude RJ, Paris DH, Newton PN, Blacksell SD. 2010. Review: Diagnosis of scrub typhus American Journal of Tropical Medicine and Hygiene, 82 (3), pp. 368-370. | Show Abstract | Read more

Scrub typhus is transmitted by trombiculid mites and is endemic to East and Southeast Asia and Northern Australia. The clinical syndrome classically consists of a fever, rash, and eschar, but scrub typhus also commonly presents as an undifferentiated fever that requires laboratory confirmation of the diagnosis, usually by indirect fluorescent antibody (IFA) assay. We discuss the limitations of IFA, debate the value of other methods based on antigen detection and nucleic acid amplification, and outline recommendations for future study. Copyright © 2010 by The American Society of Tropical Medicine and Hygiene.

Maude RJ, Lubell Y, Socheat D, Yeung S, Saralamba S, Pongtavornpinyo W, Cooper BS, Dondorp AM, White NJ, White LJ. 2010. The role of mathematical modelling in guiding the science and economics of malaria elimination. Int Health, 2 (4), pp. 239-246. | Show Abstract | Read more

Unprecedented efforts are now underway to eliminate malaria from many regions. Despite the enormous financial resources committed, if malaria elimination is perceived as failing it is likely that this funding will not be sustained. It is imperative that methods are developed to use the limited data available to design site-specific, cost-effective elimination programmes. Mathematical modelling is a way of including mechanistic understanding to use available data to make predictions. Different strategies can be evaluated much more rapidly than is possible through trial and error in the field. Mathematical modelling has great potential as a tool to guide and inform current elimination efforts. Economic modelling weighs costs against characterised effects or predicted benefits in order to determine the most cost-efficient strategy but has traditionally used static models of disease not suitable for elimination. Dynamic mathematical modelling and economic modelling techniques need to be combined to contribute most effectively to ongoing policy discussions. We review the role of modelling in previous malaria control efforts as well as the unique nature of elimination and the consequent need for its explicit modelling, and emphasise the importance of good disease surveillance. The difficulties and complexities of economic evaluation of malaria control, particularly the end stages of elimination, are discussed.

Maude RJ, Buapetch W, Silamut K. 2009. A simplified, low-cost method for polarized light microscopy. Am J Trop Med Hyg, 81 (5), pp. 782-783. | Show Abstract | Read more

Malaria pigment is an intracellular inclusion body that appears in blood and tissue specimens on microscopic examination and can help in establishing the diagnosis of malaria. In simple light microscopy, it can be difficult to discern from cellular background and artifacts. It has long been known that if polarized light microscopy is used, malaria pigment can be much easier to distinguish. However, this technique is rarely used because of the need for a relatively costly polarization microscope. We describe a simple and economical technique to convert any standard light microscope suitable for examination of malaria films into a polarization microscope.

Wozniak MA, Maude RJ, Innes JA, Hawkey PM, Itzhaki RF. 2009. Apolipoprotein E-epsilon2 confers risk of pulmonary tuberculosis in women from the Indian subcontinent--a preliminary study. J Infect, 59 (3), pp. 219-222. | Read more

Maude RJ, Beare NA. 2009. Fluorescein angiography findings strengthen the theoretical basis for trialling neuroprotective agents in cerebral malaria. Trends Parasitol, 25 (8), pp. 350-351. | Read more

Maude RJ, Beare NA, Abu Sayeed A, Chang CC, Charunwatthana P, Faiz MA, Hossain A, Yunus EB, Hoque MG, Hasan MU et al. 2009. The spectrum of retinopathy in adults with Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg, 103 (7), pp. 665-671. | Show Abstract | Read more

A specific retinopathy has been described in African children with cerebral malaria, but in adults this has not been extensively studied. Since the structure and function of the retinal vasculature greatly resembles the cerebral vasculature, study of retinal changes can reveal insights into the pathophysiology of cerebral malaria. A detailed observational study of malarial retinopathy in Bangladeshi adults was performed using high-definition portable retinal photography. Retinopathy was present in 17/27 adults (63%) with severe malaria and 14/20 adults (70%) with cerebral malaria. Moderate or severe retinopathy was more frequent in cerebral malaria (11/20, 55%) than in uncomplicated malaria (3/15, 20%; P=0.039), bacterial sepsis (0/5, 0%; P=0.038) or healthy controls (0/18, 0%; P<0.001). The spectrum of malarial retinopathy was similar to that previously described in African children, but no vessel discolouration was observed. The severity of retinal whitening correlated with admission venous plasma lactate (P=0.046), suggesting that retinal ischaemia represents systemic ischaemia. In conclusion, retinal changes related to microvascular obstruction were common in adults with severe falciparum malaria and correlated with disease severity and coma, suggesting that a compromised microcirculation has important pathophysiological significance in severe and cerebral malaria. Portable retinal photography has potential as a valuable tool to study malarial retinopathy.

