Professor Yoel Lubell

Research Area: Global Health
Technology Exchange: Bioinformatics, Computational biology and Medical statistics
Scientific Themes: Tropical Medicine & Global Health and Clinical Trials & Epidemiology
Keywords: Health Economics; Epidemiology; Malaria
Web Links:

I lead the Economics and Translational Research Group (ETRG) at the Mahidol Oxford Tropical Medicine Research Unit in Bangkok, Thailand. ETRG focuses on the evaluation of diagnostics, treatments and vaccines for malaria and other infectious diseases. These evaluations are pursued using a variety of approaches ranging from economic and epidemiological modelling through laboratory investigations to clinical trials and qualitative research. Our ultimate aim is to provide policy makers with pragmatic and context specific assessments of the impact of new interventions if implemented in routine care. Where relevant we strive to take a broader view of the costs and benefits of new interventions accounting for factors such as their indirect impact on disease transmission and antimicrobial resistance as well as how such interventions’ cost-effectiveness varies in different epidemiological and socio-economic contexts or due to factors such as patents and health workers’ acceptance. 

Name Department Institution Country
Professor Lisa J White Tropical Medicine Oxford University, Bangkok Thailand
Professor Nicholas PJ Day FMedSci FRCP Tropical Medicine Oxford University, Bangkok Thailand
Professor Adrianus Dondorp Tropical Medicine Oxford University, Bangkok Thailand
Professor Sir Nicholas J White FRS Tropical Medicine Oxford University, Bangkok Thailand
Professor Phaik Yeong Cheah Tropical Medicine Oxford University, Bangkok Thailand
Professor Ben Cooper Tropical Medicine Oxford University, Bangkok Thailand
Professor Richard Price Tropical Medicine Oxford University, Asia Pacific Australia
Associate Professor Maciej F Boni Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Professor Susanna J Dunachie FRCP FRCPath Tropical Medicine Oxford University, Peter Medawar Building United Kingdom
Professor Daniel H Paris Tropical Medicine Oxford University, Bangkok Thailand
Bonell A, Lubell Y, Newton PN, Crump JA, Paris DH. 2017. Estimating the burden of scrub typhus: A systematic review. PLoS Negl Trop Dis, 11 (9), pp. e0005838. | Show Abstract | Read more

BACKGROUND: Scrub typhus is a vector-borne zoonotic disease that can be life-threatening. There are no licensed vaccines, or vector control efforts in place. Despite increasing awareness in endemic regions, the public health burden and global distribution of scrub typhus remains poorly known. METHODS: We systematically reviewed all literature from public health records, fever studies and reports available on the Ovid MEDLINE, Embase Classic + Embase and EconLit databases, to estimate the burden of scrub typhus since the year 2000. FINDINGS: In prospective fever studies from Asia, scrub typhus is a leading cause of treatable non-malarial febrile illness. Sero-epidemiological data also suggest that Orientia tsutsugamushi infection is common across Asia, with seroprevalence ranging from 9.3%-27.9% (median 22.2% IQR 18.6-25.7). A substantial apparent rise in minimum disease incidence (median 4.6/100,000/10 years, highest in China with 11.2/100,000/10 years) was reported through passive national surveillance systems in South Korea, Japan, China, and Thailand. Case fatality risks from areas of reduced drug-susceptibility are reported at 12.2% and 13.6% for South India and northern Thailand, respectively. Mortality reports vary widely around a median mortality of 6.0% for untreated and 1.4% for treated scrub typhus. Limited evidence suggests high mortality in complicated scrub typhus with CNS involvement (13.6% mortality), multi-organ dysfunction (24.1%) and high pregnancy miscarriage rates with poor neonatal outcomes. INTERPRETATION: Scrub typhus appears to be a truly neglected tropical disease mainly affecting rural populations, but increasingly also metropolitan areas. Rising minimum incidence rates have been reported over the past 8-10 years from countries with an established surveillance system. A wider distribution of scrub typhus beyond Asia is likely, based on reports from South America and Africa. Unfortunately, the quality and quantity of the available data on scrub typhus epidemiology is currently too limited for any economical, mathematical modeling or mapping approaches.

Devine A, Parmiter M, Chu CS, Bancone G, Nosten F, Price RN, Lubell Y, Yeung S. 2017. Using G6PD tests to enable the safe treatment of Plasmodium vivax infections with primaquine on the Thailand-Myanmar border: A cost-effectiveness analysis. PLoS Negl Trop Dis, 11 (5), pp. e0005602. | Show Abstract | Read more

BACKGROUND: Primaquine is the only licensed antimalarial for the radical cure of Plasmodium vivax infections. Many countries, however, do not administer primaquine due to fear of hemolysis in those with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In other settings, primaquine is given without G6PD testing, putting patients at risk of hemolysis. New rapid diagnostic tests (RDTs) offer the opportunity to screen for G6PD deficiency prior to treatment with primaquine. Here we assessed the cost-effectiveness of using G6PD RDTs on the Thailand-Myanmar border and provide the model as an online tool for use in other settings. METHODS/PRINCIPAL FINDINGS: Decision tree models for the management of P. vivax malaria evaluated the costs and disability-adjusted life-years (DALYs) associated with recurrences and primaquine-induced hemolysis from a health care provider perspective. Screening with G6PD RDTs before primaquine use was compared to (1) giving chloroquine alone and (2) giving primaquine without screening. Data were taken from a recent study on the impact of primaquine on P. vivax recurrences and a literature review. Compared to the use of chloroquine alone, the screening strategy had similar costs while averting 0.026 and 0.024 DALYs per primary infection in males and females respectively. Compared to primaquine administered without screening, the screening strategy provided modest cost savings while averting 0.011 and 0.004 DALYs in males and females respectively. The probabilistic sensitivity analyses resulted in a greater than 75% certainty that the screening strategy was cost-effective at a willingness to pay threshold of US$500, which is well below the common benchmark of per capita gross domestic product for Myanmar. CONCLUSIONS/SIGNIFICANCE: In this setting G6PD RDTs could avert DALYs by reducing recurrences and reducing hemolytic risk in G6PD deficient patients at low costs or cost savings. The model results are limited by the paucity of data available in the literature for some parameter values, including the mortality rates for both primaquine-induced hemolysis and P. vivax. The online model provides an opportunity to use different parameter estimates to examine the validity of these findings in other settings.

Tun STT, Lubell Y, Dondorp AM, Fieldman T, Tun KM, Celhay O, Chan XH, Saralamba S, White LJ. 2017. Identifying artemisinin resistance from parasite clearance half-life data with a simple Shiny web application. PLoS One, 12 (5), pp. e0177840. | Show Abstract | Read more

The emergence of artemisinin-resistant Plasmodium falciparum malaria is a major threat to malaria elimination. New tools for supporting the surveillance of artemisinin resistance are critical for current and future malaria control and elimination strategies. We have developed an open-access, user-friendly, web-based tool to analyse parasite clearance half-life data of P. falciparum infected patients after treatment with artemisinin derivatives, so that resistance to artemisinin can be identified. The tool can be accessed at bit.ly/id_artemisinin_resistance.

Lubell Y, Althaus T. 2017. Biomarker tests for bacterial infection-a costly wait for the holy grail. Lancet Infect Dis, 17 (4), pp. 369-370. | Read more

Schultz MJ, Dunser MW, Dondorp AM, Adhikari NKJ, Iyer S, Kwizera A, Lubell Y, Papali A, Pisani L, Riviello BD et al. 2017. Current challenges in the management of sepsis in ICUs in resource-poor settings and suggestions for the future. Intensive Care Med, 43 (5), pp. 612-624. | Show Abstract | Read more

BACKGROUND: Sepsis is a major reason for intensive care unit (ICU) admission, also in resource-poor settings. ICUs in low- and middle-income countries (LMICs) face many challenges that could affect patient outcome. AIM: To describe differences between resource-poor and resource-rich settings regarding the epidemiology, pathophysiology, economics and research aspects of sepsis. We restricted this manuscript to the ICU setting even knowing that many sepsis patients in LMICs are treated outside an ICU. FINDINGS: Although many bacterial pathogens causing sepsis in LMICs are similar to those in high-income countries, resistance patterns to antimicrobial drugs can be very different; in addition, causes of sepsis in LMICs often include tropical diseases in which direct damaging effects of pathogens and their products can sometimes be more important than the response of the host. There are substantial and persisting differences in ICU capacities around the world; not surprisingly the lowest capacities are found in LMICs, but with important heterogeneity within individual LMICs. Although many aspects of sepsis management developed in rich countries are applicable in LMICs, implementation requires strong consideration of cost implications and the important differences in resources. CONCLUSIONS: Addressing both disease-specific and setting-specific factors is important to improve performance of ICUs in LMICs. Although critical care for severe sepsis is likely cost-effective in LMIC setting, more detailed evaluation at both at a macro- and micro-economy level is necessary. Sepsis management in resource-limited settings is a largely unexplored frontier with important opportunities for research, training, and other initiatives for improvement.

Haniffa R, Lubell Y, Cooper BS, Mohanty S, Alam S, Karki A, Pattnaik R, Maswood A, Haque R, Pangeni R et al. 2017. Impact of a structured ICU training programme in resource-limited settings in Asia. PLoS One, 12 (3), pp. e0173483. | Show Abstract | Read more

OBJECTIVE: To assess the impact on ICU performance of a modular training program in three resource-limited general adult ICUs in India, Bangladesh, and Nepal. METHOD: A modular ICU training programme was evaluated using performance indicators from June 2009 to June 2012 using an interrupted time series design with an 8 to 15 month pre-intervention and 18 to 24 month post-intervention period. ICU physicians and nurses trained in Europe and the USA provided training for ICU doctors and nurses. The training program consisted of six modules on basic intensive care practices of 2-3 weeks each over 20 months. The performance indicators consisting of ICU mortality, time to ICU discharge, rate at which patients were discharged alive from the ICU, discontinuation of mechanical ventilation or vasoactive drugs and duration of antibiotic use were extracted. Stepwise changes and changes in trends associated with the intervention were analysed. RESULTS: Pre-Training ICU mortality in Rourkela (India), and Patan (Nepal) Chittagong (Bangladesh), was 28%, 41% and 62%, respectively, compared to 30%, 18% and 51% post-intervention. The intervention was associated with a stepwise reduction in cumulative incidence of in-ICU mortality in Chittagong (adjusted subdistribution hazard ratio [aSHR] (95% CI): 0.62 (0.40, 0.97), p = 0.03) and Patan (aSHR 0.16 (0.06, 0.41), p<0.001), but not in Rourkela (aSHR: 1.17 (0.75, 1.82), p = 0.49). The intervention was associated with earlier discontinuation of vasoactive drugs at Rourkela (adjusted hazard ratio for weekly change [aHR] 1.08 (1.03, 1.14), earlier discontinuation of mechanical ventilation in Chittagong (aHR 2.97 (1.24, 7.14), p = 0.02), and earlier ICU discharge in Patan (aHR 1.87 (1.02, 3.43), p = 0.04). CONCLUSION: This structured training program was associated with a decrease in ICU mortality in two of three sites and improvement of other performance indicators. A larger cluster randomised study assessing process outcomes and longer-term indicators is warranted.

Drake TL, Lubell Y. 2017. Erratum to: Malaria and Economic Evaluation Methods: Challenges and Opportunities. Appl Health Econ Health Policy, 15 (3), pp. 435. | Show Abstract | Read more

© 2017, Springer International Publishing Switzerland. An Online First version of this article was made available at http://link.springer.com/journal/40258/onlineFirst/page/ 1 on 19 Jan 2017. However, there was an error in Fig. 2. Although the figure was correct in the original manuscript, an error was introduced while replacing it with a higher resolution file during the production of the article. The article has now been updated with a corrected version of Fig. 2, which is also provided in this erratum.

Drake TL, Lubell Y, Kyaw SS, Devine A, Kyaw MP, Day NPJ, Smithuis FM, White LJ. 2017. Geographic Resource Allocation Based on Cost Effectiveness: An Application to Malaria Policy. Appl Health Econ Health Policy, 15 (3), pp. 299-306. | Show Abstract | Read more

Healthcare services are often provided to a country as a whole, though in many cases the available resources can be more effectively targeted to specific geographically defined populations. In the case of malaria, risk is highly geographically heterogeneous, and many interventions, such as insecticide-treated bed nets and malaria community health workers, can be targeted to populations in a way that maximises impact for the resources available. This paper describes a framework for geographically targeted budget allocation based on the principles of cost-effectiveness analysis and applied to priority setting in malaria control and elimination. The approach can be used with any underlying model able to estimate intervention costs and effects given relevant local data. Efficient geographic targeting of core malaria interventions could significantly increase the impact of the resources available, accelerating progress towards elimination. These methods may also be applicable to priority setting in other disease areas.

Hearn P, Miliya T, Seng S, Ngoun C, Day NPJ, Lubell Y, Turner C, Turner P. 2017. Prospective surveillance of healthcare associated infections in a Cambodian pediatric hospital. Antimicrob Resist Infect Control, 6 (1), pp. 16. | Show Abstract | Read more

BACKGROUND: Healthcare associated infections (HAI) are the most common preventable adverse events following admission to healthcare facilities. Data from low-income countries are scarce. We sought to prospectively define HAI incidence at Angkor Hospital for Children (AHC), a Cambodian pediatric referral hospital. METHODS: Prospective HAI surveillance was introduced for medical admissions to AHC. Cases were identified on daily ward rounds and confirmed using locally adapted Centers for Disease Control and Prevention (CDC) definitions. During the surveillance period, established infection prevention and control (IPC) activities continued, including hand hygiene surveillance. In addition, antimicrobial stewardship practices such as the creation of an antimicrobial guideline smartphone app were introduced. RESULTS: Between 1st January and 31st December 2015 there were 3,263 medical admissions and 102 HAI cases. The incidence of HAI was 4.6/1,000 patient-days (95% confidence interval 3.8-5.6) and rates were highest amongst neonates. Median length of stay was significantly longer in HAI cases: 25 days versus 5 days for non-HAI cases (p < 0.0001). All-cause in-hospital mortality increased from 2.0 to 16.1% with HAI (p < 0.0001). Respiratory infections were the most common HAI (54/102; 52.9%). Amongst culture positive infections, Gram-negative organisms predominated (13/16; 81.3%). Resistance to third generation cephalosporins was common, supporting the use of more expensive carbapenem drugs empirically in HAI cases. The total cost of treatment for all 102 HCAI cases combined, based on additional inpatient days, was estimated to be $299,608. CONCLUSIONS: Prospective HAI surveillance can form part of routine practice in low-income healthcare settings. HAI incidence at AHC was relatively low, but human and financial costs remained high due to increased carbapenem use, prolonged admissions and higher mortality rates.

Drake TL, Lubell Y. 2017. Malaria and Economic Evaluation Methods: Challenges and Opportunities. Appl Health Econ Health Policy, 15 (3), pp. 291-297. | Show Abstract | Read more

There is a growing evidence base on the cost effectiveness of malaria interventions. However, certain characteristics of malaria decision problems present a challenge to the application of healthcare economic evaluation methods. This paper identifies five such challenges. The complexities of (i) declining incidence and cost effectiveness in the context of an elimination campaign; (ii) international aid and its effect on resource constraints; and (iii) supranational priority setting, all affect how health economists might use a cost-effectiveness threshold. Consensus and guidance on how to determine and interpret cost-effectiveness thresholds in the context of internationally financed elimination campaigns is greatly needed. (iv) Malaria interventions are often complimentary and evaluations may need to construct intervention bundles to represent relevant policy positions as sets of mutually exclusive alternatives. (v) Geographic targeting is a key aspect of malaria policy making that is only beginning to be addressed in economic evaluations. An approach to budget-based geographic resource allocation is described in an accompanying paper in this issue and addresses some of these methodological challenges.

