Methodological issues of retrospective surveys for measuring mortality of highly clustered diseases: case study of the 2014-16 Ebola outbreak in Bo District, Sierra Leone.

BACKGROUND: There is a lack of empirical data on design effects (DEFF) for mortality rate for highly clustered data such as with Ebola virus disease (EVD), along with a lack of documentation of methodological limitations and operational utility of mortality estimated from cluster-sampled studies when the DEFF is high. OBJECTIVES: The objectives of this paper are to report EVD mortality rate and DEFF estimates, and discuss the methodological limitations of cluster surveys when data are highly clustered such as during an EVD outbreak. METHODS: We analysed the outputs of two independent population-based surveys conducted at the end of the 2014-2016 EVD outbreak in Bo District, Sierra Leone, in urban and rural areas. In each area, 35 clusters of 14 households were selected with probability proportional to population size. We collected information on morbidity, mortality and changes in household composition during the recall period (May 2014 to April 2015). Rates were calculated for all-cause, all-age, under-5 and EVD-specific mortality, respectively, by areas and overall. Crude and adjusted mortality rates were estimated using Poisson regression, accounting for the surveys sample weights and the clustered design. RESULTS: Overall 980 households and 6,522 individuals participated in both surveys. A total of 64 deaths were reported, of which 20 were attributed to EVD. The crude and EVD-specific mortality rates were 0.35/10,000 person-days (95%CI: 0.23-0.52) and 0.12/10,000 person-days (95%CI: 0.05-0.32), respectively. The DEFF for EVD mortality was 5.53, and for non-EVD mortality, it was 1.53. DEFF for EVD-specific mortality was 6.18 in the rural area and 0.58 in the urban area. DEFF for non-EVD-specific mortality was 1.87 in the rural area and 0.44 in the urban area. CONCLUSION: Our findings demonstrate a high degree of clustering; this contributed to imprecise mortality estimates, which have limited utility when assessing the impact of disease. We provide DEFF estimates that can inform future cluster surveys and discuss design improvements to mitigate the limitations of surveys for highly clustered data.

Main findings: For humanitarian organizations it is imperative to document the methodological limitations of cluster surveys and discuss the utility.Added knowledge: This paper adds new knowledge on cluster surveys for highly clustered data such us in Ebola virus disease.Global health impact of policy and action: We provided empirical estimates and discuss design improvements to inform future study.

Differential symptomology of possible and confirmed Ebola virus disease infection in the Democratic Republic of the Congo: a retrospective cohort study.

BACKGROUND: In its earliest phases, Ebola virus disease's rapid-onset, high fever, and gastrointestinal symptoms are largely indistinguishable from other infectious illnesses. We aimed to characterise the clinical indicators associated with Ebola virus disease to improve outbreak response. METHODS: In this retrospective analysis, we assessed routinely collected data from individuals with possible Ebola virus disease attending 30 Ebola health facilities in two provinces of the Democratic Republic of the Congo between Aug 1, 2018, and Aug 28, 2019. We used logistic regression analysis to model the probability of Ebola infection across 34 clinical variables and four types of possible Ebola virus disease exposures: contact with an individual known to have Ebola virus disease, attendance at any funeral, health facility consultation, or consultation with an informal health practitioner. FINDINGS: Data for 24 666 individuals were included. If a patient presented to care in the early symptomatic phase (ie, days 0-2), Ebola virus disease positivity was most associated with previous exposure to an individual with Ebola virus disease (odds ratio [OR] 11·9, 95% CI 9·1-15·8), funeral attendance (2·1, 1·6-2·7), or health facility consultations (2·1, 1·6-2·8), rather than clinical parameters. If presentation occurred on day 3 or later (after symptom onset), bleeding at an injection site (OR 33·9, 95% CI 12·7-101·3), bleeding gums (7·5, 3·7-15·4), conjunctivitis (2·4, 1·7-3·4), asthenia (1·9, 1·5-2·3), sore throat (1·8, 1·3-2·4), dysphagia (1·8, 1·4-2·3), and diarrhoea (1·6, 1·3-1·9) were additional strong predictors of Ebola virus disease. Some Ebola virus disease-specific signs were less prevalent among vaccinated individuals who were positive for Ebola virus disease when compared with the unvaccinated, such as dysphagia (-47%, p=0·0024), haematemesis (-90%, p=0·0131), and bleeding gums (-100%, p=0·0035). INTERPRETATION: Establishing the exact time an individual first had symptoms is essential to assessing their infection risk. An individual's exposure history remains of paramount importance, especially in the early phase. Ebola virus disease vaccination reduces symptom severity and should also be considered when assessing the likelihood of infection. These findings about symptomatology should be translated into practice during triage and should inform testing and quarantine procedures. FUNDING: Médecins Sans Frontières and its research affiliate Epicentre.