Maude RJ, Dondorp AM, Abu Sayeed A, Day NP, White NJ, Beare NA. 2009. The eye in cerebral malaria: what can it teach us? Trans R Soc Trop Med Hyg, 103 (7), pp. 661-664. | Show Abstract | Read more

The pathophysiology of coma in cerebral malaria (CM) is not well understood. Obstruction of microcirculatory flow is thought to play a central role, but other hypotheses include roles for parasite- and host-derived factors such as immune mediators, and for increased blood-brain barrier permeability leading to raised intracranial pressure. The retinal vasculature is a direct extension of the cerebral vasculature. It is the only vascular bed easily accessible for visualisation and provides a unique opportunity to observe vascular pathology and its effect on neurological tissue. A specific retinopathy has been well described in African children with CM and its severity correlates with outcome. This retinopathy has been less well described in adults. The central mechanism causing malarial retinopathy appears to be microvascular obstruction, which has been demonstrated in affected retinas by fluorescein angiography. The presence in a central nervous system tissue of microvascular obstruction strongly supports the hypothesis that the sequestration of erythrocytes in small blood vessels and consequent obstruction of microcirculatory flow is an important mechanism causing coma and death in CM. Despite advances in the antimalarial treatment of severe malaria, its mortality remains approximately 15-20%. Adjunctive treatment targeting sequestration is a promising strategy to further lower mortality.

Maude RJ, Pontavornpinyo W, Saralamba S, Dondorp AM, Day NP, White NJ, White LJ. 2009. The role of mathematical modelling in malaria elimination and eradication (Comment on: Can malaria be eliminated?). Trans R Soc Trop Med Hyg, 103 (6), pp. 643-644. | Read more

Maude RJ, Hassan MU, Beare NA. 2009. Severe retinal whitening in an adult with cerebral malaria. Am J Trop Med Hyg, 80 (6), pp. 881.

Pongtavornpinyo W, Hastings IM, Dondorp A, White LJ, Maude RJ, Saralamba S, Day NP, White NJ, Boni MF. 2009. Probability of emergence of antimalarial resistance in different stages of the parasite life cycle. Evol Appl, 2 (1), pp. 52-61. | Show Abstract | Read more

Understanding the evolution of drug resistance in malaria is a central area of study at the intersection of evolution and medicine. Antimalarial drug resistance is a major threat to malaria control and directly related to trends in malaria attributable mortality. Artemisinin combination therapies (ACT) are now recommended worldwide as first line treatment for uncomplicated malaria, and losing them to resistance would be a disaster for malaria control. Understanding the emergence and spread of antimalarial drug resistance in the context of different scenarios of antimalarial drug use is essential for the development of strategies protecting ACTs. In this study, we review the basic mechanisms of resistance emergence and describe several simple equations that can be used to estimate the probabilities of de novo resistance mutations at three stages of the parasite life cycle: sporozoite, hepatic merozoite and asexual blood stages; we discuss the factors that affect parasite survival in a single host in the context of different levels of antimalarial drug use, immunity and parasitaemia. We show that in the absence of drug effects, and despite very different parasite numbers, the probability of resistance emerging at each stage is very low and similar in all stages (for example per-infection probability of 10(-10)-10(-9) if the per-parasite chance of mutation is 10(-10) per asexual division). However, under the selective pressure provided by antimalarial treatment and particularly in the presence of hyperparasitaemia, the probability of resistance emerging in the blood stage of the parasite can be approximately five orders of magnitude higher than in the absence of drugs. Detailed models built upon these basic methods should allow us to assess the relative probabilities of resistance emergence in the different phases of the parasite life cycle.

Charunwatthana P, Abul Faiz M, Ruangveerayut R, Maude RJ, Rahman MR, Roberts LJ, Moore K, Bin Yunus E, Hoque MG, Hasan MU et al. 2009. N-acetylcysteine as adjunctive treatment in severe malaria: a randomized, double-blinded placebo-controlled clinical trial. Crit Care Med, 37 (2), pp. 516-522. | Show Abstract | Read more

OBJECTIVE: Markers of oxidative stress are reported to be increased in severe malaria. It has been suggested that the antioxidant N-acetylcysteine (NAC) may be beneficial in treatment. We studied the efficacy and safety of parenteral NAC as an adjunct to artesunate treatment of severe falciparum malaria. DESIGN: A randomized, double-blind, placebo-controlled trial on the use of high-dose intravenous NAC as adjunctive treatment to artesunate. SETTING: A provincial hospital in Western Thailand and a tertiary referral hospital in Chittagong, Bangladesh. PATIENTS: One hundred eight adult patients with severe falciparum malaria. INTERVENTIONS: Patients were randomized to receive NAC or placebo as an adjunctive treatment to intravenous artesunate. MEASUREMENTS AND MAIN RESULTS: A total of 56 patients were treated with NAC and 52 received placebo. NAC had no significant effect on mortality, lactate clearance times (p = 0.74), or coma recovery times (p = 0.46). Parasite clearance time was increased from 30 hours (range, 6-144 hours) to 36 hours (range, 6-120 hours) (p = 0.03), but this could be explained by differences in admission parasitemia. Urinary F2-isoprostane metabolites, measured as a marker of oxidative stress, were increased in severe malaria compared with patients with uncomplicated malaria and healthy volunteers. Admission red cell rigidity correlated with mortality, but did not improve with NAC. CONCLUSION: Systemic oxidative stress is increased in severe malaria. Treatment with NAC had no effect on outcome in patients with severe falciparum malaria in this setting.