Do NTT, Ta NTD, Tran NTH, Than HM, Vu BTN, Hoang LB, van Doorn HR, Vu DTV, Cals JWL, Chandna A et al. 2016. Point-of-care C-reactive protein testing to reduce inappropriate use of antibiotics for non-severe acute respiratory infections in Vietnamese primary health care: a randomised controlled trial. Lancet Glob Health, 4 (9), pp. e633-e641. | Show Abstract | Read more

BACKGROUND: Inappropriate antibiotic use for acute respiratory tract infections is common in primary health care, but distinguishing serious from self-limiting infections is difficult, particularly in low-resource settings. We assessed whether C-reactive protein point-of-care testing can safely reduce antibiotic use in patients with non-severe acute respiratory tract infections in Vietnam. METHOD: We did a multicentre open-label randomised controlled trial in ten primary health-care centres in northern Vietnam. Patients aged 1-65 years with at least one focal and one systemic symptom of acute respiratory tract infection were assigned 1:1 to receive either C-reactive protein point-of-care testing or routine care, following which antibiotic prescribing decisions were made. Patients with severe acute respiratory tract infection were excluded. Enrolled patients were reassessed on day 3, 4, or 5, and on day 14 a structured telephone interview was done blind to the intervention. Randomised assignments were concealed from prescribers and patients but not masked as the test result was used to assist treatment decisions. The primary outcome was antibiotic use within 14 days of follow-up. All analyses were prespecified in the protocol and the statistical analysis plan. All analyses were done on the intention-to-treat population and the analysis of the primary endpoint was repeated in the per-protocol population. This trial is registered under number NCT01918579. FINDINGS: Between March 17, 2014, and July 3, 2015, 2037 patients (1028 children and 1009 adults) were enrolled and randomised. One adult patient withdrew immediately after randomisation. 1017 patients were assigned to receive C-reactive protein point-of-care testing, and 1019 patients were assigned to receive routine care. 115 patients in the C-reactive protein point-of-care group and 72 patients in the routine care group were excluded in the intention-to-treat analysis due to missing primary endpoint. The number of patients who used antibiotics within 14 days was 581 (64%) of 902 patients in the C-reactive protein group versus 738 (78%) of 947 patients in the control group (odds ratio [OR] 0·49, 95% CI 0·40-0·61; p<0·0001). Highly significant differences were seen in both children and adults, with substantial heterogeneity of the intervention effect across the 10 sites (I(2)=84%, 95% CI 66-96). 140 patients in the C-reactive protein group and 137 patients in the routine care group missed the urine test on day 3, 4, or 5. Antibiotic activity in urine on day 3, 4, or 5 was found in 267 (30%) of 877 patients in the C-reactive protein group versus 314 (36%) of 882 patients in the routine treatment group (OR 0·78, 95% CI 0·63-0·95; p=0·015). Time to resolution of symptoms was similar in both groups. Adverse events were rare, with no deaths and a total of 14 hospital admissions (six in the C-reactive protein group and eight in the control group). INTERPRETATION: C-reactive protein point-of-care testing reduced antibiotic use for non-severe acute respiratory tract infection without compromising patients' recovery in primary health care in Vietnam. Health-care providers might have become familiar with the clinical picture of low C-reactive protein, leading to reduction in antibiotic prescribing in both groups, but this would have led to a reduction in observed effect, rather than overestimation. Qualitative analysis is needed to address differences in context in order to implement this strategy to improve rational antibiotic use for patients with acute respiratory infection in low-income and middle-income countries. FUNDING: Wellcome Trust, UK, and Global Antibiotic Resistance Partnership, USA.

Peto TJ, Kloprogge SE, Tripura R, Nguon C, Sanann N, Yok S, Heng C, Promnarate C, Chalk J, Song N et al. 2016. History of malaria treatment as a predictor of subsequent subclinical parasitaemia: a cross-sectional survey and malaria case records from three villages in Pailin, western Cambodia. Malar J, 15 (1), pp. 240. | Show Abstract | Read more

BACKGROUND: Treatment of the sub-clinical reservoir of malaria, which may maintain transmission, could be an important component of elimination strategies. The reliable detection of asymptomatic infections with low levels of parasitaemia requires high-volume quantitative polymerase chain reaction (uPCR), which is impractical to conduct on a large scale. It is unknown to what extent sub-clinical parasitaemias originate from recent or older clinical episodes. This study explored the association between clinical history of malaria and subsequent sub-clinical parasitaemia. METHODS: In June 2013 a cross-sectional survey was conducted in three villages in Pailin, western Cambodia. Demographic and epidemiological data and blood samples were collected. Blood was tested for malaria by high-volume qPCR. Positive samples were analysed by nested PCR to determine the Plasmodium species. To identify previous episodes of malaria, case records were collected from village malaria workers and local health facilities and linked to study participants. RESULTS: Among 1343 participants, 40/122 (32.8 %) with a history of clinical malaria were parasitaemic during the cross-sectional survey, compared to 172/1221 (14.1 %) without this history (p < 0.001). Among the 212 parasitaemic participants in the survey, 40 (18.9 %) had a history of clinical malaria, compared to 87 out of 1131 (7.7 %) parasite-negative participants; p < 0.001, adjusted OR 3.3 (95 % CI; 2.1-5.1). A history of Plasmodium vivax was associated with sub-clinical P. vivax parasitaemia in the survey (p < 0.001), but this association was not seen with Plasmodium falciparum (p = 0.253); only three participants had both P. falciparum parasites in the survey and a clinical history of P. falciparum. CONCLUSIONS: A clinical episode of vivax malaria was associated with subsequent sub-clinical parasitaemia. Treatment of P. vivax with artemisinin-based combination therapy without primaquine often resulted in recurrent episodes. Targeting individuals with a history of clinical malaria will be insufficient to eliminate the sub-clinical reservoir as they constitute a minority of parasitaemias.

Drake TL, Devine A, Yeung S, Day NPJ, White LJ, Lubell Y. 2016. Dynamic Transmission Economic Evaluation of Infectious Disease Interventions in Low- and Middle-Income Countries: A Systematic Literature Review. Health Econ, 25 Suppl 1 pp. 124-139. | Show Abstract | Read more

Economic evaluation using dynamic transmission models is important for capturing the indirect effects of infectious disease interventions. We examine the use of these methods in low- and middle-income countries, where infectious diseases constitute a major burden. This review is comprised of two parts: (1) a summary of dynamic transmission economic evaluations across all disease areas published between 2011 and mid-2014 and (2) an in-depth review of mosquito-borne disease studies focusing on health economic methods and reporting. Studies were identified through a systematic search of the MEDLINE database and supplemented by reference list screening. Fifty-seven studies were eligible for inclusion in the all-disease review. The most common subject disease was HIV/AIDS, followed by malaria. A diverse range of modelling methods, outcome metrics and sensitivity analyses were used, indicating little standardisation. Seventeen studies were included in the mosquito-borne disease review. With notable exceptions, most studies did not employ economic evaluation methods beyond calculating a cost-effectiveness ratio or net benefit. Many did not adhere to health care economic evaluations reporting guidelines, particularly with respect to full model reporting and uncertainty analysis. We present a summary of the state-of-the-art and offer recommendations for improved implementation and reporting of health economic methods in this crossover discipline.

Dittrich S, Tadesse BT, Moussy F, Chua A, Zorzet A, Tängdén T, Dolinger DL, Page A-L, Crump JA, D'Acremont V et al. 2016. Target Product Profile for a Diagnostic Assay to Differentiate between Bacterial and Non-Bacterial Infections and Reduce Antimicrobial Overuse in Resource-Limited Settings: An Expert Consensus. PLoS One, 11 (8), pp. e0161721. | Show Abstract | Read more

Acute fever is one of the most common presenting symptoms globally. In order to reduce the empiric use of antimicrobial drugs and improve outcomes, it is essential to improve diagnostic capabilities. In the absence of microbiology facilities in low-income settings, an assay to distinguish bacterial from non-bacterial causes would be a critical first step. To ensure that patient and market needs are met, the requirements of such a test should be specified in a target product profile (TPP). To identify minimal/optimal characteristics for a bacterial vs. non-bacterial fever test, experts from academia and international organizations with expertise in infectious diseases, diagnostic test development, laboratory medicine, global health, and health economics were convened. Proposed TPPs were reviewed by this working group, and consensus characteristics were defined. The working group defined non-severely ill, non-malaria infected children as the target population for the desired assay. To provide access to the most patients, the test should be deployable to community health centers and informal health settings, and staff should require <2 days of training to perform the assay. Further, given that the aim is to reduce inappropriate antimicrobial use as well as to deliver appropriate treatment for patients with bacterial infections, the group agreed on minimal diagnostic performance requirements of >90% and >80% for sensitivity and specificity, respectively. Other key characteristics, to account for the challenging environment at which the test is targeted, included: i) time-to-result <10 min (but maximally <2 hrs); ii) storage conditions at 0-40°C, ≤90% non-condensing humidity with a minimal shelf life of 12 months; iii) operational conditions of 5-40°C, ≤90% non-condensing humidity; and iv) minimal sample collection needs (50-100μL, capillary blood). This expert approach to define assay requirements for a bacterial vs. non-bacterial assay should guide product development, and enable targeted and timely efforts by industry partners and academic institutions.

Peto TJ, Tripura R, Lee SJ, Althaus T, Dunachie S, Nguon C, Dhorda M, Promnarate C, Chalk J, Imwong M et al. 2016. Association between Subclinical Malaria Infection and Inflammatory Host Response in a Pre-Elimination Setting. PLoS One, 11 (7), pp. e0158656. | Show Abstract | Read more

BACKGROUND: Subclinical infections in endemic areas of Southeast Asia sustain malaria transmission. These asymptomatic infections might sustain immunity against clinical malaria and have been considered benign for the host, but if they are associated with chronic low-grade inflammation this could be harmful. We conducted a case-control study to explore the association between subclinical malaria and C-reactive protein (CRP), an established biomarker of inflammation. METHODS: Blood samples from asymptomatic villagers in Pailin, Western Cambodia were tested for malaria by high-volume ultra-sensitive polymerase chain reaction (uPCR) to determine the Plasmodium species. Plasma CRP concentration was measured in 328 individuals with parasitaemia (cases) and compared with: i) the same individual's value at the first time point when they had no detectable parasites (n = 282); and ii) age- sex- and village-matched controls (n = 328) free of Plasmodium infection. Plasma CRP concentrations were compared against thresholds of 3mg/L and 10mg/L. Subgroup analysis was carried out for cases with P vivax and P falciparum mono-infections. RESULTS: Median plasma CRP level for all samples was 0.59mg/L (interquartile range: 0.24-1.64mg/L). CRP concentrations were higher in parasitaemic individuals compared with same-person-controls (p = 0.050); and matched-controls (p = 0.025). 4.9% of samples had CRP concentrations above 10mg/L and 14.6% were above 3mg/L. Cases were more likely to have plasma CRP concentrations above these thresholds than age/sex matched controls, odds ratio 3.5 (95%CI 1.5-9.8) and 1.8 (95%CI 1.1-2.9), respectively. Amongst cases, parasite density and CRP were positively correlated (p<0.001), an association that remained significant when controlling for age and fever. Individuals with P.vivax mono-infections had the highest plasma CRP concentrations with the greatest association with parasitaemia. DISCUSSION: In this setting persistent malaria infections in asymptomatic individuals were associated with moderately elevated plasma CRP concentrations; chiefly evident in cases with P.vivax mono-infections. As well as interrupting malaria transmission within the community, treatment of asymptomatic malaria infections, in particular radical cure of vivax malaria, may benefit the health of infected individuals.

Lubell Y, Althaus T, Blacksell SD, Paris DH, Mayxay M, Pan-Ngum W, White LJ, Day NPJ, Newton PN. 2016. Modelling the Impact and Cost-Effectiveness of Biomarker Tests as Compared with Pathogen-Specific Diagnostics in the Management of Undifferentiated Fever in Remote Tropical Settings. PLoS One, 11 (3), pp. e0152420. | Show Abstract | Read more

BACKGROUND: Malaria accounts for a small fraction of febrile cases in increasingly large areas of the malaria endemic world. Point-of-care tests to improve the management of non-malarial fevers appropriate for primary care are few, consisting of either diagnostic tests for specific pathogens or testing for biomarkers of host response that indicate whether antibiotics might be required. The impact and cost-effectiveness of these approaches are relatively unexplored and methods to do so are not well-developed. METHODS: We model the ability of dengue and scrub typhus rapid tests to inform antibiotic treatment, as compared with testing for elevated C-Reactive Protein (CRP), a biomarker of host-inflammation. Using data on causes of fever in rural Laos, we estimate the proportion of outpatients that would be correctly classified as requiring an antibiotic and the likely cost-effectiveness of the approaches. RESULTS: Use of either pathogen-specific test slightly increased the proportion of patients correctly classified as requiring antibiotics. CRP testing was consistently superior to the pathogen-specific tests, despite heterogeneity in causes of fever. All testing strategies are likely to result in higher average costs, but only the scrub typhus and CRP tests are likely to be cost-effective when considering direct health benefits, with median cost per disability adjusted life year averted of approximately $48 USD and $94 USD, respectively. CONCLUSIONS: Testing for viral infections is unlikely to be cost-effective when considering only direct health benefits to patients. Testing for prevalent bacterial pathogens can be cost-effective, having the benefit of informing not only whether treatment is required, but also as to the most appropriate antibiotic; this advantage, however, varies widely in response to heterogeneity in causes of fever. Testing for biomarkers of host inflammation is likely to be consistently cost-effective despite high heterogeneity, and can also offer substantial reductions in over-use of antimicrobials in viral infections.

Phommasone K, Althaus T, Souvanthong P, Phakhounthong K, Soyvienvong L, Malapheth P, Mayxay M, Pavlicek RL, Paris DH, Dance D et al. 2016. Accuracy of commercially available c-reactive protein rapid tests in the context of undifferentiated fevers in rural Laos. BMC Infect Dis, 16 (1), pp. 61. | Show Abstract | Read more

BACKGROUND: C-Reactive Protein (CRP) has been shown to be an accurate biomarker for discriminating bacterial from viral infections in febrile patients in Southeast Asia. Here we investigate the accuracy of existing rapid qualitative and semi-quantitative tests as compared with a quantitative reference test to assess their potential for use in remote tropical settings. METHODS: Blood samples were obtained from consecutive patients recruited to a prospective fever study at three sites in rural Laos. At each site, one of three rapid qualitative or semi-quantitative tests was performed, as well as a corresponding quantitative NycoCard Reader II as a reference test. We estimate the sensitivity and specificity of the three tests against a threshold of 10 mg/L and kappa values for the agreement of the two semi-quantitative tests with the results of the reference test. RESULTS: All three tests showed high sensitivity, specificity and kappa values as compared with the NycoCard Reader II. With a threshold of 10 mg/L the sensitivity of the tests ranged from 87-98 % and the specificity from 91-98 %. The weighted kappa values for the semi-quantitative tests were 0.7 and 0.8. CONCLUSION: The use of CRP rapid tests could offer an inexpensive and effective approach to improve the targeting of antibiotics in remote settings where health facilities are basic and laboratories are absent. This study demonstrates that accurate CRP rapid tests are commercially available; evaluations of their clinical impact and cost-effectiveness at point of care is warranted.