Feasibility of satellite image and GIS sampling for population representative surveys: a case study from rural Guatemala.

BACKGROUND: Population-representative household survey methods require up-to-date sampling frames and sample designs that minimize time and cost of fieldwork especially in low- and middle-income countries. Traditional methods such as multi-stage cluster sampling, random-walk, or spatial sampling can be cumbersome, costly or inaccurate, leading to well-known biases. However, a new tool, Epicentre's Geo-Sampler program, allows simple random sampling of structures, which can eliminate some of these biases. We describe the study design process, experiences and lessons learned using Geo-Sampler for selection of a population representative sample for a kidney disease survey in two sites in Guatemala. RESULTS: We successfully used Epicentre's Geo-sampler tool to sample 650 structures in two semi-urban Guatemalan communities. Overall, 82% of sampled structures were residential and could be approached for recruitment. Sample selection could be conducted by one person after 30 min of training. The process from sample selection to creating field maps took approximately 40 h. CONCLUSION: In combination with our design protocols, the Epicentre Geo-Sampler tool provided a feasible, rapid and lower-cost alternative to select a representative population sample for a prevalence survey in our semi-urban Guatemalan setting. The tool may work less well in settings with heavy arboreal cover or densely populated urban settings with multiple living units per structure. Similarly, while the method is an efficient step forward for including non-traditional living arrangements (people residing permanently or temporarily in businesses, religious institutions or other structures), it does not account for some of the most marginalized and vulnerable people in a population-the unhoused, street dwellers or people living in vehicles.

Clinical and epidemiological performance of WHO Ebola case definitions: a systematic review and meta-analysis.

BACKGROUND: Ebola virus disease case definition is a crucial surveillance tool to detect suspected cases for referral and as a screening tool for clinicians to support admission and laboratory testing decisions at Ebola health facilities. We aimed to assess the performance of the WHO Ebola virus disease case definitions and other screening scores. METHODS: In this systematic review and meta-analysis, we searched PubMed, Scopus, Embase, and Web of Science for studies published in English between June 13, 1978, and Jan 14, 2020. We included studies that estimated the sensitivity and specificity of WHO Ebola virus disease case definitions, clinical and epidemiological characteristics (symptoms at admission and contact history), and predictive risk scores against the reference standard (laboratory-confirmed Ebola virus disease). Summary estimates of sensitivity and specificity were calculated using bivariate and hierarchical summary receiver operating characteristic (when four or more studies provided data) or random-effects meta-analysis (fewer than four studies provided data). FINDINGS: We identified 2493 publications, of which 14 studies from four countries (Sierra Leone, Guinea, Liberia, and Angola) were included in the analysis. 12 021 people with suspected disease were included, of whom 4874 were confirmed as positive for Ebola virus infection. Six studies explored the performance of WHO case definitions in non-paediatric populations, and in all of these studies, suspected and probable cases were combined and could not be disaggregated for analysis. The pooled sensitivity of the WHO Ebola virus disease case definitions from these studies was 81·5% (95% CI 74·1-87·2) and pooled specificity was 35·7% (28·5-43·6). History of contact or epidemiological link was a key predictor for the WHO case definitions (seven studies) and for risk scores (six studies). The most sensitive symptom was intense fatigue (79·0% [95% CI 74·4-83·0]), assessed in seven studies, and the least sensitive symptom was pain behind the eyes (1·0% [0·0-7·0]), assessed in three studies. The performance of fever as a symptom varied depending on the cutoff used to define fever. INTERPRETATION: WHO Ebola virus disease case definitions perform suboptimally to identify cases at both community level and during triage at Ebola health facilities. Inclusion of intense fatigue as a key symptom and contact history could improve the performance of case definitions, but implementation of these changes will require effective collaboration with, and trust of, affected communities. FUNDING: Médecins sans Frontières.