White NJ, Pongtavornpinyo W, Maude RJ, Saralamba S, Aguas R, Stepniewska K, Lee SJ, Dondorp AM, White LJ, Day NP. 2009. Hyperparasitaemia and low dosing are an important source of anti-malarial drug resistance. Malar J, 8 (1), pp. 253. | Show Abstract | Read more

BACKGROUND: Preventing the emergence of anti-malarial drug resistance is critical for the success of current malaria elimination efforts. Prevention strategies have focused predominantly on qualitative factors, such as choice of drugs, use of combinations and deployment of multiple first-line treatments. The importance of anti-malarial treatment dosing has been underappreciated. Treatment recommendations are often for the lowest doses that produce "satisfactory" results. METHODS: The probability of de-novo resistant malaria parasites surviving and transmitting depends on the relationship between their degree of resistance and the blood concentration profiles of the anti-malarial drug to which they are exposed. The conditions required for the in-vivo selection of de-novo emergent resistant malaria parasites were examined and relative probabilities assessed. RESULTS: Recrudescence is essential for the transmission of de-novo resistance. For rapidly eliminated anti-malarials high-grade resistance can arise from a single drug exposure, but low-grade resistance can arise only from repeated inadequate treatments. Resistance to artemisinins is, therefore, unlikely to emerge with single drug exposures. Hyperparasitaemic patients are an important source of de-novo anti-malarial drug resistance. Their parasite populations are larger, their control of the infection insufficient, and their rates of recrudescence following anti-malarial treatment are high. As use of substandard drugs, poor adherence, unusual pharmacokinetics, and inadequate immune responses are host characteristics, likely to pertain to each recurrence of infection, a small subgroup of patients provides the particular circumstances conducive to de-novo resistance selection and transmission. CONCLUSION: Current dosing recommendations provide a resistance selection opportunity in those patients with low drug levels and high parasite burdens (often children or pregnant women). Patients with hyperparasitaemia who receive outpatient treatments provide the greatest risk of selecting de-novo resistant parasites. This emphasizes the importance of ensuring that only quality-assured anti-malarial combinations are used, that treatment doses are optimized on the basis of pharmacodynamic and pharmacokinetic assessments in the target populations, and that patients with heavy parasite burdens are identified and receive sufficient treatment to prevent recrudescence.

Hanson J, Hossain A, Charunwatthana P, Hassan MU, Davis TM, Lam SW, Chubb SA, Maude RJ, Yunus EB, Haque G et al. 2009. Hyponatremia in severe malaria: evidence for an appropriate anti-diuretic hormone response to hypovolemia. Am J Trop Med Hyg, 80 (1), pp. 141-145. | Show Abstract

Although hyponatremia occurs in most patients with severe malaria, its pathogenesis, prognostic significance, and optimal management have not been established. Clinical and biochemical data were prospectively collected from 171 consecutive Bangladeshi adults with severe malaria. On admission, 57% of patients were hyponatremic. Plasma sodium and Glasgow Coma Score were inversely related (r(s) = -0.36, P < 0.0001). Plasma antidiuretic hormone concentrations were similar in hyponatremic and normonatremic patients (median, range: 6.1, 2.3-85.3 versus 32.7, 3.0-56.4 pmol/L; P = 0.19). Mortality was lower in hyponatremic than normonatremic patients (31.6% versus 51.4%; odds ratio [95% confidence interval]: 0.44 [0.23-0.82]; P = 0.01 by univariate analysis). Plasma sodium normalized with crystalloid rehydration from (median, range) 127 (123-140) mmol/L on admission to 136 (128-149) mmol/L at 24 hours (P = 0.01). Hyponatremia in adults with severe malaria is common and associated with preserved consciousness and decreased mortality. It likely reflects continued oral hypotonic fluid intake in the setting of hypovolemia and requires no therapy beyond rehydration.

Maude RJ, Plewes K, Faiz MA, Hanson J, Charunwatthana P, Lee SJ, Tärning J, Yunus EB, Hoque MG, Hasan MU et al. 2009. Does artesunate prolong the electrocardiograph QT interval in patients with severe malaria? Am J Trop Med Hyg, 80 (1), pp. 126-132. | Show Abstract

Several antimalarials can cause significant prolongation of the electrocardiograph QT interval, which can be associated with an increased risk of potentially lethal ventricular arrhythmias. High doses of artemether and artemotil have been associated with QT prolongation in dogs, raising the possibility of a class effect with the artemisinin derivatives. Serial electrocardiograms were recorded, and QTc interval was calculated before and after administration of artesunate by intravenous injection in patients with severe falciparum malaria in Bangladesh. Of 21 adult patients with severe malaria enrolled, 8 (38%) died. The mean QTc interval was unaffected by bolus intravenous artesunate (2.4 mg/kg). In two patients, the QTc interval exceeded 0.5 seconds, but in both cases, an alternative explanation was plausible. No effect was observed on the JTc or PR interval, QRS width, blood pressure, or heart rate. Intravenous artesunate does not have significant cardiovascular effects in patients with severe falciparum malaria.