Kyaw SS, Drake T, Thi A, Kyaw MP, Hlaing T, Smithuis FM, White LJ, Lubell Y. 2016. Malaria community health workers in Myanmar: a cost analysis. Malar J, 15 (1), pp. 41. | Show Abstract | Read more

BACKGROUND: Myanmar has the highest malaria incidence and attributed mortality in South East Asia with limited healthcare infrastructure to manage this burden. Establishing malaria Community Health Worker (CHW) programmes is one possible strategy to improve access to malaria diagnosis and treatment, particularly in remote areas. Despite considerable donor support for implementing CHW programmes in Myanmar, the cost implications are not well understood. METHODS: An ingredients based micro-costing approach was used to develop a model of the annual implementation cost of malaria CHWs in Myanmar. A cost model was constructed based on activity centres comprising of training, patient malaria services, monitoring and supervision, programme management, overheads and incentives. The model takes a provider perspective. Financial data on CHWs programmes were obtained from the 2013 financial reports of the Three Millennium Development Goal fund implementing partners that have been working on malaria control and elimination in Myanmar. Sensitivity and scenario analyses were undertaken to outline parameter uncertainty and explore changes to programme cost for key assumptions. RESULTS: The range of total annual costs for the support of one CHW was US$ 966-2486. The largest driver of CHW cost was monitoring and supervision (31-60% of annual CHW cost). Other important determinants of cost included programme management (15-28% of annual CHW cost) and patient services (6-12% of annual CHW cost). Within patient services, malaria rapid diagnostic tests are the major contributor to cost (64% of patient service costs). CONCLUSION: The annual cost of a malaria CHW in Myanmar varies considerably depending on the context and the design of the programme, in particular remoteness and the approach to monitoring and evaluation. The estimates provide information to policy makers and CHW programme planners in Myanmar as well as supporting economic evaluations of their cost-effectiveness.

de Haan F, Onyamboko MA, Fanello CI, Woodrow CJ, Lubell Y, Boon WPC, Dondorp AM. 2015. Exploring health practitioners' acceptability of a prospective semi-quantitative pfHRP2 device to define severe malaria in the Democratic Republic of Congo. Malar J, 14 (1), pp. 503. | Show Abstract | Read more

BACKGROUND: A rapid diagnostic tool is being developed to discern severely ill children with severe malaria from children who are ill with alternative febrile diseases but have coincidental peripheral blood parasitaemia. The device semi-quantitatively measures plasma pfHRP2 and has the potential to reduce mortality in children with severe febrile illnesses by improving diagnosis. The aim of this study is to identify contributing and inhibiting factors that affect healthcare practitioners' acceptability of this prospective diagnostic device in a high malaria transmission setting in the Democratic Republic of Congo. METHODS: Data were collected qualitatively by conducting semi-structured interviews with a purposeful sample of health professionals in Kinshasa, capital of Democratic Republic of Congo. In total, 11 interviews were held with professionals at four different institutes. RESULTS: Four key findings emerged: (1) Congolese practitioners perceive the semi-quantitative pfHRP2 device as a welcome intervention as they recognize the limited reliability of their current diagnostic and therapeutic approaches to severe febrile illnesses; (2) compatibility of the semi-quantitative pfHRP2 device with clinical equipment and competences of Congolese health practitioners is considered to be limited, especially in rural settings; (3) a formal training programme is crucial for correct understanding and application of the semi-quantitative pfHRP2 device; and, (4) provision of evidence to practitioners, and support from health authorities would be important to establish confidence in the semi-quantitative pfHRP2 device. CONCLUSIONS: Congolese practitioners perceive the prospective semi-quantitative pfHRP2 device as a welcome addition to their clinical equipment. The device could improve current diagnostic work-up of severe febrile illness, which might consequently improve treatment choices. However, despite this recognized potential, several hurdles and drivers need to be taken into account when implementing this device in DR Congo.

IMPROV Study Group. 2015. Improving the radical cure of vivax malaria (IMPROV): a study protocol for a multicentre randomised, placebo-controlled comparison of short and long course primaquine regimens. BMC Infect Dis, 15 (1), pp. 558. | Show Abstract | Read more

BACKGROUND: Plasmodium vivax malaria is a major cause of morbidity and recognised as an important contributor to mortality in some endemic areas. The current recommended treatment regimen for the radical cure of P. vivax includes a schizontocidal antimalarial, usually chloroquine, combined with a 14 day regimen of primaquine. The long treatment course frequently results in poor adherence and effectiveness. Shorter courses of higher daily doses of primaquine have the potential to improve adherence and thus effectiveness without compromising safety. The proposed multicentre randomised clinical trial aims to provide evidence across a variety of endemic settings on the safety and efficacy of high dose short course primaquine in glucose-6-phosphate-dehydrogenase (G6PD) normal patients. DESIGN: This study is designed as a placebo controlled, double blinded, randomized trial in four countries: Indonesia, Vietnam, Afghanistan and Ethiopia. G6PD normal patients diagnosed with vivax malaria are randomized to receive either 7 or 14 days high dose primaquine or placebo. G6PD deficient (G6PDd) patients are allocated to weekly primaquine doses for 8weeks. All treatment is directly observed and recurrent episodes are treated with the same treatment than allocated at the enrolment episode. Patients are followed daily until completion of treatment, weekly until 8 weeks and then monthly until 1 year after initiation of the treatment. The primary endpoint is the incidence rate (per person year) of symptomatic recurrent P. vivax parasitaemia over 12 months of follow-up, for all individuals, controlling for site, comparing the 7 versus 14-day primaquine treatment arms. Secondary endpoints are other efficacy measures such as incidence risk at different time points. Further endpoints are risks of haemolysis and severe adverse events. DISCUSSION: This study has been approved by relevant institutional ethics committees in the UK and Australia, and all participating countries. Results will be disseminated to inform P. vivax malaria treatment policy through peer-reviewed publications and academic presentations. Findings will contribute to a better understanding of the risks and benefits of primaquine which is crucial in persuading policy makers as well as clinicians of the importance of radical cure of vivax malaria, contributing to decreased transmission and a reduce parasite reservoir. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01814683 . Registered March 18, 2013.

Hantrakun V, Chierakul W, Chetchotisakd P, Anunnatsiri S, Currie BJ, Peacock SJ, Day NPJ, Cheah PY, Limmathurotsakul D, Lubell Y. 2015. Cost-effectiveness analysis of parenteral antimicrobials for acute melioidosis in Thailand. Trans R Soc Trop Med Hyg, 109 (12), pp. 803. | Read more

Ley B, Luter N, Espino FE, Devine A, Kalnoky M, Lubell Y, Thriemer K, Baird JK, Poirot E, Conan N et al. 2015. The challenges of introducing routine G6PD testing into radical cure: a workshop report. Malar J, 14 (1), pp. 377. | Show Abstract | Read more

The only currently available drug that effectively removes malaria hypnozoites from the human host is primaquine. The use of 8-aminoquinolines is hampered by haemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. Recently a number of qualitative and a quantitative rapid diagnostic test (RDT) format have been developed that provide an alternative to the current standard G6PD activity assays. The WHO has recently recommended routine testing of G6PD status prior to primaquine radical cure whenever possible. A workshop was held in the Philippines in early 2015 to discuss key challenges and knowledge gaps that hinder the introduction of routine G6PD testing. Two point-of-care (PoC) test formats for the measurement of G6PD activity are currently available: qualitative tests comparable to malaria RDT as well as biosensors that provide a quantitative reading. Qualitative G6PD PoC tests provide a binomial test result, are easy to use and some products are comparable in price to the widely used fluorescent spot test. Qualitative test results can accurately classify hemizygous males, heterozygous females, but may misclassify females with intermediate G6PD activity. Biosensors provide a more complex quantitative readout and are better suited to identify heterozygous females. While associated with higher costs per sample tested biosensors have the potential for broader use in other scenarios where knowledge of G6PD activity is relevant as well. The introduction of routine G6PD testing is associated with additional costs on top of routine treatment that will vary by setting and will need to be assessed prior to test introduction. Reliable G6PD PoC tests have the potential to play an essential role in future malaria elimination programmes, however require an improved understanding on how to best integrate routine G6PD testing into different health settings.

Lubell Y, Blacksell SD, Dunachie S, Tanganuchitcharnchai A, Althaus T, Watthanaworawit W, Paris DH, Mayxay M, Peto TJ, Dondorp AM et al. 2015. Performance of C-reactive protein and procalcitonin to distinguish viral from bacterial and malarial causes of fever in Southeast Asia. BMC Infect Dis, 15 (1), pp. 511. | Show Abstract | Read more

BACKGROUND: Poor targeting of antimicrobial drugs contributes to the millions of deaths each year from malaria, pneumonia, and other tropical infectious diseases. While malaria rapid diagnostic tests have improved use of antimalarial drugs, there are no similar tests to guide the use of antibiotics in undifferentiated fevers. In this study we estimate the diagnostic accuracy of two well established biomarkers of bacterial infection, procalcitonin and C-reactive protein (CRP) in discriminating between common viral and bacterial infections in malaria endemic settings of Southeast Asia. METHODS: Serum procalcitonin and CRP levels were measured in stored serum samples from febrile patients enrolled in three prospective studies conducted in Cambodia, Laos and, Thailand. Of the 1372 patients with a microbiologically confirmed diagnosis, 1105 had a single viral, bacterial or malarial infection. Procalcitonin and CRP levels were compared amongst these aetiological groups and their sensitivity and specificity in distinguishing bacterial infections and bacteraemias from viral infections were estimated using standard thresholds. RESULTS: Serum concentrations of both biomarkers were significantly higher in bacterial infections and malaria than in viral infections. The AUROC for CRP in discriminating between bacterial and viral infections was 0.83 (0.81-0.86) compared with 0.74 (0.71-0.77) for procalcitonin (p < 0.0001). This relative advantage was evident in all sites and when stratifying patients by age and admission status. For CRP at a threshold of 10 mg/L, the sensitivity of detecting bacterial infections was 95% with a specificity of 49%. At a threshold of 20 mg/L sensitivity was 86% with a specificity of 67%. For procalcitonin at a low threshold of 0.1 ng/mL the sensitivity was 90% with a specificity of 39%. At a higher threshold of 0.5 ng/ul sensitivity was 60% with a specificity of 76%. CONCLUSION: In samples from febrile patients with mono-infections from rural settings in Southeast Asia, CRP was a highly sensitive and moderately specific biomarker for discriminating between viral and bacterial infections. Use of a CRP rapid test in peripheral health settings could potentially be a simple and affordable measure to better identify patients in need of antibacterial treatment and part of a global strategy to combat the emergence of antibiotic resistance.

Imwong M, Nguyen TN, Tripura R, Peto TJ, Lee SJ, Lwin KM, Suangkanarat P, Jeeyapant A, Vihokhern B, Wongsaen K et al. 2015. The epidemiology of subclinical malaria infections in South-East Asia: findings from cross-sectional surveys in Thailand-Myanmar border areas, Cambodia, and Vietnam. Malar J, 14 (1), pp. 381. | Show Abstract | Read more

BACKGROUND: The importance of the submicroscopic reservoir of Plasmodium infections for malaria elimination depends on its size, which is generally considered small in low transmission settings. The precise estimation of this reservoir requires more sensitive parasite detection methods. The prevalence of asymptomatic, sub-microscopic malaria was assessed by a sensitive, high blood volume quantitative real-time polymerase chain reaction method in three countries of the Greater Mekong Sub-region. METHODS: Cross-sectional surveys were conducted in three villages in western Cambodia, four villages along the Thailand-Myanmar border and four villages in southwest Vietnam. Malaria parasitaemia was assessed by Plasmodium falciparum/pan malaria rapid diagnostic tests (RDTs), microscopy and a high volume ultra-sensitive real-time polymerase chain reaction (HVUSqPCR: limit of detection 22 parasites/mL). All villagers older than 6 months were invited to participate. RESULTS: A census before the surveys identified 7355 residents in the study villages. Parasite prevalence was 224/5008 (4 %) by RDT, 229/5111 (5 %) by microscopy, and 988/4975 (20 %) when assessed by HVUSqPCR. Of these 164 (3 %) were infected with P. falciparum, 357 (7 %) with Plasmodium vivax, 56 (1 %) with a mixed infection, and 411 (8 %) had parasite densities that were too low for species identification. A history of fever, male sex, and age of 15 years or older were independently associated with parasitaemia in a multivariate regression model stratified by site. CONCLUSION: Light microscopy and RDTs identified only a quarter of all parasitaemic participants. The asymptomatic Plasmodium reservoir is considerable, even in low transmission settings. Novel strategies are needed to eliminate this previously under recognized reservoir of malaria transmission.

Drake TL, Kyaw SS, Kyaw MP, Smithuis FM, Day NPJ, White LJ, Lubell Y. 2015. Cost effectiveness and resource allocation of Plasmodium falciparum malaria control in Myanmar: a modelling analysis of bed nets and community health workers. Malar J, 14 (1), pp. 376. | Show Abstract | Read more

BACKGROUND: Funding for malaria control and elimination in Myanmar has increased markedly in recent years. While there are various malaria control tools currently available, two interventions receive the majority of malaria control funding in Myanmar: (1) insecticide-treated bed nets and (2) early diagnosis and treatment through malaria community health workers. This study aims to provide practical recommendations on how to maximize impact from investment in these interventions. METHODS: A simple decision tree is used to model intervention costs and effects in terms of years of life lost. The evaluation is from the perspective of the service provider and costs and effects are calculated in line with standard methodology. Sensitivity and scenario analysis are undertaken to identify key drivers of cost effectiveness. Standard cost effectiveness analysis is then extended via a spatially explicit resource allocation model. FINDINGS: Community health workers have the potential for high impact on malaria, particularly where there are few alternatives to access malaria treatment, but are relatively costly. Insecticide-treated bed nets are comparatively inexpensive and modestly effective in Myanmar, representing a low risk but modest return intervention. Unlike some healthcare interventions, bed nets and community health workers are not mutually exclusive nor are they necessarily at their most efficient when universally applied. Modelled resource allocation scenarios highlight that in this case there is no "one size fits all" cost effectiveness result. Health gains will be maximized by effective targeting of both interventions.

Hantrakun V, Chierakul W, Chetchotisakd P, Anunnatsiri S, Currie BJ, Peacock SJ, Day NPJ, Cheah PY, Limmathurotsakul D, Lubell Y. 2015. Cost-effectiveness analysis of parenteral antimicrobials for acute melioidosis in Thailand. Trans R Soc Trop Med Hyg, 109 (6), pp. 416-418. | Show Abstract | Read more

BACKGROUND: Melioidosis is a common community-acquired infectious disease in northeast Thailand associated with overall mortality of approximately 40% in hospitalized patients, and over 70% in severe cases. Ceftazidime is recommended for parenteral treatment in patients with suspected melioidosis. Meropenem is increasingly used but evidence to support this is lacking. METHODS: A decision tree was used to estimate the cost-effectiveness of treating non-severe and severe suspected acute melioidosis cases with either ceftazidime or meropenem. RESULTS: Empirical treatment with meropenem is likely to be cost-effective providing meropenem reduces mortality in severe cases by at least 9% and the proportion with subsequent culture-confirmed melioidosis is over 20%. CONCLUSIONS: In this context, treatment of severe cases with meropenem is likely to be cost-effective, while the evidence to support the use of meropenem in non-severe suspected melioidosis is not yet available.