Effectiveness of oral cholera vaccine in preventing cholera among fishermen in Lake Chilwa, Malawi: A case-control study.

BACKGROUND: In response to a cholera outbreak among mobile, difficult-to-reach fishermen on Lake Chilwa, Malawi in 2016, a novel vaccine distribution strategy exploited the proven vaccine thermostability. Fishermen, while taking the first vaccine dose under supervision, received the second dose in a sealed bag, and were told to drink it two weeks later. This study assessed short-term vaccine protection of this strategy. METHODS: Patients with diarrhoea admitted to health facilities around lake were interviewed and a stool sample collected for PCR testing. Vaccine effectiveness was assessed in a case-control test-negative design by comparing cases (PCR-positive for V. cholerae O1) and controls (patients with diarrhoea but PCR-negative) and with the screening method that compared the proportions of vaccinated among cholera cases versus the general fishermen population. RESULTS: Of 145 study participants, 120 were fishermen living on the lake. Vaccine effectiveness at three-months was 90.0% [95%CI:38.8;98.4] among fishermen and 83.3% [95%CI: 20.8; 96.5] among all participants in the case-control test-negative design, and 97.5% [95%CI: 90.9;99.3] with the screening method. CONCLUSION: This strategy was effective in providing short-term protection in fishermen against cholera. Further research is needed to determine the adding value of the second dose and to identify the optimal vaccination strategies for different contexts.

Oral cholera vaccination in hard-to-reach communities, Lake Chilwa, Malawi.

OBJECTIVE: To evaluate vaccination coverage, identify reasons for non-vaccination and assess satisfaction with two innovative strategies for distributing second doses in an oral cholera vaccine campaign in 2016 in Lake Chilwa, Malawi, in response to a cholera outbreak. METHODS: We performed a two-stage cluster survey. The population interviewed was divided in three strata according to the second-dose vaccine distribution strategy: (i) a standard strategy in 1477 individuals (68 clusters of 5 households) on the lake shores; (ii) a simplified cold-chain strategy in 1153 individuals (59 clusters of 5 households) on islands in the lake; and (iii) an out-of-cold-chain strategy in 295 fishermen (46 clusters of 5 to 15 fishermen) in floating homes, called zimboweras. FINDING: Vaccination coverage with at least one dose was 79.5% (1153/1451) on the lake shores, 99.3% (1098/1106) on the islands and 84.7% (200/236) on zimboweras. Coverage with two doses was 53.0% (769/1451), 91.1% (1010/1106) and 78.8% (186/236), in the three strata, respectively. The most common reason for non-vaccination was absence from home during the campaign. Most interviewees liked the novel distribution strategies. CONCLUSION: Vaccination coverage on the shores of Lake Chilwa was moderately high and the innovative distribution strategies tailored to people living on the lake provided adequate coverage, even among hard-to-reach communities. Community engagement and simplified delivery procedures were critical for success. Off-label, out-of-cold-chain administration of oral cholera vaccine should be considered as an effective strategy for achieving high coverage in hard-to-reach communities. Nevertheless, coverage and effectiveness must be monitored over the short and long term.

Oral cholera vaccine in cholera prevention and control, Malawi.