White LJ, Maude RJ, Pongtavornpinyo W, Saralamba S, Aguas R, Van Effelterre T, Day NP, White NJ. 2009. The role of simple mathematical models in malaria elimination strategy design. Malar J, 8 (1), pp. 212. | Show Abstract | Read more

BACKGROUND: Malaria has recently been identified as a candidate for global eradication. This process will take the form of a series of national eliminations. Key issues must be considered specifically for elimination strategy when compared to the control of disease. Namely the spread of drug resistance, data scarcity and the adverse effects of failed elimination attempts. Mathematical models of various levels of complexity have been produced to consider the control and elimination of malaria infection. If available, detailed data on malaria transmission (such as the vector life cycle and behaviour, human population behaviour, the acquisition and decay of immunity, heterogeneities in transmission intensity, age profiles of clinical and subclinical infection) can be used to populate complex transmission models that can then be used to design control strategy. However, in many malaria countries reliable data are not available and policy must be formed based on information like an estimate of the average parasite prevalence. METHODS: A simple deterministic model, that requires data in the form of a single estimate of parasite prevalence as an input, is developed for the purpose of comparison with other more complex models. The model is designed to include key aspects of malaria transmission and integrated control. RESULTS: The simple model is shown to have similar short-term dynamic behaviour to three complex models. The model is used to demonstrate the potential of alternative methods of delivery of controls. The adverse effects on clinical infection and spread of resistance are predicted for failed elimination attempts. Since elimination strategies present an increased risk of the spread of drug resistance, the model is used to demonstrate the population level protective effect of multiple controls against this very serious threat. CONCLUSION: A simple model structure for the elimination of malaria is suitable for situations where data are sparse yet strategy design requirements are urgent with the caveat that more complex models, populated with new data, would provide more information, especially in the long-term.

Maude RJ, Pontavornpinyo W, Saralamba S, Aguas R, Yeung S, Dondorp AM, Day NP, White NJ, White LJ. 2009. The last man standing is the most resistant: eliminating artemisinin-resistant malaria in Cambodia. Malar J, 8 (1), pp. 31. | Show Abstract | Read more

BACKGROUND: Artemisinin combination therapy (ACT) is now the recommended first-line treatment for falciparum malaria throughout the world. Initiatives to eliminate malaria are critically dependent on its efficacy. There is recent worrying evidence that artemisinin resistance has arisen on the Thai-Cambodian border. Urgent containment interventions are planned and about to be executed. Mathematical modeling approaches to intervention design are now integrated into the field of malaria epidemiology and control. The use of such an approach to investigate the likely effectiveness of different containment measures with the ultimate aim of eliminating artemisinin-resistant malaria is described. METHODS: A population dynamic mathematical modeling framework was developed to explore the relative effectiveness of a variety of containment interventions in eliminating artemisinin-resistant malaria in western Cambodia. RESULTS: The most effective intervention to eliminate artemisinin-resistant malaria was a switch of treatment from artemisinin monotherapy to ACT (mean time to elimination 3.42 years (95% CI 3.32-3.60 years). However, with this approach it is predicted that elimination of artemisinin-resistant malaria using ACT can be achieved only by elimination of all malaria. This is because the various forms of ACT are more effective against infections with artemisinin-sensitive parasites, leaving the more resistant infections as an increasing proportion of the dwindling parasite population. CONCLUSION: Containment of artemisinin-resistant malaria can be achieved by elimination of malaria from western Cambodia using ACT. The "last man standing" is the most resistant and thus this strategy must be sustained until elimination is truly achieved.

Chang CC, Cheng AC, Maude RJ, Slavin M. 2009. Antiviral prophylaxis for varicella zoster in immunocompromised patients (excluding haematological malignancies) Cochrane Database of Systematic Reviews, (4), | Read more

Maude RJ, Dondorp AM, Faiz MA, Yunus EB, Samad R, Hossain A, Rahman MR. 2008. Malaria in southeast Bangladesh: a descriptive study. Bangladesh Med Res Counc Bull, 34 (3), pp. 87-89. | Show Abstract | Read more

Malaria in Asia is thought to be grossly under-reported and this is evident from previously published statistics from Bangladesh. Malaria screening data from four Upazillas was analysed alongside census data to assess the trends in malaria incidence over time and distribution of malaria by age and gender. Malaria incidence in this area has decreased by around two thirds since 2003, although control measures were not significantly increased until 2005. Malaria occurred in people of all ages with the highest incidence being in young adults. This is consistent with higher occupational exposure in this group. The probability of being screened for malaria decreased with age suggesting significant numbers of adults with malaria may be being missed.

Maude RJ, Koh GC, Silamut K. 2008. Taking photographs with a microscope. Am J Trop Med Hyg, 79 (3), pp. 471-472. | Show Abstract

We describe a simple, economical, and highly practical technique for taking digital photographs of specimens visualized through a light microscope. Most models of light microscope and compact digital camera, and even some cameraphones, can be used. The technique is quick to learn and can easily be performed in a resource-poor setting. It can be used to assist with diagnosis in remote areas and can be extremely useful for teaching.