White LJ, Flegg JA, Phyo AP, Wiladpai-ngern JH, Bethell D, Plowe C, Anderson T, Nkhoma S, Nair S, Tripura R et al. 2015. Defining the in vivo phenotype of artemisinin-resistant falciparum malaria: a modelling approach. PLoS Med, 12 (4), pp. e1001823. | Show Abstract | Read more

BACKGROUND: Artemisinin-resistant falciparum malaria has emerged in Southeast Asia, posing a major threat to malaria control. It is characterised by delayed asexual-stage parasite clearance, which is the reference comparator for the molecular marker 'Kelch 13' and in vitro sensitivity tests. However, current cut-off values denoting slow clearance based on the proportion of individuals remaining parasitaemic on the third day of treatment ('day-3'), or on peripheral blood parasite half-life, are not well supported. We here explore the parasite clearance distributions in an area of artemisinin resistance with the aim refining the in vivo phenotypic definitions. METHODS AND FINDINGS: Data from 1,518 patients on the Thai-Myanmar and Thai-Cambodian borders with parasite half-life assessments after artesunate treatment were analysed. Half-lives followed a bimodal distribution. A statistical approach was developed to infer the characteristics of the component distributions and their relative contribution to the composite mixture. A model representing two parasite subpopulations with geometric mean (IQR) parasite half-lives of 3.0 (2.4-3.9) hours and 6.50 (5.7-7.4) hours was consistent with the data. For individual patients, the parasite half-life provided a predicted likelihood of an artemisinin-resistant infection which depends on the population prevalence of resistance in that area. Consequently, a half-life where the probability is 0.5 varied between 3.5 and 5.5 hours. Using this model, the current 'day-3' cut-off value of 10% predicts the potential presence of artemisinin-resistant infections in most but not all scenarios. These findings are relevant to the low-transmission setting of Southeast Asia. Generalisation to a high transmission setting as in regions of Sub-Saharan Africa will need additional evaluation. CONCLUSIONS: Characterisation of overlapping distributions of parasite half-lives provides quantitative insight into the relationship between parasite clearance and artemisinin resistance, as well as the predictive value of the 10% cut-off in 'day-3' parasitaemia. The findings are important for the interpretation of in vitro sensitivity tests and molecular markers for artemisinin resistance and for contextualising the 'day 3' threshold to account for initial parasitaemia and sample size.

Luangasanatip N, Hongsuwan M, Limmathurotsakul D, Lubell Y, Lee AS, Harbarth S, Day NPJ, Graves N, Cooper BS. 2015. Comparative efficacy of interventions to promote hand hygiene in hospital: systematic review and network meta-analysis. BMJ, 351 pp. h3728. | Show Abstract | Read more

OBJECTIVE: To evaluate the relative efficacy of the World Health Organization 2005 campaign (WHO-5) and other interventions to promote hand hygiene among healthcare workers in hospital settings and to summarize associated information on use of resources. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Medline, Embase, CINAHL, NHS Economic Evaluation Database, NHS Centre for Reviews and Dissemination, Cochrane Library, and the EPOC register (December 2009 to February 2014); studies selected by the same search terms in previous systematic reviews (1980-2009). REVIEW METHODS: Included studies were randomised controlled trials, non-randomised trials, controlled before-after trials, and interrupted time series studies implementing an intervention to improve compliance with hand hygiene among healthcare workers in hospital settings and measuring compliance or appropriate proxies that met predefined quality inclusion criteria. When studies had not used appropriate analytical methods, primary data were re-analysed. Random effects and network meta-analyses were performed on studies reporting directly observed compliance with hand hygiene when they were considered sufficiently homogeneous with regard to interventions and participants. Information on resources required for interventions was extracted and graded into three levels. RESULTS: Of 3639 studies retrieved, 41 met the inclusion criteria (six randomised controlled trials, 32 interrupted time series, one non-randomised trial, and two controlled before-after studies). Meta-analysis of two randomised controlled trials showed the addition of goal setting to WHO-5 was associated with improved compliance (pooled odds ratio 1.35, 95% confidence interval 1.04 to 1.76; I(2)=81%). Of 22 pairwise comparisons from interrupted time series, 18 showed stepwise increases in compliance with hand hygiene, and all but four showed a trend for increasing compliance after the intervention. Network meta-analysis indicated considerable uncertainty in the relative effectiveness of interventions, but nonetheless provided evidence that WHO-5 is effective and that compliance can be further improved by adding interventions including goal setting, reward incentives, and accountability. Nineteen studies reported clinical outcomes; data from these were consistent with clinically important reductions in rates of infection resulting from improved hand hygiene for some but not all important hospital pathogens. Reported costs of interventions ranged from $225 to $4669 (£146-£3035; €204-€4229) per 1000 bed days. CONCLUSION: Promotion of hand hygiene with WHO-5 is effective at increasing compliance in healthcare workers. Addition of goal setting, reward incentives, and accountability strategies can lead to further improvements. Reporting of resources required for such interventions remains inadequate.

Luangasanatip N, Hongsuwan M, Lubell Y, Cooper BS. 2014. Effectiveness of Hand Hygiene Promotion in Relation to Level of Investment: A Systematic Review. Value Health, 17 (7), pp. A803. | Read more

Lubell Y, White L, Varadan S, Drake T, Yeung S, Cheah PY, Maude RJ, Dondorp A, Day NPJ, 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.

Yadav RP, Nishikiori N, Satha P, Eang MT, Lubell Y. 2014. Cost-effectiveness of a tuberculosis active case finding program targeting household and neighborhood contacts in Cambodia. Am J Trop Med Hyg, 90 (5), pp. 866-872. | Show Abstract | Read more

In many high-risk populations, access to tuberculosis (TB) diagnosis and treatment is limited and pockets of high prevalence persist. We estimated the cost-effectiveness of an extensive active case finding program in areas of Cambodia where TB notifications and household poverty rates are highest and access to care is restricted. Thirty operational health districts with high TB incidence and household poverty were randomized into intervention and control groups. In intervention operational health districts, all household and symptomatic neighborhood contacts of registered TB patients of the past two years were encouraged to attend screening at mobile centers. In control districts, routine passive case finding activities continued. The program screened more than 35,000 household and neighborhood contacts and identified 810 bacteriologically confirmed cases. The cost-effectiveness analysis estimated that in these cases the reduction in mortality from 14% to 2% would result in a cost per daily adjusted life year averted of $330, suggesting that active case finding was highly cost-effective.

Lubell Y. 2014. Investment in malaria elimination: a leap of faith in need of direction. Lancet Glob Health, 2 (2), pp. e63-e64. | Read more

Lubell Y, Dondorp A, Guérin PJ, Drake T, Meek S, Ashley E, Day NPJ, White NJ, White LJ. 2014. Artemisinin resistance--modelling the potential human and economic costs. Malar J, 13 (1), pp. 452. | Show Abstract | Read more

BACKGROUND: Artemisinin combination therapy is recommended as first-line treatment for falciparum malaria across the endemic world and is increasingly relied upon for treating vivax malaria where chloroquine is failing. Artemisinin resistance was first detected in western Cambodia in 2007, and is now confirmed in the Greater Mekong region, raising the spectre of a malaria resurgence that could undo a decade of progress in control, and threaten the feasibility of elimination. The magnitude of this threat has not been quantified. METHODS: This analysis compares the health and economic consequences of two future scenarios occurring once artemisinin-based treatments are available with high coverage. In the first scenario, artemisinin combination therapy (ACT) is largely effective in the management of uncomplicated malaria and severe malaria is treated with artesunate, while in the second scenario ACT are failing at a rate of 30%, and treatment of severe malaria reverts to quinine. The model is applied to all malaria-endemic countries using their specific estimates for malaria incidence, transmission intensity and GDP. The model describes the direct medical costs for repeated diagnosis and retreatment of clinical failures as well as admission costs for severe malaria. For productivity losses, the conservative friction costing method is used, which assumes a limited economic impact for individuals that are no longer economically active until they are replaced from the unemployment pool. RESULTS: Using conservative assumptions and parameter estimates, the model projects an excess of 116,000 deaths annually in the scenario of widespread artemisinin resistance. The predicted medical costs for retreatment of clinical failures and for management of severe malaria exceed US$32 million per year. Productivity losses resulting from excess morbidity and mortality were estimated at US$385 million for each year during which failing ACT remained in use as first-line treatment. CONCLUSIONS: These 'ballpark' figures for the magnitude of the health and economic threat posed by artemisinin resistance add weight to the call for urgent action to detect the emergence of resistance as early as possible and contain its spread from known locations in the Mekong region to elsewhere in the endemic world.

Kyaw SS, Drake T, Ruangveerayuth R, Chierakul W, White NJ, Newton PN, Lubell Y. 2014. Cost of treating inpatient falciparum malaria on the Thai-Myanmar border. Malar J, 13 (1), pp. 416. | Show Abstract | Read more

BACKGROUND: Despite demonstrated benefits and World Health Organization (WHO) endorsement, parenteral artesunate is the recommended treatment for patients with severe Plasmodium falciparum malaria in only one fifth of endemic countries. One possible reason for this slow uptake is that a treatment course of parenteral artesunate is costlier than quinine and might, therefore, pose a substantial economic burden to health care systems. This analysis presents a detailed account of the resources used in treating falciparum malaria by either parenteral artesunate or quinine in a hospital on the Thai-Myanmar border. METHODS: The analysis used data from four studies, with random allocation of inpatients with falciparum malaria to treatment with parenteral artesunate or quinine, conducted in Mae Sot Hospital, Thailand from 1995 to 2001. Detailed resource use data were collected during admission and unit costs from the 2008 hospital price list were applied to these. Total admission costs were broken down into five categories: 1) medication; 2) intravenous fluids; 3) disposables; 4) laboratory tests; and 5) services. RESULTS: While the medication costs were higher for patients treated with artesunate, total admission costs were similar in those treated with quinine, US$ 243 (95% CI: 167.5-349.7) and in those treated with artesunate US$ 190 (95% CI: 131.0-263.2) (P=0.375). For cases classified as severe malaria (59%), the total cost of admission was US$ 298 (95% CI: 203.6-438.7) in the quinine group as compared with US$ 284 (95% CI: 181.3-407) in the artesunate group (P=0.869). CONCLUSION: This analysis finds no evidence for a difference in total admission costs for malaria inpatients treated with artesunate as compared with quinine. Assuming this is generalizable to other settings, the higher cost of a course of artesunate should not be considered a barrier for its implementation in the treatment of malaria.

Smithuis FM, Kyaw MK, Phe UO, van der Broek I, Katterman N, Rogers C, Almeida P, Kager PA, Stepniewska K, Lubell Y et al. 2013. The effect of insecticide-treated bed nets on the incidence and prevalence of malaria in children in an area of unstable seasonal transmission in western Myanmar. Malar J, 12 (1), pp. 363. | Show Abstract | Read more

BACKGROUND: Insecticide-treated bed nets (ITN) reduce malaria morbidity and mortality consistently in Africa, but their benefits have been less consistent in Asia. This study's objective was to evaluate the malaria protective efficacy of village-wide usage of ITN in Western Myanmar and estimate the cost-effectiveness of ITN compared with extending early diagnosis and treatment services. METHODS: A cluster-randomized controlled trial was conducted in Rakhine State to assess the efficacy of ITNs in preventing malaria and anaemia in children and their secondary effects on nutrition and development. The data were aggregated for each village to obtain cluster-level infection rates. In total 8,175 children under 10 years of age were followed up for 10 months, which included the main malaria transmission period. The incidence and prevalence of Plasmodium falciparum and Plasmodium vivax infections, and the biting behaviour of Anopheles mosquitoes in the area were studied concurrently. The trial data along with costs for current recommended treatment practices were modelled to estimate the cost-effectiveness of ITNs compared with, or in addition to extending the coverage of early diagnosis and treatment services. RESULTS: In aggregate, malaria infections, spleen rates, haemoglobin concentrations, and weight for height, did not differ significantly during the study period between villages with and without ITNs, with a weighted mean difference of -2.6 P. falciparum episodes per 1,000 weeks at risk (95% Confidence Interval -7 to 1.8). In areas with a higher incidence of malaria there was some evidence ITN protective efficacy. The economic analysis indicated that, despite the uncertainty and variability in their protective efficacy in the different study sites, ITN could still be cost-effective, but not if they displaced funding for early diagnosis and effective treatment which is substantially more cost-effective. CONCLUSION: In Western Myanmar deployment of ITNs did not provide consistent protection against malaria in children living in malaria endemic villages. Early diagnosis and effective treatment is a more cost effective malaria control strategy than deployment of ITNs in this area where the main vector bites early in the evening, often before people are protected by an ITN.

Smithuis FM, Kyaw MK, Phe UO, van der Broek I, Katterman N, Rogers C, Almeida P, Kager PA, Stepniewska K, Lubell Y et al. 2013. Entomological determinants of insecticide-treated bed net effectiveness in Western Myanmar. Malar J, 12 (1), pp. 364. | Show Abstract | Read more

BACKGROUND: In a large cluster randomized control trial of insecticide-treated bed nets (ITN) in Western Myanmar the malaria protective effect of ITN was found to be highly variable and, in aggregate, the effect was not statistically significant. A coincident entomological investigation measured malaria vector abundance and biting behaviour and the human population sleeping habits, factors relevant to ITN effectiveness. METHODS: Entomological surveys were carried out using different catching methods to identify potential malaria vector species and characterise their biting habits. The salivary glands were dissected from all female anophelines caught to identify sporozoites by microscopy. FINDINGS: Between 1995 and 2000 a total of 4,824 female anopheline mosquitoes were caught with various catching methods. A total of 916 person nights yielded 3,009 female anopheline mosquitoes between 6 pm and 6 am. Except for Anopheles annularis, which showed no apparent preference (51% outdoor biting), all major species showed a strong preference for outdoor biting; Anopheles epiroticus (79%), Anopheles subpictus (72%), Anopheles maculatus (92%), Anopheles aconitus (85%) and Anopheles vagus (72%). Most human biting occurred in the early evening with the peak biting time between 6 pm and 7 pm (35%). Overall 51% (1447/2837) of all bites recorded were between 6 pm and 8 pm. A large proportion of children were not sleeping under an ITN during peak biting times. Only one An. annularis mosquito (0.02%) had malaria sporozoites identified in the salivary glands. CONCLUSIONS: Peak vector biting occurred early in the evening and mainly occurred outdoors. The limited efficacy of ITN in this area of Western Myanmar may be explained by the biting behaviour of the prevalent Anopheles mosquito vectors in this area.