PROBLEM: With limited global supplies of oral cholera vaccine, countries need to identify priority areas for vaccination while longer-term solutions, such as water and sanitation infrastructure, are being developed. APPROACH: In 2017, Malawi integrated oral cholera vaccine into its national cholera control plan. The process started with a desk review and analysis of previous surveillance and risk factor data. At a consultative meeting, researchers, national health and water officials and representatives from nongovernmental and international organizations reviewed the data and local epidemiological knowledge to determine priority districts for oral cholera vaccination. The final stage was preparation of an application to the global oral cholera vaccine stockpile for non-emergency use. LOCAL SETTING: Malawi collects annual data on cholera and most districts have reported cases at least once since the 1970s. RELEVANT CHANGES: The government's application for 3.2 million doses of vaccine to be provided over 20 months in 12 districts was accepted in April 2017. By April 2018, over 1 million doses had been administered in five districts. Continuing surveillance in districts showed that cholera outbreaks were notably absent in vaccinated high-risk areas, despite a national outbreak in 2017-2018. LESSONS LEARNT: Augmenting advanced mapping techniques with local information helped us extend priority areas beyond those identified as high-risk based on cholera incidence reported at the district level. Involvement of the water, sanitation and hygiene sectors is key to ensuring that short-term gains from cholera vaccine are backed by longer-term progress in reducing cholera transmission.

Near real-time forecasting for cholera decision making in Haiti after Hurricane Matthew.

Computational models of cholera transmission can provide objective insights into the course of an ongoing epidemic and aid decision making on allocation of health care resources. However, models are typically designed, calibrated and interpreted post-hoc. Here, we report the efforts of a team from academia, field research and humanitarian organizations to model in near real-time the Haitian cholera outbreak after Hurricane Matthew in October 2016, to assess risk and to quantitatively estimate the efficacy of a then ongoing vaccination campaign. A rainfall-driven, spatially-explicit meta-community model of cholera transmission was coupled to a data assimilation scheme for computing short-term projections of the epidemic in near real-time. The model was used to forecast cholera incidence for the months after the passage of the hurricane (October-December 2016) and to predict the impact of a planned oral cholera vaccination campaign. Our first projection, from October 29 to December 31, predicted the highest incidence in the departments of Grande Anse and Sud, accounting for about 45% of the total cases in Haiti. The projection included a second peak in cholera incidence in early December largely driven by heavy rainfall forecasts, confirming the urgency for rapid intervention. A second projection (from November 12 to December 31) used updated rainfall forecasts to estimate that 835 cases would be averted by vaccinations in Grande Anse (90% Prediction Interval [PI] 476-1284) and 995 in Sud (90% PI 508-2043). The experience gained by this modeling effort shows that state-of-the-art computational modeling and data-assimilation methods can produce informative near real-time projections of cholera incidence. Collaboration among modelers and field epidemiologists is indispensable to gain fast access to field data and to translate model results into operational recommendations for emergency management during an outbreak. Future efforts should thus draw together multi-disciplinary teams to ensure model outputs are appropriately based, interpreted and communicated.

Efficacy of artesunate-amodiaquine, dihydroartemisinin-piperaquine and artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Maradi, Niger.