Parker DM, Landier J, von Seidlein L, Dondorp A, White L, Hanboonkunupakarn B, Maude RJ, Nosten FH. 2016. Limitations of malaria reactive case detection in an area of low and unstable transmission on the Myanmar-Thailand border. Malar J, 15 (1), pp. 571. | Show Abstract | Read more

BACKGROUND: Reactive case detection is an approach that has been proposed as a tool for malaria elimination in low-transmission settings. It is an intuitively justified approach based on the concept of space-time clustering of malaria cases. When an index malaria clinical case is detected, it triggers reactive screening and treatment in the index house and neighbouring houses. However, the efficacy of this approach at varying screening radii and malaria prevalence remains ill defined. METHODS: Data were obtained from a detailed demographic and geographic surveillance study in four villages on the Myanmar-Thailand border. Clinical cases were recorded at village malaria clinics and were linked back to patients' residencies. These data were used to simulate the efficacy of reactive case detection for clinical cases using rapid diagnostic tests (RDT). Simulations took clinical cases in a given month and tabulated the number of cases that would have been detected in the following month at varying screening radii around the index houses. Simulations were run independently for both falciparum and vivax malaria. Each simulation of a reactive case detection effort was run in comparison with a strategy using random selection of houses for screening. RESULTS: In approximately half of the screenings for falciparum and 10% for vivax it would have been impossible to detect any malaria cases regardless of the screening strategy because the screening would have occurred during times when there were no cases. When geographically linked cases were present in the simulation, reactive case detection would have only been successful at detecting most malaria cases using larger screening radii (150-m radius and above). At this screening radius and above, reactive case detection does not perform better than random screening of an equal number of houses in the village. Screening within very small radii detects only a very small proportion of cases, but despite this low performance is better than random screening with the same sample size. CONCLUSIONS: The results of these simulations indicate that reactive case detection for clinical cases using RDTs has limited ability in halting transmission in regions of low and unstable transmission. This is linked to high spatial heterogeneity of cases, acquisition of malaria infections outside the village, as well missing asymptomatic infections. When cases are few and sporadic, reactive case detection would result in major time and budgetary losses.

Grist EP, Flegg JA, Humphreys G, Mas IS, Anderson TJ, Ashley EA, Day NP, Dhorda M, Dondorp AM, Faiz MA et al. 2016. Optimal health and disease management using spatial uncertainty: a geographic characterization of emergent artemisinin-resistant Plasmodium falciparum distributions in Southeast Asia. Int J Health Geogr, 15 (1), pp. 37. | Show Abstract | Read more

BACKGROUND: Artemisinin-resistant Plasmodium falciparum malaria parasites are now present across much of mainland Southeast Asia, where ongoing surveys are measuring and mapping their spatial distribution. These efforts require substantial resources. Here we propose a generic 'smart surveillance' methodology to identify optimal candidate sites for future sampling and thus map the distribution of artemisinin resistance most efficiently. METHODS: The approach uses the 'uncertainty' map generated iteratively by a geostatistical model to determine optimal locations for subsequent sampling. RESULTS: The methodology is illustrated using recent data on the prevalence of the K13-propeller polymorphism (a genetic marker of artemisinin resistance) in the Greater Mekong Subregion. CONCLUSION: This methodology, which has broader application to geostatistical mapping in general, could improve the quality and efficiency of drug resistance mapping and thereby guide practical operations to eliminate malaria in affected areas.

Govindasamy G, Barber BE, Ghani SA, William T, Grigg MJ, Borooah S, Dhillon B, Dondorp AM, Yeo TW, Anstey NM, Maude RJ. 2016. Retinal Changes in Uncomplicated and Severe Plasmodium knowlesi Malaria. J Infect Dis, 213 (9), pp. 1476-1482. | Show Abstract | Read more

BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

Herdman MT, Maude RJ, Chowdhury MS, Kingston HW, Jeeyapant A, Samad R, Karim R, Dondorp AM, Hossain MA. 2016. The Relationship between Poverty and Healthcare Seeking among Patients Hospitalized with Acute Febrile Illnesses in Chittagong, Bangladesh. PLoS One, 11 (4), pp. e0152965. | Show Abstract | Read more