Luangasanatip N, Hongsuwan M, Lubell Y, Limmathurotsakul D, Teparrukkul P, Chaowarat S, Day NPJ, Graves N, Cooper BS. 2013. Long-term survival after intensive care unit discharge in Thailand: a retrospective study. Crit Care, 17 (5), pp. R219. | Show Abstract | Read more

INTRODUCTION: Economic evaluations of interventions in the hospital setting often rely on the estimated long-term impact on patient survival. Estimates of mortality rates and long-term outcomes among patients discharged alive from the intensive care unit (ICU) are lacking from lower- and middle-income countries. This study aimed to assess the long-term survival and life expectancy (LE) amongst post-ICU patients in Thailand, a middle-income country. METHODS: In this retrospective cohort study, data from a regional tertiary hospital in northeast Thailand and the regional death registry were linked and used to assess patient survival time after ICU discharge. Adult ICU patients aged at least 15 years who had been discharged alive from an ICU between 1 January 2004 and 31 December 2005 were included in the study, and the death registry was used to determine deaths occurring in this cohort up to 31st December 2010. These data were used in conjunction with standard mortality life tables to estimate annual mortality and life expectancy. RESULTS: This analysis included 10,321 ICU patients. During ICU admission, 3,251 patients (31.5%) died. Of 7,070 patients discharged alive, 2,527 (35.7%) were known to have died within the five-year follow-up period, a mortality rate 2.5 times higher than that in the Thai general population (age and sex matched). The mean LE was estimated as 18.3 years compared with 25.2 years in the general population. CONCLUSIONS: Post-ICU patients experienced much higher rates of mortality than members of the general population over the five-year follow-up period, particularly in the first year after discharge. Further work assessing Health Related Quality of Life (HRQOL) in both post-ICU patients and in the general population in developing countries is needed.

Kulpeng W, Sornsrivichai V, Chongsuvivatwong V, Rattanavipapong W, Leelahavarong P, Cairns J, Lubell Y, Teerawattananon Y. 2013. Variation of health-related quality of life assessed by caregivers and patients affected by severe childhood infections. BMC Pediatr, 13 (1), pp. 122. | Show Abstract | Read more

BACKGROUND: The agreement between self-reported and proxy measures of health status in ill children is not well established. This study aimed to quantify the variation in health-related quality of life (HRQOL) derived from young patients and their carers using different instruments. METHODS: A hospital-based cross-sectional survey was conducted between August 2010 and March 2011. Children with meningitis, bacteremia, pneumonia, acute otitis media, hearing loss, chronic lung disease, epilepsy, mild mental retardation, severe mental retardation, and mental retardation combined with epilepsy, aged between five to 14 years in seven tertiary hospitals were selected for participation in this study. The Health Utilities Index Mark 2 (HUI2), and Mark 3 (HUI3), and the EuroQoL Descriptive System (EQ-5D) and Visual Analogue Scale (EQ-VAS) were applied to both paediatric patients (self-assessment) and caregivers (proxy-assessment). RESULTS: The EQ-5D scores were lowest for acute conditions such as meningitis, bacteremia, and pneumonia, whereas the HUI3 scores were lowest for most chronic conditions such as hearing loss and severe mental retardation. Comparing patient and proxy scores (n = 74), the EQ-5D exhibited high correlation (r = 0.77) while in the HUI2 and HUI3 patient and caregiver scores were moderately correlated (r = 0.58 and 0.67 respectively). The mean difference between self and proxy-assessment using the HUI2, HUI3, EQ-5D and EQ-VAS scores were 0.03, 0.05, -0.03 and -0.02, respectively. In hearing-impaired and chronic lung patients the self-rated HRQOL differed significantly from their caregivers. CONCLUSIONS: The use of caregivers as proxies for measuring HRQOL in young patients affected by pneumococcal infection and its sequelae should be employed with caution. Given the high correlation between instruments, each of the HRQOL instruments appears acceptable apart from the EQ-VAS which exhibited low correlation with the others.

Choosakulchart P, Kittisopee T, Takdhada S, Lubell Y, Robinson J. 2013. Cost-utility evaluation of influenza vaccination patients with existing coronary heart diseases in Thailand ASIAN BIOMEDICINE, 7 (3), pp. 425-435. | Show Abstract | Read more

Background: Influenza can exacerbate chronic coronary heart diseases (CHD) and health policy recommends influenza vaccination in this population group. However, cost effectiveness of influenza vaccination in protecting CHD population has not been, to our knowledge, well studied before especially in CHD patients with different disease severities. Objectives: To assess life-time cost utility of influenza vaccination in CHD patients either with angina and/or cardiac arrest/myocardial infarction (CA/MI) and to identify the most cost-effective influenza vaccination strategies. Method: The Markov model of CHD progression concurrent with the influenza infection was developed to quantify life-time costs and health effects of the three influenza vaccination strategies compared with no influenza vaccination (base case): (1) influenza vaccination in all CHD patients, (2) influenza vaccination in CA/MI patients-only, and (3) influenza vaccination in angina patients-only. The cost-effectiveness analysis (CEA) was based on the societal perspective. Deterministic and probabilistic sensitivity analyses were performed to identify variables that influence the sensitivity of the results and examine the effects of model parameters uncertainty, respectively. Results: For the base case, the expected value (EV) results of no influenza vaccination, influenza vaccination in all CHD groups, influenza vaccination in angina patients, and influenza vaccination in CA/MI are 346,437 Thai baht (THB) yielded 18.26 Quality adjusted life year (QALYs), 454,664 THB yielded 21.46 QALYs, 360,786 THB yielded 19.96 QALYs, and 437,901 THB yielded 19.72 QALYs; respectively. CEA graph comparing all influenza vaccination strategies shows that vaccination in all CHD patients groups and angina patients are in the costeffectiveness frontier, but not influenza vaccination in CA/MI patients. The cost-effectiveness rankings report shows that the willingness-to-pay (WTP) threshold (100,000 THB) is greater than the incremental cost effectiveness ratio (ICER) of vaccination in all CHD groups (ICER = 33,813 THB per QALY gained) and angina group (8,420 THB per QALY gained) and therefore the vaccination in all CHD groups, which is more expensive, but more effective would be recommended. The deterministic sensitivity analysis shows the most influential parameters driving the cost-effectiveness of vaccination strategies are the effect of influenza vaccination on CHD both for acute myocardial infarction and cardiovascular death, respectively. The probabilistic sensitivity analysis shows the same influenza strategy recommendation (vaccination in all CHD groups) as the base case analysis. Conclusion: From a societal perspective, influenza vaccination in all CHD groups is recommended. The information from economic modeling should be confirmed by primary economic research.

Luangasanatip N, Hongsuwan M, Lubell Y, Limmathurotsakul D, Teparrukkul P, Chaowarat S, Day NPJ, Graves N, Cooper BS. 2013. Long-term survival after intensive care unit discharge in Thailand: a retrospective study CRITICAL CARE, 17 (5), | Read more

Pan-ngum W, Blacksell SD, Lubell Y, Pukrittayakamee S, Bailey MS, de Silva HJ, Lalloo DG, Day NPJ, White LJ, Limmathurotsakul D. 2013. Estimating the true accuracy of diagnostic tests for dengue infection using bayesian latent class models. PLoS One, 8 (1), pp. e50765. | Show Abstract | Read more

BACKGROUND: Accuracy of rapid diagnostic tests for dengue infection has been repeatedly estimated by comparing those tests with reference assays. We hypothesized that those estimates might be inaccurate if the accuracy of the reference assays is not perfect. Here, we investigated this using statistical modeling. METHODS/PRINCIPAL FINDINGS: Data from a cohort study of 549 patients suspected of dengue infection presenting at Colombo North Teaching Hospital, Ragama, Sri Lanka, that described the application of our reference assay (a combination of Dengue IgM antibody capture ELISA and IgG antibody capture ELISA) and of three rapid diagnostic tests (Panbio NS1 antigen, IgM antibody and IgG antibody rapid immunochromatographic cassette tests) were re-evaluated using bayesian latent class models (LCMs). The estimated sensitivity and specificity of the reference assay were 62.0% and 99.6%, respectively. Prevalence of dengue infection (24.3%), and sensitivities and specificities of the Panbio NS1 (45.9% and 97.9%), IgM (54.5% and 95.5%) and IgG (62.1% and 84.5%) estimated by bayesian LCMs were significantly different from those estimated by assuming that the reference assay was perfect. Sensitivity, specificity, PPV and NPV for a combination of NS1, IgM and IgG cassette tests on admission samples were 87.0%, 82.8%, 62.0% and 95.2%, respectively. CONCLUSIONS: Our reference assay is an imperfect gold standard. In our setting, the combination of NS1, IgM and IgG rapid diagnostic tests could be used on admission to rule out dengue infection with a high level of accuracy (NPV 95.2%). Further evaluation of rapid diagnostic tests for dengue infection should include the use of appropriate statistical models.

Deen J, White NJ, Lubell Y. 2013. Bloodstream infections in south and southeast Asia - authors' reply. Lancet Infect Dis, 13 (1), pp. 15. | Read more

Deen J, von Seidlein L, Andersen F, Elle N, White NJ, Lubell Y. 2012. Community-acquired bacterial bloodstream infections in developing countries in south and southeast Asia: a systematic review. Lancet Infect Dis, 12 (6), pp. 480-487. | Show Abstract | Read more

Information about community-acquired bacteraemia in developing countries in south and southeast Asia is scarce. We aimed to establish the case fraction of bacteraemia in febrile patients admitted to hospital. We searched four databases and identified studies of south and southeast Asia published between 1990 and 2010 that prospectively assessed patients admitted to hospital and from whom a blood culture was taken. We reviewed 17 eligible studies describing 40,644 patients. Pathogenic organisms were isolated from 3506 patients (9%; range 1-51%); 1784 (12%) of 14,386 adults and 1722 (7%) of 26,258 children. Salmonella enterica serotype Typhi was the most common bacterial pathogen, accounting for 532 of 1798 (30%) isolates in adults and 432 of 1723 (25%) in children. Other commonly isolated organisms in adults were Staphylococcus aureus, Escherichia coli, and other gram-negative organisms, and in children were Streptococcus pneumoniae and Haemophilus influenzae. A substantial case fraction of bacteraemia occurs in patients admitted to hospital with fever in this region. Management could be improved if diagnostic microbiology facilities were more widely available. The prevailing organisms causing bacteraemia and their susceptibility patterns could inform empirical treatment regimens and prevention strategies.

Luangasanatip N, Hongsuwan M, Lubell Y, Srisamang P, Limmathurotsakul D, Cooper B. 2012. Excess length of stay due to hospital-associated infections in Thailand: 8 years retrospective data INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 16 pp. E378-E379. | Read more

Peacock SJ, Limmathurotsakul D, Lubell Y, Koh GCKW, White LJ, Day NPJ, Titball RW. 2012. Melioidosis vaccines: a systematic review and appraisal of the potential to exploit biodefense vaccines for public health purposes. PLoS Negl Trop Dis, 6 (1), pp. e1488. | Show Abstract | Read more

BACKGROUND: Burkholderia pseudomallei is a Category B select agent and the cause of melioidosis. Research funding for vaccine development has largely considered protection within the biothreat context, but the resulting vaccines could be applicable to populations who are at risk of naturally acquired melioidosis. Here, we discuss target populations for vaccination, consider the cost-benefit of different vaccination strategies and review potential vaccine candidates. METHODS AND FINDINGS: Melioidosis is highly endemic in Thailand and northern Australia, where a biodefense vaccine might be adopted for public health purposes. A cost-effectiveness analysis model was developed, which showed that a vaccine could be a cost-effective intervention in Thailand, particularly if used in high-risk populations such as diabetics. Cost-effectiveness was observed in a model in which only partial immunity was assumed. The review systematically summarized all melioidosis vaccine candidates and studies in animal models that had evaluated their protectiveness. Possible candidates included live attenuated, whole cell killed, sub-unit, plasmid DNA and dendritic cell vaccines. Live attenuated vaccines were not considered favorably because of possible reversion to virulence and hypothetical risk of latent infection, while the other candidates need further development and evaluation. Melioidosis is acquired by skin inoculation, inhalation and ingestion, but routes of animal inoculation in most published studies to date do not reflect all of this. We found a lack of studies using diabetic models, which will be central to any evaluation of a melioidosis vaccine for natural infection since diabetes is the most important risk factor. CONCLUSION: Vaccines could represent one strand of a public health initiative to reduce the global incidence of melioidosis.

Lubell Y, Turner P, Ashley EA, White NJ. 2011. Susceptibility of bacterial isolates from community-acquired infections in sub-Saharan Africa and Asia to macrolide antibiotics. Trop Med Int Health, 16 (10), pp. 1192-1205. | Show Abstract | Read more

OBJECTIVE: To review the literature on the susceptibility of common community pathogens in sub-Saharan Africa and Asia to the macrolide antibiotics. METHODS: Inclusion criteria required that isolates were collected since 2004 to ensure results were of contemporary relevance. The data were aggregated by region, age group and sterility of site of culture sample. RESULTS: A total of 51 studies were identified, which reported the macrolide antimicrobial susceptibilities of common bacterial pathogens isolated since 2004. In general, there was less macrolide resistance in African than in Asian isolates. Most African studies reported high levels of macrolide susceptibility in Streptococcus pneumoniae, whereas most Chinese studies reported high levels of resistance. There was very little information available for Gram-negative organisms. CONCLUSIONS: Susceptibility of the pneumococcus to macrolides in SSA remains high in many areas, and good activity of azithromycin has been shown against Salmonellae spp. in Asia. In urban areas where high antibiotic consumption is prevalent, there was evidence of increased resistance to macrolides. However, there is no information on susceptibility from large areas in both continents.

Lubell Y, Riewpaiboon A, Dondorp AM, von Seidlein L, Mokuolu OA, Nansumba M, Gesase S, Kent A, Mtove G, Olaosebikan R et al. 2011. Cost-effectiveness of parenteral artesunate for treating children with severe malaria in sub-Saharan Africa. Bull World Health Organ, 89 (7), pp. 504-512. | Show Abstract | Read more

OBJECTIVE: To explore the cost-effectiveness of parenteral artesunate for the treatment of severe malaria in children and its potential impact on hospital budgets. METHODS: The costs of inpatient care of children with severe malaria were assessed in four of the 11 sites included in the African Quinine Artesunate Malaria Treatment trial, conducted with over 5400 children. The drugs, laboratory tests and intravenous fluids provided to 2300 patients from admission to discharge were recorded, as was the length of inpatient stay, to calculate the cost of inpatient care. The data were matched with pooled clinical outcomes and entered into a decision model to calculate the cost per disability-adjusted life year (DALY) averted and the cost per death averted. FINDINGS: The mean cost of treating severe malaria patients was similar in the two study groups: 63.5 United States dollars (US$) (95% confidence interval, CI: 61.7-65.2) in the quinine arm and US$ 66.5 (95% CI: 63.7-69.2) in the artesunate arm. Children treated with artesunate had 22.5% lower mortality than those treated with quinine and the same rate of neurological sequelae: (artesunate arm: 2.3 DALYs per patient; quinine arm: 3.0 DALYs per patient). Compared with quinine as a baseline, artesunate showed an incremental cost per DALY averted and an incremental cost per death averted of US$ 3.8 and US$ 123, respectively. CONCLUSION: Artesunate is a highly cost-effective and affordable alternative to quinine for treating children with severe malaria. The budgetary implications of adopting artesunate for routine use in hospital-based care are negligible.