BACKGROUND: Malaria endemic countries need to assess efficacy of anti-malarial treatments on a regular basis. Moreover, resistance to artemisinin that is established across mainland South-East Asia represents today a major threat to global health. Monitoring the efficacy of artemisinin-based combination therapies is of paramount importance to detect as early as possible the emergence of resistance in African countries that toll the highest burden of malaria morbidity and mortality. METHODS: A WHO standard protocol was used to assess efficacy of the combinations artesunate-amodiaquine (AS-AQ Winthrop®), dihydroartemisinin-piperaquine (DHA-PPQ, Eurartesim®) and artemether-lumefantrine (AM-LM, Coartem®) taken under supervision and respecting pharmaceutical recommendations. The study enrolled for each treatment arm 212 children aged 6-59 months living in Maradi (Niger) and suffering with uncomplicated falciparum malaria. The Kaplan-Meier 42-day PCR-adjusted cure rate was the primary outcome. A standardized parasite clearance estimator was used to assess delayed parasite clearance as surrogate maker of suspected artemisinin resistance. RESULTS: No early treatment failures were found in any of the study treatment arms. The day-42 PCR-adjusted cure rate estimates were 99.5, 98.4 and 99.0% in the AS-AQ, DHA-PPQ and AM-LM arms, respectively. The reinfection rate (expressed also as Kaplan-Meier estimates) was higher in the AM-LM arm (32.4%) than in the AS-AQ (13.8%) and the DHA-PPQ arm (24.9%). The parasite clearance rate constant was 0.27, 0.26 and 0.25 per hour for AS-AQ, DHA-PPQ and AM-LM, respectively. CONCLUSIONS: All the three treatments evaluated largely meet WHO criteria (at least 95% efficacy). AS-AQ and AL-LM may continue to be used and DHA-PPQ may be also recommended as first-line treatment for uncomplicated falciparum malaria in Maradi. The parasite clearance rate were consistent with reference values indicating no suspected artemisinin resistance. Nevertheless, the monitoring of anti-malarial drug efficacy should continue. Trial registration details Registry number at ClinicalTrial.gov: NCT01755559.

Oral cholera vaccination in hard-to-reach communities, Lake Chilwa, Malawi

Objective To evaluate vaccination coverage, identify reasons for non-vaccination and assess satisfaction with two innovative strategies for distributing second doses in an oral cholera vaccine campaign in 2016 in Lake Chilwa, Malawi, in response to a cholera outbreak. Methods We performed a two-stage cluster survey. The population interviewed was divided in three strata according to the second-dose vaccine distribution strategy: (i) a standard strategy in 1477 individuals (68 clusters of 5 households) on the lake shores; (ii) a simplifiedcold-chain strategy in 1153 individuals (59 clusters of 5 households) on islands in the lake; and (iii) an out-of-cold-chain strategy in 295 fishermen (46 clusters of 5 to 15 fishermen) in floating homes, called zimboweras. Finding Vaccination coverage with at least one dose was 79.5% (1153/1451) on the lake shores, 99.3% (1098/1106) on the islands and 84.7% (200/236) on zimboweras. Coverage with two doses was 53.0% (769/1451), 91.1% (1010/1106) and 78.8% (186/236), in the three strata, respectively. The most common reason for non-vaccination was absence from home during the campaign. Most interviewees liked the novel distribution strategies. Conclusion Vaccination coverage on the shores of Lake Chilwa was moderately high and the innovative distribution strategies tailored to people living on the lake provided adequate coverage, even among hard-to-reach communities. Community engagement and simplified delivery procedures were critical for success. Off-label, out-of-cold-chain administration of oral cholera vaccine should be considered as an effective strategy for achieving high coverage in hard-to-reach communities. Nevertheless, coverage and effectiveness must be monitored over the short and long term

Cholera Rapid Test with Enrichment Step Has Diagnostic Performance Equivalent to Culture.

Cholera rapid diagnostic tests (RDT) could play a central role in outbreak detection and surveillance in low-resource settings, but their modest performance has hindered their broad adoption. The addition of an enrichment step may improve test specificity. We describe the results of a prospective diagnostic evaluation of the Crystal VC RDT (Span Diagnostics, India) with enrichment step and of culture, each compared to polymerase chain reaction (PCR), during a cholera outbreak in South Sudan. RDTs were performed on alkaline peptone water inoculated with stool and incubated for 4-6 hours at ambient temperature. Cholera culture was performed from wet filter paper inoculated with stool. Molecular detection of Vibrio cholerae O1 by PCR was done from dry Whatman 903 filter papers inoculated with stool, and from wet filter paper supernatant. In August and September 2015, 101 consecutive suspected cholera cases were enrolled, of which 36 were confirmed by PCR. The enriched RDT had 86.1% (95% CI: 70.5-95.3) sensitivity and 100% (95% CI: 94.4-100) specificity compared to PCR as the reference standard. The sensitivity of culture versus PCR was 83.3% (95% CI: 67.2-93.6) for culture performed on site and 72.2% (95% CI: 54.8-85.8) at the international reference laboratory, where samples were tested after an average delay of two months after sample collection, and specificity was 98.5% (95% CI: 91.7-100) and 100% (95% CI: 94.5-100), respectively. The RDT with enrichment showed performance comparable to that of culture and could be a sustainable alternative to culture confirmation where laboratory capacity is limited.