Delays in seeking appropriate healthcare can increase the case fatality of acute febrile illnesses, and circuitous routes of care-seeking can have a catastrophic financial impact upon patients in low-income settings. To investigate the relationship between poverty and pre-hospital delays for patients with acute febrile illnesses, we recruited a cross-sectional, convenience sample of 527 acutely ill adults and children aged over 6 months, with a documented fever ≥38.0 °C and symptoms of up to 14 days' duration, presenting to a tertiary referral hospital in Chittagong, Bangladesh, over the course of one year from September 2011 to September 2012. Participants were classified according to the socioeconomic status of their households, defined by the Oxford Poverty and Human Development Initiative's multidimensional poverty index (MPI). 51% of participants were classified as multidimensionally poor (MPI>0.33). Median time from onset of any symptoms to arrival at hospital was 22 hours longer for MPI poor adults compared to non-poor adults (123 vs. 101 hours) rising to a difference of 26 hours with adjustment in a multivariate regression model (95% confidence interval 7 to 46 hours; P = 0.009). There was no difference in delays for children from poor and non-poor households (97 vs. 119 hours; P = 0.394). Case fatality was 5.9% vs. 0.8% in poor and non-poor individuals respectively (P = 0.001)-5.1% vs. 0.0% for poor and non-poor adults (P = 0.010) and 6.4% vs. 1.8% for poor and non-poor children (P = 0.083). Deaths were attributed to central nervous system infection (11), malaria (3), urinary tract infection (2), gastrointestinal infection (1) and undifferentiated sepsis (1). Both poor and non-poor households relied predominantly upon the (often informal) private sector for medical advice before reaching the referral hospital, but MPI poor participants were less likely to have consulted a qualified doctor. Poor participants were more likely to attribute delays in decision-making and travel to a lack of money (P<0.001), and more likely to face catastrophic expenditure of more than 25% of monthly household income (P<0.001). We conclude that multidimensional poverty is associated with greater pre-hospital delays and expenditure in this setting. Closer links between health and development agendas could address these consequences of poverty and streamline access to adequate healthcare.

Tun KM, Imwong M, Lwin KM, Win AA, Hlaing TM, Hlaing T, Lin K, Kyaw MP, Plewes K, Faiz MA et al. 2015. Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker. Lancet Infect Dis, 15 (4), pp. 415-421. | Show Abstract | Read more

BACKGROUND: Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global control of Plasmodium falciparum malaria. Discovery of the K13 marker has transformed approaches to the monitoring of artemisinin resistance, allowing introduction of molecular surveillance in remote areas through analysis of DNA. We aimed to assess the spread of artemisinin-resistant P falciparum in Myanmar by determining the relative prevalence of P falciparum parasites carrying K13-propeller mutations. METHODS: We did this cross-sectional survey at malaria treatment centres at 55 sites in ten administrative regions in Myanmar, and in relevant border regions in Thailand and Bangladesh, between January, 2013, and September, 2014. K13 sequences from P falciparum infections were obtained mainly by passive case detection. We entered data into two geostatistical models to produce predictive maps of the estimated prevalence of mutations of the K13 propeller region across Myanmar. FINDINGS: Overall, 371 (39%) of 940 samples carried a K13-propeller mutation. We recorded 26 different mutations, including nine mutations not described previously in southeast Asia. In seven (70%) of the ten administrative regions of Myanmar, the combined K13-mutation prevalence was more than 20%. Geospatial mapping showed that the overall prevalence of K13 mutations exceeded 10% in much of the east and north of the country. In Homalin, Sagaing Region, 25 km from the Indian border, 21 (47%) of 45 parasite samples carried K13-propeller mutations. INTERPRETATION: Artemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided. FUNDING: Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme and the Bill & Melinda Gates Foundation.

Lubell Y, White L, Varadan S, Drake T, Yeung S, Cheah PY, Maude RJ, Dondorp A, Day NP, White NJ, Parker M. 2014. Ethics, economics, and the use of primaquine to reduce falciparum malaria transmission in asymptomatic populations. PLoS Med, 11 (8), pp. e1001704. | Show Abstract | Read more

Yoel Lubell and colleagues consider ethical and economic perspectives on mass drug administration of primaquine to limit transmission of P. falciparum malaria. Please see later in the article for the Editors' Summary.

Maude RJ, Nguon C, Dondorp AM, White LJ, White NJ. 2014. The diminishing returns of atovaquone-proguanil for elimination of Plasmodium falciparum malaria: modelling mass drug administration and treatment. Malar J, 13 (1), pp. 380. | Show Abstract | Read more

BACKGROUND: Artemisinin resistance is a major threat to current efforts to eliminate Plasmodium falciparum malaria which rely heavily on the continuing efficacy of artemisinin combination therapy (ACT). It has been suggested that ACT should not be used in mass drug administration (MDA) in areas where artemisinin-resistant P. falciparum is prevalent, and that atovaquone-proguanil (A-P) might be a preferable alternative. However, a single point mutation in the cytochrome b gene confers high level resistance to atovaquone, and such mutant parasites arise frequently during treatment making A-P a vulnerable tool for elimination. METHODS: A deterministic, population level, mathematical model was developed based on data from Cambodia to explore the possible effects of large-scale use of A-P compared to dihydroartemisinin-piperaquine ACT for mass drug administration and/or treatment of P. falciparum malaria, with and without adjunctive primaquine (PQ) and long-lasting insecticide-treated bed nets (LLIN). The aim was local elimination. RESULTS: The model showed the initial efficacy of ACT and A-P for MDA to be similar. However, each round of A-P MDA resulted in rapid acquisition and spread of atovaquone resistance. Even a single round of MDA could compromise efficacy sufficient to preclude its use for treatment or prophylaxis. A switch to A-P for treatment of symptomatic episodes resulted in a complete loss of efficacy in the population within four to five years of its introduction. The impact of MDA was temporary and a combination of maintained high coverage with ACT treatment for symptomatic individuals and LLIN was necessary for elimination. CONCLUSION: For malaria elimination, A-P for MDA or treatment of symptomatic cases should be avoided. A combined strategy of high coverage with ACT for treatment of symptomatic episodes, LLIN and ACT + P MDA would be preferable.