Ashley EA, Lubell Y, White NJ, Turner P. 2011. Antimicrobial susceptibility of bacterial isolates from community acquired infections in Sub-Saharan Africa and Asian low and middle income countries. Trop Med Int Health, 16 (9), pp. 1167-1179. | Show Abstract | Read more

OBJECTIVE: Antimicrobial resistance has arisen across the globe in both nosocomial and community settings as a consequence of widespread antibiotic consumption. Poor availability of laboratory diagnosis means that resistance frequently goes unrecognised and may only be detected as clinical treatment failure. In this review, we provide an overview of the reported susceptibility of common community acquired bacterial pathogens in Sub-Saharan Africa and Asia to the antibiotics that are most widely used in these areas. METHODS: We reviewed the literature for reports of the susceptibility of prevalent pathogens in the community in SSA and Asia to a range of commonly prescribed antibiotics. Inclusion criteria required that isolates were collected since 2004 and that they were obtained from either normally sterile sites or urine. The data were aggregated by region and by age group. RESULTS: Eighty-three studies were identified since 2004 which reported the antimicrobial susceptibilities of common bacterial pathogens. Different methods were used to assess in-vitro susceptibility in the different studies. The quality of testing (evidenced by resistance profiles) also varied considerably. For Streptococcus pneumoniae and Neisseria meningitidis most drugs maintained relatively high efficacy, apart from co-trimoxazole to which there were high levels of resistance in most of the pathogens surveyed. CONCLUSIONS: Compared with the enormous infectious disease burden and widespread use of antibiotics there are relatively few reliable data on antimicrobial susceptibility from tropical Asia and Africa upon which to draw firm conclusions, although it is evident that many commonly used antibiotics face considerable resistance in prevalent bacterial pathogens. This is likely to exacerbate morbidity and mortality. Investment in improved antimicrobial susceptibility testing and surveillance systems is likely to be a highly cost-effective strategy and should be complemented by centralized and readily accessible information resources.

Lubell Y, Staedke SG, Greenwood BM, Kamya MR, Molyneux M, Newton PN, Reyburn H, Snow RW, D'Alessandro U, English M et al. 2011. Likely health outcomes for untreated acute febrile illness in the tropics in decision and economic models; a Delphi survey. PLoS One, 6 (2), pp. e17439. | Show Abstract | Read more

BACKGROUND: Modelling is widely used to inform decisions about management of malaria and acute febrile illnesses. Most models depend on estimates of the probability that untreated patients with malaria or bacterial illnesses will progress to severe disease or death. However, data on these key parameters are lacking and assumptions are frequently made based on expert opinion. Widely diverse opinions can lead to conflicting outcomes in models they inform. METHODS AND FINDINGS: A Delphi survey was conducted with malaria experts aiming to reach consensus on key parameters for public health and economic models, relating to the outcome of untreated febrile illnesses. Survey questions were stratified by malaria transmission intensity, patient age, and HIV prevalence. The impact of the variability in opinion on decision models is illustrated with a model previously used to assess the cost-effectiveness of malaria rapid diagnostic tests. Some consensus was reached around the probability that patients from higher transmission settings with untreated malaria would progress to severe disease (median 3%, inter-quartile range (IQR) 1-5%), and the probability that a non-malaria illness required antibiotics in areas of low HIV prevalence (median 20%). Children living in low transmission areas were considered to be at higher risk of progressing to severe malaria (median 30%, IQR 10-58%) than those from higher transmission areas (median 13%, IQR 7-30%). Estimates of the probability of dying from severe malaria were high in all settings (medians 60-73%). However, opinions varied widely for most parameters, and did not converge on resurveying. CONCLUSIONS: This study highlights the uncertainty around potential consequences of untreated malaria and bacterial illnesses. The lack of consensus on most parameters, the wide range of estimates, and the impact of variability in estimates on model outputs, demonstrate the importance of sensitivity analysis for decision models employing expert opinion. Results of such models should be interpreted cautiously. The diversity of expert opinion should be recognised when policy options are debated.

Lubell Y, Turner P, Ashley EA, White NJ. 2011. Susceptibility of bacterial isolates from community-acquired infections in sub-Saharan Africa and Asia to macrolide antibiotics Tropical Medicine and International Health, 16 (10), pp. 1192-1205. | Show Abstract | Read more

Objective To review the literature on the susceptibility of common community pathogens in sub-Saharan Africa and Asia to the macrolide antibiotics. Methods Inclusion criteria required that isolates were collected since 2004 to ensure results were of contemporary relevance. The data were aggregated by region, age group and sterility of site of culture sample. Results A total of 51 studies were identified, which reported the macrolide antimicrobial susceptibilities of common bacterial pathogens isolated since 2004. In general, there was less macrolide resistance in African than in Asian isolates. Most African studies reported high levels of macrolide susceptibility in Streptococcus pneumoniae, whereas most Chinese studies reported high levels of resistance. There was very little information available for Gram-negative organisms. Conclusions Susceptibility of the pneumococcus to macrolides in SSA remains high in many areas, and good activity of azithromycin has been shown against Salmonellae spp. in Asia. In urban areas where high antibiotic consumption is prevalent, there was evidence of increased resistance to macrolides. However, there is no information on susceptibility from large areas in both continents. © 2011 Blackwell Publishing Ltd.

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Lubell Y, Riewpaiboon A, Dondorp AM, Von Seidlein L, Mokuolu OA, Nansumba M, Gesase S, Kent A, Mtove G, Olaosebikan R et al. 2011. Cost-effectiveness of parenteral artesunate for treating children with severe malaria in sub-saharan Africa Bulletin of the World Health Organization, 89 (7), pp. 504-512. | Show Abstract | Read more

Objective To explore the cost-effectiveness of parenteral artesunate for the treatment of severe malaria in children and its potential impact on hospital budgets. Methods The costs of inpatient care of children with severe malaria were assessed in four of the 11 sites included in the African Quinine Artesunate Malaria Treatment trial, conducted with over 5400 children. The drugs, laboratory tests and intravenous fluids provided to 2300 patients from admission to discharge were recorded, as was the length of inpatient stay, to calculate the cost of inpatient care. The data were matched with pooled clinical outcomes and entered into a decision model to calculate the cost per disability-adjusted life year (DALY) averted and the cost per death averted. Findings The mean cost of treating severe malaria patients was similar in the two study groups: 63.5 United States dollars (US$) (95% confidence interval, CI: 61.7-65.2) in the quinine arm and US$ 66.5 (95% CI: 63.7-69.2) in the artesunate arm. Children treated with artesunate had 22.5% lower mortality than those treated with quinine and the same rate of neurological sequelae: (artesunate arm: 2.3 DALYs per patient; quinine arm: 3.0 DALYs per patient). Compared with quinine as a baseline, artesunate showed an incremental cost per DALY averted and an incremental cost per death averted of US$ 3.8 and US$ 123, respectively. Conclusion Artesunate is a highly cost-effective and affordable alternative to quinine for treating children with severe malaria. The budgetary implications of adopting artesunate for routine use in hospital-based care are negligible.

Cited:

29

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Ashley EA, Lubell Y, White NJ, Turner P. 2011. Antimicrobial susceptibility of bacterial isolates from community acquired infections in Sub-Saharan Africa and Asian low and middle income countries Tropical Medicine and International Health, 16 (9), pp. 1167-1179. | Show Abstract | Read more

Objective Antimicrobial resistance has arisen across the globe in both nosocomial and community settings as a consequence of widespread antibiotic consumption. Poor availability of laboratory diagnosis means that resistance frequently goes unrecognised and may only be detected as clinical treatment failure. In this review, we provide an overview of the reported susceptibility of common community acquired bacterial pathogens in Sub-Saharan Africa and Asia to the antibiotics that are most widely used in these areas. Methods We reviewed the literature for reports of the susceptibility of prevalent pathogens in the community in SSA and Asia to a range of commonly prescribed antibiotics. Inclusion criteria required that isolates were collected since 2004 and that they were obtained from either normally sterile sites or urine. The data were aggregated by region and by age group. Results Eighty-three studies were identified since 2004 which reported the antimicrobial susceptibilities of common bacterial pathogens. Different methods were used to assess in-vitro susceptibility in the different studies. The quality of testing (evidenced by resistance profiles) also varied considerably. For Streptococcus pneumoniae and Neisseria meningitidis most drugs maintained relatively high efficacy, apart from co-trimoxazole to which there were high levels of resistance in most of the pathogens surveyed. Conclusions Compared with the enormous infectious disease burden and widespread use of antibiotics there are relatively few reliable data o n antimicrobial susceptibility from tropical Asia and Africa upon which to draw firm conclusions, although it is evident that many commonly used antibiotics face considerable resistance in prevalent bacterial pathogens. This is likely to exacerbate morbidity and mortality. Investment in improved antimicrobial susceptibility testing and surveillance systems is likely to be a highly cost-effective strategy and should be complemented by centralized and readily accessible information resources. © 2011 Blackwell Publishing Ltd.

Lubell Y. 2010. Cost-effective use of prereferral treatment for severe malaria. Lancet, 376 (9756), pp. 1880-1881. | Read more

Lubell Y, Ashley EA, Turner C, Turner P, White NJ. 2011. Susceptibility of community-acquired pathogens to antibiotics in Africa and Asia in neonates--an alarmingly short review. Trop Med Int Health, 16 (2), pp. 145-151. | Show Abstract | Read more

OBJECTIVE: To assess the susceptibility of community-acquired pathogens in neonatal sepsis to commonly prescribed antibiotics in sub-Saharan Africa and Asia since 2002. METHODS: Literature review in PubMed and Embase. Susceptibility was estimated for pathogens individually and stratified by region. Isolates were also classified into Gram positive and Gram negative pathogens to estimate their pooled susceptibility. RESULTS AND CONCLUSIONS: Only nine studies met the inclusion criteria. The available data indicated poor susceptibility to almost all commonly used antibiotics in pathogens such as Staphylococcus aureus and Klebsiella spp. Only Streptococcus pneumoniae exhibited good susceptibility to all drugs other than cotrimoxazole. The extreme scarcity of data prevents drawing any firm conclusions beyond the urgent need for more studies to identify the best treatments for neonatal sepsis in the developing world.

Suputtamongkol Y, Pongtavornpinyo W, Lubell Y, Suttinont C, Hoontrakul S, Phimda K, Losuwanaluk K, Suwancharoen D, Silpasakorn S, Chierakul W, Day N. 2010. Strategies for diagnosis and treatment of suspected leptospirosis: a cost-benefit analysis. PLoS Negl Trop Dis, 4 (2), pp. e610. | Show Abstract | Read more

BACKGROUND: Symptoms and signs of leptospirosis are non-specific. Several diagnostic tests for leptospirosis are available and in some instances are being used prior to treatment of leptospirosis-suspected patients. There is therefore a need to evaluate the cost-effectiveness of the different treatment strategies in order to avoid misuse of scarce resources and ensure best possible health outcomes for patients. METHODS: The study population was adult patients, presented with uncomplicated acute febrile illness, without an obvious focus of infection or malaria or typical dengue infection. We compared the cost and effectiveness of 5 management strategies: 1) no patients tested or given antibiotic treatment; 2) all patients given empirical doxycycline treatment; patients given doxycycline when a patient is tested positive for leptospirosis using: 3) lateral flow; 4) MCAT; 5) latex test. The framework used is a cost-benefit analysis, accounting for all direct medical costs in diagnosing and treating patients suspected of leptospirosis. Outcomes are measured in length of fever after treatment which is then converted to productivity losses to capture the full economic costs. FINDINGS: Empirical doxycycline treatment was the most efficient strategy, being both the least costly alternative and the one that resulted in the shortest duration of fever. The limited sensitivity of all three diagnostic tests implied that their use to guide treatment was not cost-effective. The most influential parameter driving these results was the cost of treating patients with complications for patients who did not receive adequate treatment as a result of incorrect diagnosis or a strategy of no-antibiotic-treatment. CONCLUSIONS: Clinicians should continue treating suspected cases of leptospirosis on an empirical basis. This conclusion holds true as long as policy makers are not prioritizing the reduction of use of antibiotics, in which case the use of the latex test would be the most efficient strategy.

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.

Lubell Y, Mills AJ, Whitty CJM, Staedke SG. 2010. An economic evaluation of home management of malaria in Uganda: an interactive Markov model. PLoS One, 5 (8), pp. e12439. | Show Abstract | Read more

BACKGROUND: Home management of malaria (HMM), promoting presumptive treatment of febrile children in the community, is advocated to improve prompt appropriate treatment of malaria in Africa. The cost-effectiveness of HMM is likely to vary widely in different settings and with the antimalarial drugs used. However, no data on the cost-effectiveness of HMM programmes are available. METHODS/PRINCIPAL FINDINGS: A Markov model was constructed to estimate the cost-effectiveness of HMM as compared to conventional care for febrile illnesses in children without HMM. The model was populated with data from Uganda, but is designed to be interactive, allowing the user to adjust certain parameters, including the antimalarials distributed. The model calculates the cost per disability adjusted life year averted and presents the incremental cost-effectiveness ratio compared to a threshold value. Model output is stratified by level of malaria transmission and the probability that a child would receive appropriate care from a health facility, to indicate the circumstances in which HMM is likely to be cost-effective. The model output suggests that the cost-effectiveness of HMM varies with malaria transmission, the probability of appropriate care, and the drug distributed. Where transmission is high and the probability of appropriate care is limited, HMM is likely to be cost-effective from a provider perspective. Even with the most effective antimalarials, HMM remains an attractive intervention only in areas of high malaria transmission and in medium transmission areas with a lower probability of appropriate care. HMM is generally not cost-effective in low transmission areas, regardless of which antimalarial is distributed. Considering the analysis from the societal perspective decreases the attractiveness of HMM. CONCLUSION: Syndromic HMM for children with fever may be a useful strategy for higher transmission settings with limited health care and diagnosis, but is not appropriate for all settings. HMM may need to be tailored to specific settings, accounting for local malaria transmission intensity and availability of health services.

Leelahavarong P, Chaikledkaew U, Hongeng S, Kasemsup V, Lubell Y, Teerawattananon Y. 2010. A cost-utility and budget impact analysis of allogeneic hematopoietic stem cell transplantation for severe thalassemic patients in Thailand. BMC Health Serv Res, 10 (1), pp. 209. | Show Abstract | Read more

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is the only curative treatment available to severe thalassemic patients. The treatment, however, is very costly, particularly in the context of low and middle income countries, and no studies have been carried out to explore its economic justifiability. This study aimed to estimate the cost-utility of HSCT compared with blood transfusions combined with iron chelating therapy (BT-ICT) for severe thalassemia in Thailand, and to investigate the affordability of HSCT using a budget impact analysis. METHODS: A Markov model was used to estimate the relevant costs and health outcomes over the patients' lifetimes taking a societal perspective as recommended by Thailand's health technology assessment guidelines. All future costs and outcomes were discounted at a rate of 3% per annum. Primary outcomes of interest were lifetime costs, quality adjusted life years (QALYs) gained, and the incremental cost-effectiveness ratio (ICER) in Thai baht (THB) per QALY gained. RESULTS: Compared to BT-ICT, the incremental cost-effectiveness ratio increased with patient age from 80,700 to 183,000 THB per QALY gained for related HSCT and 209,000 to 953,000 THB per QALY gained for unrelated HSCT among patients aged 1 to 15 years (US$1= 34 THB). The governmental budget impact analysis showed that providing 200 related HSCT to patients aged 1 to 10 years, in accordance with the current infrastructure limitations, would initially require approximately 90 million additional THB per year. CONCLUSIONS: At a societal willingness to pay of 100,000 THB per QALY gained, related HSCT was likely to be a cost-effective and affordable treatment for young children with severe thalassemia in Thailand.