Effectiveness of one dose of oral cholera vaccine in response to an outbreak: a case-cohort study.

BACKGROUND: Oral cholera vaccines represent a new effective tool to fight cholera and are licensed as two-dose regimens with 2-4 weeks between doses. Evidence from previous studies suggests that a single dose of oral cholera vaccine might provide substantial direct protection against cholera. During a cholera outbreak in May, 2015, in Juba, South Sudan, the Ministry of Health, Médecins Sans Frontières, and partners engaged in the first field deployment of a single dose of oral cholera vaccine to enhance the outbreak response. We did a vaccine effectiveness study in conjunction with this large public health intervention. METHODS: We did a case-cohort study, combining information on the vaccination status and disease outcomes from a random cohort recruited from throughout the city of Juba with that from all the cases detected. Eligible cases were those aged 1 year or older on the first day of the vaccination campaign who sought care for diarrhoea at all three cholera treatment centres and seven rehydration posts throughout Juba. Confirmed cases were suspected cases who tested positive to PCR for Vibrio cholerae O1. We estimated the short-term protection (direct and indirect) conferred by one dose of cholera vaccine (Shanchol, Shantha Biotechnics, Hyderabad, India). FINDINGS: Between Aug 9, 2015, and Sept 29, 2015, we enrolled 87 individuals with suspected cholera, and an 898-person cohort from throughout Juba. Of the 87 individuals with suspected cholera, 34 were classified as cholera positive, 52 as cholera negative, and one had indeterminate results. Of the 858 cohort members who completed a follow-up visit, none developed clinical cholera during follow-up. The unadjusted single-dose vaccine effectiveness was 80·2% (95% CI 61·5-100·0) and after adjusting for potential confounders was 87·3% (70·2-100·0). INTERPRETATION: One dose of Shanchol was effective in preventing medically attended cholera in this study. These results support the use of a single-dose strategy in outbreaks in similar epidemiological settings. FUNDING: Médecins Sans Frontières.

Efficacy of artemether-lumefantrine in relation to drug exposure in children with and without severe acute malnutrition: an open comparative intervention study in Mali and Niger.

BACKGROUND: Severe acute malnutrition (SAM) affects almost all organs and has been associated with reduced intestinal absorption of medicines. However, very limited information is available on the pharmacokinetic properties of antimalarial drugs in this vulnerable population. We assessed artemether-lumefantrine (AL) clinical efficacy in children with SAM compared to those without. METHODS: Children under 5 years of age with uncomplicated P. falciparum malaria were enrolled between November 2013 and January 2015 in Mali and Niger, one third with uncomplicated SAM and two thirds without. AL was administered under direct observation with a fat intake consisting of ready-to-use therapeutic food (RUTF - Plumpy'Nut®) in SAM children, twice daily during 3 days. Children were followed for 42 days, with PCR-corrected adequate clinical and parasitological response (ACPR) at day 28 as the primary outcome. Lumefantrine concentrations were assessed in a subset of participants at different time points, including systematic measurements on day 7. RESULTS: A total of 399 children (360 in Mali and 39 in Niger) were enrolled. Children with SAM were younger than their non-SAM counterparts (mean 17 vs. 28 months, P < 0.0001). PCR-corrected ACPR was 100 % (95 % CI, 96.8-100 %) in SAM at both day 28 and 42, versus 98.8 % (96.4-99.7 %) at day 28 and 98.3 % (95.6-99.4 %) at day 42 in non-SAM (P = 0.236 and 0.168, respectively). Compared to younger children, children older than 21 months experienced more reinfections and SAM was associated with a greater risk of reinfection until day 28 (adjusted hazard ratio = 2.10 (1.04-4.22), P = 0.038). Day 7 lumefantrine concentrations were significantly lower in SAM than non-SAM (median 251 vs. 365 ng/mL, P = 0.049). CONCLUSIONS: This study shows comparable therapeutic efficacy of AL in children without SAM and in those with SAM when given in combination with RUTF, but a higher risk of reinfection in older children suffering from SAM. This could be associated with poorer exposure to the antimalarials as documented by a lower lumefantrine concentration on day 7. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01958905 , registration date: October 7, 2013.