Maude RJ, Barkhof F, Hassan MU, Ghose A, Hossain A, Abul Faiz M, Choudhury E, Rashid R, Abu Sayeed A, Charunwatthana P et al. 2014. Magnetic resonance imaging of the brain in adults with severe falciparum malaria. Malar J, 13 (1), pp. 177. | Show Abstract | Read more

BACKGROUND: Magnetic resonance imaging (MRI) allows detailed study of structural and functional changes in the brain in patients with cerebral malaria. METHODS: In a prospective observational study in adult Bangladeshi patients with severe falciparum malaria, MRI findings in the brain were correlated with clinical and laboratory parameters, retinal photography and optic nerve sheath diameter (ONSD) ultrasound (a marker of intracranial pressure). RESULTS: Of 43 enrolled patients, 31 (72%) had coma and 12 (28%) died. MRI abnormalities were present in 79% overall with mostly mild changes in a wide range of anatomical sites. There were no differences in MRI findings between patients with cerebral and non-cerebral or fatal and non-fatal disease. Subtle diffuse cerebral swelling was common (n = 22/43), but mostly without vasogenic oedema or raised intracranial pressure (ONSD). Also seen were focal extracellular oedema (n = 11/43), cytotoxic oedema (n = 8/23) and mildly raised brain lactate on magnetic resonance spectroscopy (n = 5/14). Abnormalities were much less prominent than previously described in Malawian children. Retinal whitening was present in 36/43 (84%) patients and was more common and severe in patients with coma. CONCLUSION: Cerebral swelling is mild and not specific to coma or death in adult severe falciparum malaria. This differs markedly from African children. Retinal whitening, reflecting heterogeneous obstruction of the central nervous system microcirculation by sequestered parasites resulting in small patches of ischemia, is associated with coma and this process is likely important in the pathogenesis.

Maude RJ, Silamut K, Plewes K, Charunwatthana P, Ho M, Abul Faiz M, Rahman R, Hossain MA, Hassan MU, Bin Yunus E et al. 2014. Randomized controlled trial of levamisole hydrochloride as adjunctive therapy in severe falciparum malaria with high parasitemia. J Infect Dis, 209 (1), pp. 120-129. | Show Abstract | Read more

BACKGROUND: Cytoadherence and sequestration of erythrocytes containing mature stages of Plasmodium falciparum are central to the pathogenesis of severe malaria. The oral anthelminthic drug levamisole inhibits cytoadherence in vitro and reduces sequestration of late-stage parasites in uncomplicated falciparum malaria treated with quinine. METHODS: Fifty-six adult patients with severe malaria and high parasitemia admitted to a referral hospital in Bangladesh were randomized to receive a single dose of levamisole hydrochloride (150 mg) or no adjuvant to antimalarial treatment with intravenous artesunate. RESULTS: Circulating late-stage parasites measured as the median area under the parasite clearance curves were 2150 (interquartile range [IQR], 0-28 025) parasites/µL × hour in patients treated with levamisole and 5489 (IQR, 192-25 848) parasites/µL × hour in controls (P = .25). The "sequestration ratios" at 6 and 12 hours for all parasite stages and changes in microvascular blood flow did not differ between treatment groups (all P > .40). The median time to normalization of plasma lactate (<2 mmol/L) was 24 (IQR, 12-30) hours with levamisole vs 28 (IQR, 12-36) hours without levamisole (P = .15). CONCLUSIONS: There was no benefit of a single-dose of levamisole hydrochloride as adjuvant to intravenous artesunate in the treatment of adults with severe falciparum malaria. Rapid parasite killing by intravenous artesunate might obscure the effects of levamisole.

Maude RJ, Hasan MU, Hossain MA, Sayeed AA, Kanti Paul S, Rahman W, Maude RR, Vaid N, Ghose A, Amin R et al. 2012. Temporal trends in severe malaria in Chittagong, Bangladesh. Malar J, 11 (1), pp. 323. | Show Abstract | Read more