Lubell Y, Yeung S, Dondorp AM, Day NP, Nosten F, Tjitra E, Abul Faiz M, Yunus EB, Anstey NM, Mishra SK et al. 2009. Cost-effectiveness of artesunate for the treatment of severe malaria. Trop Med Int Health, 14 (3), pp. 332-337. | Show Abstract | Read more

OBJECTIVE: To explore the cost-effectiveness of artesunate against quinine based principally on the findings of a large multi-centre trial carried out in Southeast Asia. METHODS: Trial data were used to compare mortality of patients with severe malaria, treated with either artesunate or quinine. This was combined with retrospectively collected cost data to estimate the incremental cost per death averted with the use of artesunate instead of quinine. RESULTS: The incremental cost per death averted using artesunate was approximately 140 USD. Artesunate maintained this high level of cost-effectiveness also when allowing for the uncertainty surrounding the cost and effectiveness assessments. CONCLUSION: This analysis confirms the vast superiority of artesunate for treatment of severe malaria from an economic as well as a clinical perspective.

Lubell Y, Reyburn H, Mbakilwa H, Mwangi R, Chonya S, Whitty CJM, Mills A. 2008. The impact of response to the results of diagnostic tests for malaria: cost-benefit analysis. BMJ, 336 (7637), pp. 202-205. | Show Abstract | Read more

OBJECTIVE: Rapid diagnostic tests for malaria seem cost effective in standard analyses, but these do not take account of clinicians' response to test results. This study tested the impact of clinicians' response to rapid diagnostic test or microscopy results on the costs and benefits of testing at different levels of malaria transmission and in different age groups. DESIGN: Cost-benefit analysis using a decision tree model and clinical data on the effectiveness of diagnostic tests for malaria, their costs, and clinicians' response to test results. SETTING: Tanzania. METHODS: Data were obtained from a clinical trial of 2425 patients carried out in three settings of varying transmission. RESULTS: At moderate and low levels of malaria transmission, rapid diagnostic tests were more cost beneficial than microscopy, and both more so than presumptive treatment, but only where response was consistent with test results. At the levels of prescription of antimalarial drugs to patients with negative tests that have been found in observational studies and trials, neither test methodis likely to be cost beneficial, incurring costs 10-250% higher, depending on transmission rate, than would have been the case with fully consistent responses to all test results. Microscopy becomes more cost beneficial than rapid diagnostic tests when its sensitivity under operational conditions approaches that of rapid diagnostic tests. CONCLUSIONS: Improving diagnostic methods, including rapid diagnostic tests, can reduce costs and enhance the benefits of effective antimalarial drugs, but only if the consistency of response to test results is also improved. Investing in methods to improve rational response to tests is essential. Economic evaluations of diagnostic tests should take into account whether clinicians' response is consistent with test results.

Mills A, Lubell Y, Hanson K. 2008. Malaria eradication: the economic, financial and institutional challenge. Malar J, 7 Suppl 1 (Suppl 1), pp. S11. | Show Abstract | Read more

Malaria eradication raises many economic, financial and institutional challenges. This paper reviews these challenges, drawing on evidence from previous efforts to eradicate malaria, with a special focus on resource-poor settings; summarizes more recent evidence on the challenges, drawing on the literature on the difficulties of scaling-up malaria control and strengthening health systems more broadly; and explores the implications of these bodies of evidence for the current call for elimination and intensified control. Economic analyses dating from the eradication era, and more recent analyses, suggest that, in general, the benefits of malaria control outweigh the costs, though few studies have looked at the relative returns to eradication versus long-term control. Estimates of financial costs are scanty and difficult to compare. In the 1960s, the consolidation phase appeared to cost less than $1 per capita and, in 1988, was estimated to be $2.31 per capita (both in 2006 prices). More recent estimates for high coverage of control measures suggest a per capita cost of several dollars. Institutional challenges faced by malaria eradication included limits to the rule of law (a major problem where malaria was concentrated in border areas with movement of people associated with illegal activities), the existence and performance of local implementing structures, and political sustainability at national and global levels. Recent analyses of the constraints to scaling-up malaria control, together with the historical evidence, are used to discuss the economic, financial and institutional challenges that face the renewed call for eradication and intensified control. The paper concludes by identifying a research agenda covering: issues of the allocative efficiency of malaria eradication, especially using macro-economic modelling to estimate the benefits and costs of malaria eradication and intensified control, and studies of the links between malaria control and economic development, the costs and consequences of the various tools and mixes of tools employed in control and eradication, issues concerning the extension of coverage of interventions and service delivery approaches, especially those that can reach the poorest, research on the processes of formulating and implementing malaria control and eradication policies, at both international and national levels, research on financing issues, at global and national levels.

Lubell Y, Hopkins H, Whitty CJM, Staedke SG, Mills A. 2008. An interactive model for the assessment of the economic costs and benefits of different rapid diagnostic tests for malaria. Malar J, 7 (1), pp. 21. | Show Abstract | Read more

BACKGROUND: Rapid diagnostic tests (RDTs) for malaria are increasingly being considered for routine use in Africa. However, many RDTs are available and selecting the ideal test for a particular setting is challenging. The appropriateness of RDT choice depends in part on patient population and epidemiological setting, and on decision makers' priorities. The model presented (available online) can be used by decision makers to evaluate alternative RDTs and assess the circumstances under which their use is justified on economic grounds. METHODS: An interactive model based on a decision-tree structure and a cost-benefit framework was designed to compare different diagnostic strategies. Variables included in the model can be modified by users, including RDT and treatment costs, test accuracies (sensitivity and specificity), probabilities for developing severe illness, case-fatality rates, and clinician response to negative test results. To illustrate how the model can be used, a comparison is made of presumptive treatment with two available RDTs, one detecting histidine-rich protein-2 (HRP2) and one detecting Plasmodium lactate dehydrogenase (pLDH). Data inputs were obtained from a study comparing the RDTs at seven sites in Uganda. RESULTS: Applying the model in the illustrative Ugandan context demonstrates that if only direct expenditures are considered, the pLDH test is the preferred option for adult patients except in high transmission settings, while young children are best treated presumptively in all settings. When health outcomes are considered, the HRP2 test gains an advantage in almost all settings and for all age groups. Introducing possible adverse consequences of using an antimalarial into the analysis, such as adverse drug reactions, or the development of resistance, considerably strengthens the case for using RDTs. When the model is adjusted to account for less than complete adherence to test results, the efficiency of using RDTs drops sharply. CONCLUSION: Model output demonstrates that which test is preferable varies by location, depending on factors such as malaria transmission intensity and the costs and accuracies of the RDTs under consideration. Despite the uncertainties and complexities involved, adaptable models such as the one presented here can serve as a practical tool to assist policy makers in efficient deployment of new technologies.

Lubell Y, Reyburn H, Mbakilwa H, Mwangi R, Chonya K, Whitty CJM, Mills A. 2007. The cost-effectiveness of parasitologic diagnosis for malaria-suspected patients in an era of combination therapy. Am J Trop Med Hyg, 77 (6 Suppl), pp. 128-132. | Show Abstract

The introduction of artemisinin-based combination therapy in sub-Saharan Africa has prompted calls for increased use of parasitologic diagnosis for malaria. We evaluated the cost-effectiveness of rapid diagnostic tests (RDTs) in comparison to microscopy in guiding treatment of non-severe febrile illness at varying levels of malaria endemicity using data on test accuracy and costs collected as part of a Tanzanian trial. If prescribers complied with current guidelines, microscopy would give rise to lower average costs per patient correctly treated than RDTs in areas of both high and low transmission. RDT introduction would result in an additional 2.3% and 9.4% of patients correctly treated, at an incremental cost of $25 and $7 in the low and high transmission settings, respectively. Cost-effectiveness would be worse if prescribers do not comply with test results. The cost of this additional benefit may be higher than many countries can afford without external assistance or lower RDT prices.

Bonell A, Lubell Y, Newton PN, Crump JA, Paris DH. 2017. Estimating the burden of scrub typhus: A systematic review. PLoS Negl Trop Dis, 11 (9), pp. e0005838. | Show Abstract | Read more

BACKGROUND: Scrub typhus is a vector-borne zoonotic disease that can be life-threatening. There are no licensed vaccines, or vector control efforts in place. Despite increasing awareness in endemic regions, the public health burden and global distribution of scrub typhus remains poorly known. METHODS: We systematically reviewed all literature from public health records, fever studies and reports available on the Ovid MEDLINE, Embase Classic + Embase and EconLit databases, to estimate the burden of scrub typhus since the year 2000. FINDINGS: In prospective fever studies from Asia, scrub typhus is a leading cause of treatable non-malarial febrile illness. Sero-epidemiological data also suggest that Orientia tsutsugamushi infection is common across Asia, with seroprevalence ranging from 9.3%-27.9% (median 22.2% IQR 18.6-25.7). A substantial apparent rise in minimum disease incidence (median 4.6/100,000/10 years, highest in China with 11.2/100,000/10 years) was reported through passive national surveillance systems in South Korea, Japan, China, and Thailand. Case fatality risks from areas of reduced drug-susceptibility are reported at 12.2% and 13.6% for South India and northern Thailand, respectively. Mortality reports vary widely around a median mortality of 6.0% for untreated and 1.4% for treated scrub typhus. Limited evidence suggests high mortality in complicated scrub typhus with CNS involvement (13.6% mortality), multi-organ dysfunction (24.1%) and high pregnancy miscarriage rates with poor neonatal outcomes. INTERPRETATION: Scrub typhus appears to be a truly neglected tropical disease mainly affecting rural populations, but increasingly also metropolitan areas. Rising minimum incidence rates have been reported over the past 8-10 years from countries with an established surveillance system. A wider distribution of scrub typhus beyond Asia is likely, based on reports from South America and Africa. Unfortunately, the quality and quantity of the available data on scrub typhus epidemiology is currently too limited for any economical, mathematical modeling or mapping approaches.

Devine A, Parmiter M, Chu CS, Bancone G, Nosten F, Price RN, Lubell Y, Yeung S. 2017. Using G6PD tests to enable the safe treatment of Plasmodium vivax infections with primaquine on the Thailand-Myanmar border: A cost-effectiveness analysis. PLoS Negl Trop Dis, 11 (5), pp. e0005602. | Show Abstract | Read more

BACKGROUND: Primaquine is the only licensed antimalarial for the radical cure of Plasmodium vivax infections. Many countries, however, do not administer primaquine due to fear of hemolysis in those with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In other settings, primaquine is given without G6PD testing, putting patients at risk of hemolysis. New rapid diagnostic tests (RDTs) offer the opportunity to screen for G6PD deficiency prior to treatment with primaquine. Here we assessed the cost-effectiveness of using G6PD RDTs on the Thailand-Myanmar border and provide the model as an online tool for use in other settings. METHODS/PRINCIPAL FINDINGS: Decision tree models for the management of P. vivax malaria evaluated the costs and disability-adjusted life-years (DALYs) associated with recurrences and primaquine-induced hemolysis from a health care provider perspective. Screening with G6PD RDTs before primaquine use was compared to (1) giving chloroquine alone and (2) giving primaquine without screening. Data were taken from a recent study on the impact of primaquine on P. vivax recurrences and a literature review. Compared to the use of chloroquine alone, the screening strategy had similar costs while averting 0.026 and 0.024 DALYs per primary infection in males and females respectively. Compared to primaquine administered without screening, the screening strategy provided modest cost savings while averting 0.011 and 0.004 DALYs in males and females respectively. The probabilistic sensitivity analyses resulted in a greater than 75% certainty that the screening strategy was cost-effective at a willingness to pay threshold of US$500, which is well below the common benchmark of per capita gross domestic product for Myanmar. CONCLUSIONS/SIGNIFICANCE: In this setting G6PD RDTs could avert DALYs by reducing recurrences and reducing hemolytic risk in G6PD deficient patients at low costs or cost savings. The model results are limited by the paucity of data available in the literature for some parameter values, including the mortality rates for both primaquine-induced hemolysis and P. vivax. The online model provides an opportunity to use different parameter estimates to examine the validity of these findings in other settings.

Lubell Y, Althaus T. 2017. Biomarker tests for bacterial infection-a costly wait for the holy grail. Lancet Infect Dis, 17 (4), pp. 369-370. | Read more

Schultz MJ, Dunser MW, Dondorp AM, Adhikari NKJ, Iyer S, Kwizera A, Lubell Y, Papali A, Pisani L, Riviello BD et al. 2017. Current challenges in the management of sepsis in ICUs in resource-poor settings and suggestions for the future. Intensive Care Med, 43 (5), pp. 612-624. | Show Abstract | Read more

BACKGROUND: Sepsis is a major reason for intensive care unit (ICU) admission, also in resource-poor settings. ICUs in low- and middle-income countries (LMICs) face many challenges that could affect patient outcome. AIM: To describe differences between resource-poor and resource-rich settings regarding the epidemiology, pathophysiology, economics and research aspects of sepsis. We restricted this manuscript to the ICU setting even knowing that many sepsis patients in LMICs are treated outside an ICU. FINDINGS: Although many bacterial pathogens causing sepsis in LMICs are similar to those in high-income countries, resistance patterns to antimicrobial drugs can be very different; in addition, causes of sepsis in LMICs often include tropical diseases in which direct damaging effects of pathogens and their products can sometimes be more important than the response of the host. There are substantial and persisting differences in ICU capacities around the world; not surprisingly the lowest capacities are found in LMICs, but with important heterogeneity within individual LMICs. Although many aspects of sepsis management developed in rich countries are applicable in LMICs, implementation requires strong consideration of cost implications and the important differences in resources. CONCLUSIONS: Addressing both disease-specific and setting-specific factors is important to improve performance of ICUs in LMICs. Although critical care for severe sepsis is likely cost-effective in LMIC setting, more detailed evaluation at both at a macro- and micro-economy level is necessary. Sepsis management in resource-limited settings is a largely unexplored frontier with important opportunities for research, training, and other initiatives for improvement.

Drake TL, Lubell Y, Kyaw SS, Devine A, Kyaw MP, Day NPJ, Smithuis FM, White LJ. 2017. Geographic Resource Allocation Based on Cost Effectiveness: An Application to Malaria Policy. Appl Health Econ Health Policy, 15 (3), pp. 299-306. | Show Abstract | Read more

Healthcare services are often provided to a country as a whole, though in many cases the available resources can be more effectively targeted to specific geographically defined populations. In the case of malaria, risk is highly geographically heterogeneous, and many interventions, such as insecticide-treated bed nets and malaria community health workers, can be targeted to populations in a way that maximises impact for the resources available. This paper describes a framework for geographically targeted budget allocation based on the principles of cost-effectiveness analysis and applied to priority setting in malaria control and elimination. The approach can be used with any underlying model able to estimate intervention costs and effects given relevant local data. Efficient geographic targeting of core malaria interventions could significantly increase the impact of the resources available, accelerating progress towards elimination. These methods may also be applicable to priority setting in other disease areas.

