Causes of non-malarial fever in Laos: a prospective study

Background Because of reductions in the incidence of Plasmodium falciparum malaria in Laos, identifi cation of the causes of fever in people without malaria, and discussion of the best empirical treatment options, are urgently needed. We aimed to identify the causes of non-malarial acute fever in patients in rural Laos. Methods For this prospective study, we recruited 1938 febrile patients, between May, 2008, and December, 2010, at Luang Namtha provincial hospital in northwest Laos (n=1390), and between September, 2008, and December, 2010, at Salavan provincial hospital in southern Laos (n=548). Eligible participants were aged 5–49 years with fever (≥38°C) lasting 8 days or less and were eligible for malaria testing by national guidelines. Findings With conservative defi nitions of cause, we assigned 799 (41%) patients a diagnosis. With exclusion of infl uenza, the top fi ve diagnoses when only one aetiological agent per patient was identifi ed were dengue (156 [8%] of 1927 patients), scrub typhus (122 [7%] of 1871), Japanese encephalitis virus (112 [6%] of 1924), leptospirosis (109 [6%] of 1934), and bacteraemia (43 [2%] of 1938). 115 (32%) of 358 patients at Luang Namtha hospital tested infl uenza PCR-positive between June and December, 2010, of which infl uenza B was the most frequently detected strain (n=121 [87%]). Disease frequency diff ered signifi cantly between the two sites: Japanese encephalitis virus infection (p=0·04), typhoid (p=0·006), and leptospirosis (p=0·001) were more common at Luang Namtha, whereas dengue and malaria were more common at Salavan (all p<0·0001). With use of evidence from southeast Asia when possible, we estimated that azithromycin, doxycycline, ceftriaxone, and ofl oxacin would have had signifi cant effi cacy for 258 (13%), 240 (12%), 154 (8%), and 41 (2%) of patients, respectively. Interpretation Our fi ndings suggest that a wide range of treatable or preventable pathogens are implicated in nonmalarial febrile illness in Laos. Empirical treatment with doxycycline for patients with undiff erentiated fever and negative rapid diagnostic tests for malaria and dengue could be an appropriate strategy for rural health workers in Laos. Funding Wellcome Trust, WHO–Western Pacifi c Region, Foundation for Innovative New Diagnostics, US Centers for Disease Control and Prevention

No Evidence for Spread of Plasmodium falciparum Artemisinin Resistance to Savannakhet Province, Southern Laos

We conducted an open-label, randomized clinical trial to assess parasite clearance times (PCT) and the efficacy of 4 mg/kg (group 1, n = 22) and 2 mg/kg (group 2, n = 22) of oral artesunate for three days followed by artemether-lumefantrine in patients with uncomplicated Plasmodium falciparum malaria at Xepon Interdistrict Hospital, Savannakhet Province in southern Laos. Slides were read in duplicate. The overall mean (95% confidence interval; range) PCT in hours was 23.2 (21.2–25.3; 12–46) and 22.4 (20.3–24.5; 12–46) for the first and second microscopists, respectively (P = 0.57). Ten (23%) patients remained parasitemic on day 1 after treatment (4 [18%] in group 1 and 6 [27%] in group 2; P = 0.47). No patient had patent asexual parasitemia on the second and third days of treatment. The 42-day polymerase chain reaction–corrected cure rates were 100% in both treatment groups. Serious adverse events did not develop during or after treatment in any patients. In conclusion, no evidence of P. falciparum in vivo resistance to artesunate was found in southern Laos

Characterizing the spatial distribution of multiple malaria diagnostic endpoints in a low-transmission setting in Lao PDR.

The epidemiology of malaria changes as prevalence falls in low-transmission settings, with remaining infections becoming more difficult to detect and diagnose. At this stage active surveillance is critical to detect residual hotspots of transmission. However, diagnostic tools used in active surveillance generally only detect concurrent infections, and surveys may benefit from sensitive tools such as serological assays. Serology can be used to interrogate and characterize individuals' previous exposure to malaria over longer durations, providing information essential to the detection of remaining foci of infection. We ran blood samples collected from a 2016 population-based survey in the low-transmission setting of northern Lao PDR on a multiplexed bead assay to characterize historic and recent exposures to Plasmodium falciparum and vivax. Using geostatistical methods and remote-sensing data we assessed the environmental and spatial associations with exposure, and created predictive maps of exposure within the study sites. We additionally linked the active surveillance PCR and serology data with passively collected surveillance data from health facility records. We aimed to highlight the added information which can be gained from serology as a tool in active surveillance surveys in low-transmission settings, and to identify priority areas for national surveillance programmes where malaria risk is higher. We also discuss the issues faced when linking malaria data from multiple sources using multiple diagnostic endpoints

High heterogeneity in Plasmodium falciparum risk illustrates the need for detailed mapping to guide resource allocation: a new malaria risk map of the Lao People's Democratic Republic