Performance and time to become negative after treatment of three malaria rapid diagnostic tests in low and high malaria transmission settings.

BACKGROUND: The performance of different malaria rapid diagnostic tests (RDT) may be influenced by transmission intensity and by the length of time each test requires to become negative after treatment and patient's recovery. METHODS: Results of three RDTs (two HRP2 and one pLDH antigen-based tests) were compared to blood smear microscopy (the gold standard method) in children under 5 years of age living in a high versus low malaria intensity setting in southwestern Uganda. In each setting, 212 children, who tested positive by at least one RDT and by microscopy, were treated with artemether-lumefantrine. RDTs and microscopy were then repeated at fixed intervals to estimate each test's time to negativity after treatment and patient recovery. RESULTS: In the two settings, sensitivities ranged from 98.4 to 99.2 % for the HRP2 tests and 94.7 to 96.1 % for the pLDH test. Specificities were 98.9 and 98.8 % for the HRP2 tests and 99.7 % for the pLDH test in the low-transmission setting and 79.7, 80.7 and 93.9 %, respectively, in the high-transmission setting. Median time to become negative was 35-42 or more days for the HRP2 tests and 2 days for the pLDH test. CONCLUSIONS: High transmission contexts and a long time to become negative resulted in considerably reduced specificities for the HRP2 tests. Choice of RDT for low- versus high-transmission settings should balance risks and benefits of over-treatment versus missing malaria cases. TRIAL REGISTRATION: Registry number at ClinicalTrial.gov: NCT01325974.

High-resolution spatial analysis of cholera patients reported in Artibonite department, Haiti in 2010-2011.

BACKGROUND: Cholera is caused by Vibrio cholerae, and is transmitted through fecal-oral contact. Infection occurs after the ingestion of the bacteria and is usually asymptomatic. In a minority of cases, it causes acute diarrhea and vomiting, which can lead to potentially fatal severe dehydration, especially in the absence of appropriate medical care. Immunity occurs after infection and typically lasts 6-36 months. Cholera is responsible for outbreaks in many African and Asian developing countries, and caused localised and episodic epidemics in South America until the early 1990s. Haiti, despite its low socioeconomic status and poor sanitation, had never reported cholera before the recent outbreak that started in October 2010, with over 720,000 cases and over 8700 deaths (Case fatality rate: 1.2%) through 8 december 2014. So far, this outbreak has seen 3 epidemic peaks, and it is expected that cholera will remain in Haiti for some time. METHODOLOGY/FINDINGS: To trace the path of the early epidemic and to identify hot spots and potential transmission hubs during peaks, we examined the spatial distribution of cholera patients during the first two peaks in Artibonite, the second-most populous department of Haiti. We extracted the geographic origin of 84,000 patients treated in local health facilities between October 2010 and December 2011 and mapped these addresses to 63 rural communal sections and 9 urban cities. Spatial and cluster analysis showed that during the first peak, cholera spread along the Artibonite River and the main roads, and sub-communal attack rates ranged from 0.1% to 10.7%. During the second peak, remote mountain areas were most affected, although sometimes to very different degrees even in closely neighboring locations. Sub-communal attack rates during the second peak ranged from 0.2% to 13.7%. The relative risks at the sub-communal level during the second phase showed an inverse pattern compared to the first phase. CONCLUSION/SIGNIFICANCE: These findings demonstrate the value of high-resolution mapping for pinpointing locations most affected by cholera, and in the future could help prioritize the places in need of interventions such as improvement of sanitation and vaccination. The findings also describe spatio-temporal transmission patterns of the epidemic in a cholera-naïve country such as Haiti. By identifying transmission hubs, it is possible to target prevention strategies that, over time, could reduce transmission of the disease and eventually eliminate cholera in Haiti.