Do NTT, Ta NTD, Tran NTH, Than HM, Vu BTN, Hoang LB, van Doorn HR, Vu DTV, Cals JWL, Chandna A et al. 2016. Point-of-care C-reactive protein testing to reduce inappropriate use of antibiotics for non-severe acute respiratory infections in Vietnamese primary health care: a randomised controlled trial. Lancet Glob Health, 4 (9), pp. e633-e641. | Show Abstract | Read more

BACKGROUND: Inappropriate antibiotic use for acute respiratory tract infections is common in primary health care, but distinguishing serious from self-limiting infections is difficult, particularly in low-resource settings. We assessed whether C-reactive protein point-of-care testing can safely reduce antibiotic use in patients with non-severe acute respiratory tract infections in Vietnam. METHOD: We did a multicentre open-label randomised controlled trial in ten primary health-care centres in northern Vietnam. Patients aged 1-65 years with at least one focal and one systemic symptom of acute respiratory tract infection were assigned 1:1 to receive either C-reactive protein point-of-care testing or routine care, following which antibiotic prescribing decisions were made. Patients with severe acute respiratory tract infection were excluded. Enrolled patients were reassessed on day 3, 4, or 5, and on day 14 a structured telephone interview was done blind to the intervention. Randomised assignments were concealed from prescribers and patients but not masked as the test result was used to assist treatment decisions. The primary outcome was antibiotic use within 14 days of follow-up. All analyses were prespecified in the protocol and the statistical analysis plan. All analyses were done on the intention-to-treat population and the analysis of the primary endpoint was repeated in the per-protocol population. This trial is registered under number NCT01918579. FINDINGS: Between March 17, 2014, and July 3, 2015, 2037 patients (1028 children and 1009 adults) were enrolled and randomised. One adult patient withdrew immediately after randomisation. 1017 patients were assigned to receive C-reactive protein point-of-care testing, and 1019 patients were assigned to receive routine care. 115 patients in the C-reactive protein point-of-care group and 72 patients in the routine care group were excluded in the intention-to-treat analysis due to missing primary endpoint. The number of patients who used antibiotics within 14 days was 581 (64%) of 902 patients in the C-reactive protein group versus 738 (78%) of 947 patients in the control group (odds ratio [OR] 0·49, 95% CI 0·40-0·61; p<0·0001). Highly significant differences were seen in both children and adults, with substantial heterogeneity of the intervention effect across the 10 sites (I(2)=84%, 95% CI 66-96). 140 patients in the C-reactive protein group and 137 patients in the routine care group missed the urine test on day 3, 4, or 5. Antibiotic activity in urine on day 3, 4, or 5 was found in 267 (30%) of 877 patients in the C-reactive protein group versus 314 (36%) of 882 patients in the routine treatment group (OR 0·78, 95% CI 0·63-0·95; p=0·015). Time to resolution of symptoms was similar in both groups. Adverse events were rare, with no deaths and a total of 14 hospital admissions (six in the C-reactive protein group and eight in the control group). INTERPRETATION: C-reactive protein point-of-care testing reduced antibiotic use for non-severe acute respiratory tract infection without compromising patients' recovery in primary health care in Vietnam. Health-care providers might have become familiar with the clinical picture of low C-reactive protein, leading to reduction in antibiotic prescribing in both groups, but this would have led to a reduction in observed effect, rather than overestimation. Qualitative analysis is needed to address differences in context in order to implement this strategy to improve rational antibiotic use for patients with acute respiratory infection in low-income and middle-income countries. FUNDING: Wellcome Trust, UK, and Global Antibiotic Resistance Partnership, USA.

Drake TL, Devine A, Yeung S, Day NPJ, White LJ, Lubell Y. 2016. Dynamic Transmission Economic Evaluation of Infectious Disease Interventions in Low- and Middle-Income Countries: A Systematic Literature Review. Health Econ, 25 Suppl 1 pp. 124-139. | Show Abstract | Read more

Economic evaluation using dynamic transmission models is important for capturing the indirect effects of infectious disease interventions. We examine the use of these methods in low- and middle-income countries, where infectious diseases constitute a major burden. This review is comprised of two parts: (1) a summary of dynamic transmission economic evaluations across all disease areas published between 2011 and mid-2014 and (2) an in-depth review of mosquito-borne disease studies focusing on health economic methods and reporting. Studies were identified through a systematic search of the MEDLINE database and supplemented by reference list screening. Fifty-seven studies were eligible for inclusion in the all-disease review. The most common subject disease was HIV/AIDS, followed by malaria. A diverse range of modelling methods, outcome metrics and sensitivity analyses were used, indicating little standardisation. Seventeen studies were included in the mosquito-borne disease review. With notable exceptions, most studies did not employ economic evaluation methods beyond calculating a cost-effectiveness ratio or net benefit. Many did not adhere to health care economic evaluations reporting guidelines, particularly with respect to full model reporting and uncertainty analysis. We present a summary of the state-of-the-art and offer recommendations for improved implementation and reporting of health economic methods in this crossover discipline.

Dittrich S, Tadesse BT, Moussy F, Chua A, Zorzet A, Tängdén T, Dolinger DL, Page A-L, Crump JA, D'Acremont V et al. 2016. Target Product Profile for a Diagnostic Assay to Differentiate between Bacterial and Non-Bacterial Infections and Reduce Antimicrobial Overuse in Resource-Limited Settings: An Expert Consensus. PLoS One, 11 (8), pp. e0161721. | Show Abstract | Read more

Acute fever is one of the most common presenting symptoms globally. In order to reduce the empiric use of antimicrobial drugs and improve outcomes, it is essential to improve diagnostic capabilities. In the absence of microbiology facilities in low-income settings, an assay to distinguish bacterial from non-bacterial causes would be a critical first step. To ensure that patient and market needs are met, the requirements of such a test should be specified in a target product profile (TPP). To identify minimal/optimal characteristics for a bacterial vs. non-bacterial fever test, experts from academia and international organizations with expertise in infectious diseases, diagnostic test development, laboratory medicine, global health, and health economics were convened. Proposed TPPs were reviewed by this working group, and consensus characteristics were defined. The working group defined non-severely ill, non-malaria infected children as the target population for the desired assay. To provide access to the most patients, the test should be deployable to community health centers and informal health settings, and staff should require <2 days of training to perform the assay. Further, given that the aim is to reduce inappropriate antimicrobial use as well as to deliver appropriate treatment for patients with bacterial infections, the group agreed on minimal diagnostic performance requirements of >90% and >80% for sensitivity and specificity, respectively. Other key characteristics, to account for the challenging environment at which the test is targeted, included: i) time-to-result <10 min (but maximally <2 hrs); ii) storage conditions at 0-40°C, ≤90% non-condensing humidity with a minimal shelf life of 12 months; iii) operational conditions of 5-40°C, ≤90% non-condensing humidity; and iv) minimal sample collection needs (50-100μL, capillary blood). This expert approach to define assay requirements for a bacterial vs. non-bacterial assay should guide product development, and enable targeted and timely efforts by industry partners and academic institutions.

Peto TJ, Tripura R, Lee SJ, Althaus T, Dunachie S, Nguon C, Dhorda M, Promnarate C, Chalk J, Imwong M et al. 2016. Association between Subclinical Malaria Infection and Inflammatory Host Response in a Pre-Elimination Setting. PLoS One, 11 (7), pp. e0158656. | Show Abstract | Read more

BACKGROUND: Subclinical infections in endemic areas of Southeast Asia sustain malaria transmission. These asymptomatic infections might sustain immunity against clinical malaria and have been considered benign for the host, but if they are associated with chronic low-grade inflammation this could be harmful. We conducted a case-control study to explore the association between subclinical malaria and C-reactive protein (CRP), an established biomarker of inflammation. METHODS: Blood samples from asymptomatic villagers in Pailin, Western Cambodia were tested for malaria by high-volume ultra-sensitive polymerase chain reaction (uPCR) to determine the Plasmodium species. Plasma CRP concentration was measured in 328 individuals with parasitaemia (cases) and compared with: i) the same individual's value at the first time point when they had no detectable parasites (n = 282); and ii) age- sex- and village-matched controls (n = 328) free of Plasmodium infection. Plasma CRP concentrations were compared against thresholds of 3mg/L and 10mg/L. Subgroup analysis was carried out for cases with P vivax and P falciparum mono-infections. RESULTS: Median plasma CRP level for all samples was 0.59mg/L (interquartile range: 0.24-1.64mg/L). CRP concentrations were higher in parasitaemic individuals compared with same-person-controls (p = 0.050); and matched-controls (p = 0.025). 4.9% of samples had CRP concentrations above 10mg/L and 14.6% were above 3mg/L. Cases were more likely to have plasma CRP concentrations above these thresholds than age/sex matched controls, odds ratio 3.5 (95%CI 1.5-9.8) and 1.8 (95%CI 1.1-2.9), respectively. Amongst cases, parasite density and CRP were positively correlated (p<0.001), an association that remained significant when controlling for age and fever. Individuals with P.vivax mono-infections had the highest plasma CRP concentrations with the greatest association with parasitaemia. DISCUSSION: In this setting persistent malaria infections in asymptomatic individuals were associated with moderately elevated plasma CRP concentrations; chiefly evident in cases with P.vivax mono-infections. As well as interrupting malaria transmission within the community, treatment of asymptomatic malaria infections, in particular radical cure of vivax malaria, may benefit the health of infected individuals.

Lubell Y, Althaus T, Blacksell SD, Paris DH, Mayxay M, Pan-Ngum W, White LJ, Day NPJ, Newton PN. 2016. Modelling the Impact and Cost-Effectiveness of Biomarker Tests as Compared with Pathogen-Specific Diagnostics in the Management of Undifferentiated Fever in Remote Tropical Settings. PLoS One, 11 (3), pp. e0152420. | Show Abstract | Read more

BACKGROUND: Malaria accounts for a small fraction of febrile cases in increasingly large areas of the malaria endemic world. Point-of-care tests to improve the management of non-malarial fevers appropriate for primary care are few, consisting of either diagnostic tests for specific pathogens or testing for biomarkers of host response that indicate whether antibiotics might be required. The impact and cost-effectiveness of these approaches are relatively unexplored and methods to do so are not well-developed. METHODS: We model the ability of dengue and scrub typhus rapid tests to inform antibiotic treatment, as compared with testing for elevated C-Reactive Protein (CRP), a biomarker of host-inflammation. Using data on causes of fever in rural Laos, we estimate the proportion of outpatients that would be correctly classified as requiring an antibiotic and the likely cost-effectiveness of the approaches. RESULTS: Use of either pathogen-specific test slightly increased the proportion of patients correctly classified as requiring antibiotics. CRP testing was consistently superior to the pathogen-specific tests, despite heterogeneity in causes of fever. All testing strategies are likely to result in higher average costs, but only the scrub typhus and CRP tests are likely to be cost-effective when considering direct health benefits, with median cost per disability adjusted life year averted of approximately $48 USD and $94 USD, respectively. CONCLUSIONS: Testing for viral infections is unlikely to be cost-effective when considering only direct health benefits to patients. Testing for prevalent bacterial pathogens can be cost-effective, having the benefit of informing not only whether treatment is required, but also as to the most appropriate antibiotic; this advantage, however, varies widely in response to heterogeneity in causes of fever. Testing for biomarkers of host inflammation is likely to be consistently cost-effective despite high heterogeneity, and can also offer substantial reductions in over-use of antimicrobials in viral infections.

Phommasone K, Althaus T, Souvanthong P, Phakhounthong K, Soyvienvong L, Malapheth P, Mayxay M, Pavlicek RL, Paris DH, Dance D et al. 2016. Accuracy of commercially available c-reactive protein rapid tests in the context of undifferentiated fevers in rural Laos. BMC Infect Dis, 16 (1), pp. 61. | Show Abstract | Read more

BACKGROUND: C-Reactive Protein (CRP) has been shown to be an accurate biomarker for discriminating bacterial from viral infections in febrile patients in Southeast Asia. Here we investigate the accuracy of existing rapid qualitative and semi-quantitative tests as compared with a quantitative reference test to assess their potential for use in remote tropical settings. METHODS: Blood samples were obtained from consecutive patients recruited to a prospective fever study at three sites in rural Laos. At each site, one of three rapid qualitative or semi-quantitative tests was performed, as well as a corresponding quantitative NycoCard Reader II as a reference test. We estimate the sensitivity and specificity of the three tests against a threshold of 10 mg/L and kappa values for the agreement of the two semi-quantitative tests with the results of the reference test. RESULTS: All three tests showed high sensitivity, specificity and kappa values as compared with the NycoCard Reader II. With a threshold of 10 mg/L the sensitivity of the tests ranged from 87-98 % and the specificity from 91-98 %. The weighted kappa values for the semi-quantitative tests were 0.7 and 0.8. CONCLUSION: The use of CRP rapid tests could offer an inexpensive and effective approach to improve the targeting of antibiotics in remote settings where health facilities are basic and laboratories are absent. This study demonstrates that accurate CRP rapid tests are commercially available; evaluations of their clinical impact and cost-effectiveness at point of care is warranted.

de Haan F, Onyamboko MA, Fanello CI, Woodrow CJ, Lubell Y, Boon WPC, Dondorp AM. 2015. Exploring health practitioners' acceptability of a prospective semi-quantitative pfHRP2 device to define severe malaria in the Democratic Republic of Congo. Malar J, 14 (1), pp. 503. | Show Abstract | Read more

BACKGROUND: A rapid diagnostic tool is being developed to discern severely ill children with severe malaria from children who are ill with alternative febrile diseases but have coincidental peripheral blood parasitaemia. The device semi-quantitatively measures plasma pfHRP2 and has the potential to reduce mortality in children with severe febrile illnesses by improving diagnosis. The aim of this study is to identify contributing and inhibiting factors that affect healthcare practitioners' acceptability of this prospective diagnostic device in a high malaria transmission setting in the Democratic Republic of Congo. METHODS: Data were collected qualitatively by conducting semi-structured interviews with a purposeful sample of health professionals in Kinshasa, capital of Democratic Republic of Congo. In total, 11 interviews were held with professionals at four different institutes. RESULTS: Four key findings emerged: (1) Congolese practitioners perceive the semi-quantitative pfHRP2 device as a welcome intervention as they recognize the limited reliability of their current diagnostic and therapeutic approaches to severe febrile illnesses; (2) compatibility of the semi-quantitative pfHRP2 device with clinical equipment and competences of Congolese health practitioners is considered to be limited, especially in rural settings; (3) a formal training programme is crucial for correct understanding and application of the semi-quantitative pfHRP2 device; and, (4) provision of evidence to practitioners, and support from health authorities would be important to establish confidence in the semi-quantitative pfHRP2 device. CONCLUSIONS: Congolese practitioners perceive the prospective semi-quantitative pfHRP2 device as a welcome addition to their clinical equipment. The device could improve current diagnostic work-up of severe febrile illness, which might consequently improve treatment choices. However, despite this recognized potential, several hurdles and drivers need to be taken into account when implementing this device in DR Congo.

Development of dynamic algorithms for empirical antibiotic treatment in the rural tropics

Fevers and respiratory infections are the most common reasons for seeking medical care in the community, and for subsequent prescription of antibiotics. In rural tropical settings, health workers have no diagnostic tools to determine which patients require antibiotics. Furthermore, when it is assumed that these are required, there is an absence of locally relevant empirical treatment guidelines to ensure that effective antibiotics are prescribed.This project will link with a broader research ...

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