<p>Abstract</p> <p>Background</p> <p>Accurate information on the geographical distribution of malaria is important for efficient resource allocation. The Lao People's Democratic Republic has experienced a major decline in malaria morbidity and mortality in the past decade. However, efforts to respond effectively to these changes have been impeded by lack of detailed data on malaria distribution. In 2008, a countrywide survey on <it>Plasmodium falciparum </it>diagnosed in health centres and villages was initiated to develop a detailed <it>P. falciparum </it>risk map with the aim to identify priority areas for malaria control, estimate population at risk, and guide resource allocation in the Lao People's Democratic Republic.</p> <p>Methods</p> <p><it>P. falciparum </it>incidence data were collected from point-referenced villages and health centres for the period 2006-2008 during a country-wide survey between December 2008 and January 2009. Using the highest recorded annual rate, continuous surfaces of <it>P. falciparum </it>incidence were produced by the inverse distance weighted interpolation technique.</p> <p>Results</p> <p>Incidence rates were obtained from 3,876 villages and 685 health centres. The risk map shows that <it>P. falciparum </it>is highly heterogeneous in the northern and central regions of the country with large areas of no transmission. In the southern part, transmission is pervasive and the risk of <it>P. falciparum </it>is high. It was estimated that 3.4 million people (60% of the population) live at risk of malaria.</p> <p>Conclusions</p> <p>This paper presents the first comprehensive malaria risk map of the Lao People's Democratic Republic based entirely on empirical data. The estimated population at risk is substantially lower than previous estimates, reflecting the presence of vast areas with focal or no malaria transmission as identified in this study. These findings provide important guidance for malaria control interventions in the Lao People's Democratic Republic, and underline the need for detailed data on malaria to accurately predict risk in countries with heterogeneous transmission.</p

Spread of artemisinin resistance in Plasmodium falciparum malaria.

BACKGROUND: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. METHODS: Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. RESULTS: The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. CONCLUSIONS: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.)

Malaria elimination in Lao PDR: the challenges associated with population mobility

Abstract Although the Lao People’s Democratic Republic (Lao PDR) is comparatively small landlocked country with patterns of both in- and out-migration, its human migration situation has been poorly studied. This is despite all of the country’s 18 provinces sharing both official and unofficial border checkpoints with neighboring countries. Economic reforms in the last decade have seen a gradual increase in the promotion of foreign investment, and main towns and transportation networks have been expanding thus offering new opportunities for livelihoods and economic activities. In the last decade, there has also been a significant reduction of reported malaria cases in Lao PDR and while this is an important prerequisite for eliminating malaria in the country, malaria outbreaks reported in the last four years suggest that population mobility, particularly in the south, is an important factor challenging current control efforts. Bolder investment in social sector spending should be geared towards improving health service provision and utilization, ensuring equitable access to primary health care (including malaria) through efforts to achieve universal health coverage targets. This should be extended to populations that are mobile and migrants. The local government plays a critical role in supporting policy and enforcement issues related to private sector project development in the provinces. Cross-border initiatives with neighboring countries, especially in terms of data sharing, surveillance, and response, is essential. Mechanisms to engage the private sector, especially the informal private sector, needs to be explored within the context of existing regulations and laws. Existing and new interventions for outdoor transmission of malaria, especially in forest settings, for high-risk groups including short- and long-term forest workers and their families, mobile and migrant populations, as well as the military must be combined into integrated packages with innovative delivery mechanisms through social marketing approaches. This should happen at multiple points in the mobility pathway and involve the private sector rather than being fully reliant on the national malaria vertical program This article based on the review of existing literature from abstracts and full texts, includes published, peer-reviewed English language literature sourced through PubMed and grey literature sources through Google and Google Scholar. The review included also case reports, sector reports, conference proceedings, research reports, epidemiology studies, qualitative studies, and census reports in both Lao and English languages. The authors used the search terms: malaria and mobile populations, malaria control program and elimination, health system performance, malaria outbreak, Lao PDR; and included articles published until June 2015

Spatio-Temporal Associations Between Deforestation and Malaria Incidence in Lao PDR

As countries in the Greater Mekong Sub-region (GMS) increasingly focus their malaria control and elimination efforts on reducing forest-related transmission, greater understanding of the relationship between deforestation and malaria incidence will be essential for programs to assess and meet their 2030 elimination goals. Leveraging village-level health facility surveillance data and forest cover data in a spatio-temporal modeling framework, we found evidence that deforestation is associated with short-term increases, but long-term decreases confirmed malaria case incidence in Lao People\u27s Democratic Republic (Lao PDR). We identified strong associations with deforestation measured within 30 km of villages but not with deforestation in the near (10 km) and immediate (1 km) vicinity. Results appear driven by deforestation in densely forested areas and were more pronounced for infections with Plasmodium falciparum (P. falciparum) than for Plasmodium vivax (P. vivax). These findings highlight the influence of forest activities on malaria transmission in the GMS