BACKGROUND: Epidemiological data on malaria in Bangladesh are sparse, particularly on severe and fatal malaria. This hampers the allocation of healthcare provision in this resource-poor setting. Over 85% of the estimated 150,000-250,000 annual malaria cases in Bangladesh occur in Chittagong Division with 80% in the Chittagong Hill Tracts (CHT). Chittagong Medical College Hospital (CMCH) is the major tertiary referral hospital for severe malaria in Chittagong Division. METHODS: Malaria screening data from 22,785 inpatients in CMCH from 1999-2011 were analysed to investigate the patterns of referral, temporal trends and geographical distribution of severe malaria in Chittagong Division, Bangladesh. RESULTS: From 1999 till 2011, 2,394 malaria cases were admitted, of which 96% harboured Plasmodium falciparum and 4% Plasmodium vivax. Infection was commonest in males (67%) between 15 and 34 years of age. Seasonality of malaria incidence was marked with a single peak in P. falciparum transmission from June to August coinciding with peak rainfall, whereas P. vivax showed an additional peak in February-March possibly representing relapse infections. Since 2007 there has been a substantial decrease in the absolute number of admitted malaria cases. Case fatality in severe malaria was 18% from 2008-2011, remaining steady during this period.A travel history obtained in 226 malaria patients revealed only 33% had been to the CHT in the preceding three weeks. Of all admitted malaria patients, only 9% lived in the CHT, and none in the more remote malaria endemic regions near the Indian border. CONCLUSIONS: The overall decline in admitted malaria cases to CMCH suggests recent control measures are successful. However, there are no reliable data on the incidence of severe malaria in the CHT, the most endemic area of Bangladesh, and most of these patients do not reach tertiary health facilities. Improvement of early treatment and simple supportive care for severe malaria in remote areas and implementation of a referral system for cases requiring additional supportive care could be important contributors to further reducing malaria-attributable disease and death in Bangladesh.

Maude RJ, Socheat D, Nguon C, Saroth P, Dara P, Li G, Song J, Yeung S, Dondorp AM, Day NP et al. 2012. Optimising strategies for Plasmodium falciparum malaria elimination in Cambodia: primaquine, mass drug administration and artemisinin resistance. PLoS One, 7 (5), pp. e37166. | Show Abstract | Read more

BACKGROUND: Malaria elimination requires a variety of approaches individually optimized for different transmission settings. A recent field study in an area of low seasonal transmission in South West Cambodia demonstrated dramatic reductions in malaria parasite prevalence following both mass drug administration (MDA) and high treatment coverage of symptomatic patients with artemisinin-piperaquine plus primaquine. This study employed multiple combined strategies and it was unclear what contribution each made to the reductions in malaria. METHOD AND FINDINGS: A mathematical model fitted to the trial results was used to assess the effects of the various components of these interventions, design optimal elimination strategies, and explore their interactions with artemisinin resistance, which has recently been discovered in Western Cambodia. The modelling indicated that most of the initial reduction of P. falciparum malaria resulted from MDA with artemisinin-piperaquine. The subsequent continued decline and near elimination resulted mainly from high coverage with artemisinin-piperaquine treatment. Both these strategies were more effective with the addition of primaquine. MDA with artemisinin combination therapy (ACT) increased the proportion of artemisinin resistant infections, although much less than treatment of symptomatic cases with ACT, and this increase was slowed by adding primaquine. Artemisinin resistance reduced the effectiveness of interventions using ACT when the prevalence of resistance was very high. The main results were robust to assumptions about primaquine action, and immunity. CONCLUSIONS: The key messages of these modelling results for policy makers were: high coverage with ACT treatment can produce a long-term reduction in malaria whereas the impact of MDA is generally only short-term; primaquine enhances the effect of ACT in eliminating malaria and reduces the increase in proportion of artemisinin resistant infections; parasite prevalence is a better surveillance measure for elimination programmes than numbers of symptomatic cases; combinations of interventions are most effective and sustained efforts are crucial for successful elimination.

Saralamba S, Pan-Ngum W, Maude RJ, Lee SJ, Tarning J, Lindegårdh N, Chotivanich K, Nosten F, Day NP, Socheat D et al. 2011. Intrahost modeling of artemisinin resistance in Plasmodium falciparum. Proc Natl Acad Sci U S A, 108 (1), pp. 397-402. | Show Abstract | Read more

Artemisinin-resistant Plasmodium falciparum malaria has emerged in western Cambodia. Resistance is characterized by prolonged in vivo parasite clearance times (PCTs) following artesunate treatment. The biological basis is unclear. The hypothesis that delayed parasite clearance results from a stage-specific reduction in artemisinin sensitivity of the circulating young asexual parasite ring stages was examined. A mathematical model was developed, describing the intrahost parasite stage-specific pharmacokinetic-pharmacodynamic relationships. Model parameters were estimated using detailed pharmacokinetic and parasite clearance data from 39 patients with uncomplicated falciparum malaria treated with artesunate from Pailin (western Cambodia) where artemisinin resistance was evident and 40 patients from Wang Pha (northwestern Thailand) where efficacy was preserved. The mathematical model reproduced the observed parasite clearance for each patient with an accurate goodness of fit (rmsd: 0.03-0.67 in log(10) scale). The parameter sets that provided the best fits with the observed in vivo data consist of a highly conserved concentration-effect relationship for the trophozoite and schizont parasite stages, but a variable relationship for the ring stages. The model-derived assessment suggests that the efficacy of artesunate on ring stage parasites is reduced significantly in Pailin. This result supports the hypothesis that artemisinin resistance mainly reflects reduced ring-stage susceptibility and predicts that doubling the frequency of dosing will accelerate clearance of artemisinin-resistant parasites.

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