Mortality Rates during Cholera Epidemic, Haiti, 2010-2011.

The 2010 cholera epidemic in Haiti was one of the largest cholera epidemics ever recorded. To estimate the magnitude of the death toll during the first wave of the epidemic, we retrospectively conducted surveys at 4 sites in the northern part of Haiti. Overall, 70,903 participants were included; at all sites, the crude mortality rates (19.1-35.4 deaths/1,000 person-years) were higher than the expected baseline mortality rate for Haiti (9 deaths/1,000 person-years). This finding represents an excess of 3,406 deaths (2.9-fold increase) for the 4.4% of the Haiti population covered by these surveys, suggesting a substantially higher cholera mortality rate than previously reported.

A multi-center, open-label trial to compare the efficacy and pharmacokinetics of Artemether-Lumefantrine in children with severe acute malnutrition versus children without severe acute malnutrition: study protocol for the MAL-NUT study.

BACKGROUND: Malnutrition and malaria frequently coexist in sub-Saharan African countries. Studies on efficacy of antimalarial treatments usually follow the WHO standardized protocol in which severely malnourished children are systematically excluded. Few studies have assessed the efficacy of chloroquine, sulfadoxine-pyrimethamine and quinine in severe acute malnourished children. Overall, efficacy of these treatments appeared to be reduced, attributed to lower immunity and for some antimalarials altered pharmacokinetic profiles and lower drug concentrations. However, similar research on the efficacy and pharmacokinetic profiles of artemisinin-combination therapies (ACTs) and especially artemether-lumefantrine in malnourished children is currently lacking. The main objective of this study is to assess whether artemether-lumefantrine is less efficacious in children suffering from severe acute malnutrition (SAM) compared to non-SAM children, and if so, to what extent this can be attributed to a sub-optimal pharmacokinetic profile. METHODS/DESIGN: In two sites, Ouelessebougou, Mali and Maradi, Niger, children with uncomplicated microscopically-confirmed P. falciparum malaria aged between 6 and 59 months will be enrolled. Two non-SAM children will be enrolled after the enrolment of each SAM case. Children with severe manifestations of malaria or complications of acute malnutrition needing intensive treatment will be excluded. Treatment intakes will be supervised and children will be followed-up for 42 days, according to WHO guidance for surveillance of antimalarial drug efficacy. Polymerase Chain Reaction genotyping will be used to distinguish recrudescence from re-infection. SAM children will also benefit from the national nutritional rehabilitation program. Outcomes will be compared between the SAM and non-SAM populations. The primary outcome will be adequate clinical and parasitological response at day 28 after PCR correction, estimated by Kaplan-Meier analysis. To assess the pharmacokinetic profile of lumefantrine, a sparse sampling approach will be used with randomized allocation of sampling times (5 per child). A total of 180 SAM children and 360 non-SAM children will be recruited during the 2013 and 2014 malaria seasons. DISCUSSION: This study will provide important information that is currently lacking on the effect of SAM on therapeutic efficacy and pharmacokinetic profile of artemether-lumefantrine. If it shows lower therapeutic efficacy and decreased lumefantrine concentrations, it would inform dose optimization studies in SAM children. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01958905.

The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data.

BACKGROUND: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria. METHODS: Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites. RESULTS: Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites. CONCLUSIONS: There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.