Association between recent overnight travel and use of long-lasting insecticidal nets in rural Uganda: a prospective cohort study in Tororo.

BACKGROUND: The burden of malaria in Uganda remains high, but has become increasingly heterogenous following intensified malaria control. Travel within Uganda is recognized as a risk factor for malaria, but behaviours associated with travel are not well-understood. To address this knowledge gap, malaria-relevant behaviours of cohort participants were assessed during travel and at home in Uganda. METHODS: Residents from 80 randomly selected households in Nagongera sub-county, Tororo district were enrolled into a cohort to study malaria in rural Uganda. All participants were given long-lasting insecticidal nets (LLINs) at enrolment and were evaluated every 4 weeks at the study clinic. Participants were asked if they had travelled overnight from their home, and if so, a questionnaire was administered to capture information on travel details and behaviours. Behaviour while travelling was assessed within 4 weeks following travel during the study clinic visit. Behaviour while at home was assessed using a similar questionnaire during two-weekly home visits. Behaviours while travelling vs at home were compared using log binomial regression models with generalized estimating equations adjusting for repeated measures in the same individual. Analysis of factors associated with LLIN adherence, such as destination and duration of travel, time to bed during travel, gender and age at time of travel, were assessed using log binomial regression models with generalized estimating equations adjusting for repeated measures in the same individual. RESULTS: Between October 2017 and October 2019, 527 participants were enrolled and assessed for travel. Of these, 123 (23.2%) reported taking 211 overnight trips; 149 (70.6%) trips were within Tororo. Participants were less likely to use LLINs when travelling than when at home (41.0% vs. 56.2%, relative risk [RR] 0.73, 95% CI 0.60-0.89, p = 0.002); this difference was noted for women (38.8% vs 59.2%, RR 0.66, 95% CI 0.52-0.83, p = 0.001) but not men (48.3% vs 46.6%, RR 0.96, 95% CI 0.67-1.40, p = 0.85). In an adjusted analysis, factors associated with LLIN use when travelling included destination (travelling to districts not receiving indoor residual spraying [IRS] 65.8% vs Tororo district 32.2%, RR 1.80, 95% CI 1.31-2.46, p  7 nights 60.3% vs one night 24.4%, RR 1.97, 95% CI 1.07-3.64, p = 0.03). CONCLUSIONS: Travellers, particularly women, were less likely to use LLINs when travelling than when at home. LLIN adherence was higher among those who travelled to non-IRS districts and for more than 1 week, suggesting that perceived malaria risk influences LLIN use. Strategies are needed to raise awareness of the importance of using LLINs while travelling

Protective effi cacy of prolonged co-trimoxazole prophylaxis in HIV-exposed children up to age 4 years for the prevention of malaria in Uganda: a randomised controlled open-label trial

Background WHO recommends daily co-trimoxazole for children born to HIV-infected mothers from 6 weeks of age until breastfeeding cessation and exclusion of HIV infection. We have previously reported on the eff ectiveness of continuation of co-trimoxazole prophylaxis up to age 2 years in these children. We assessed the protective effi cacy and safety of prolonging co-trimoxazole prophylaxis until age 4 years in HIV-exposed children. Methods We undertook an open-label randomised controlled trial alongside two observational cohorts in eastern Uganda, an area with high HIV prevalence, malaria transmission intensity, and antifolate resistance. We enrolled HIVexposed infants between 6 weeks and 9 months of age and prescribed them daily co-trimoxazole until breastfeeding cessation and HIV-status confi rmation. At the end of breastfeeding, children who remained HIV-uninfected were randomly assigned (1:1) to discontinue co-trimoxazole or to continue taking it up to age 2 years. At age 2 years, children who continued co-trimoxazole prophylaxis were randomly assigned (1:1) to discontinue or continue prophylaxis from age 2 years to age 4 years. The primary outcome was incidence of malaria (defi ned as the number of treatments for new episodes of malaria diagnosed with positive thick smear) at age 4 years. For additional comparisons, we observed 48 HIV-infected children who took continuous co-trimoxazole prophylaxis and 100 HIV-unexposed uninfected children who never received prophylaxis. We measured grade 3 and 4 serious adverse events and hospital admissions. All children were followed up to age 5 years and all analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00527800. Findings 203 HIV-exposed infants were enrolled between Aug 10, 2007, and March 28, 2008. After breastfeeding ended, 185 children were not infected with HIV and were randomly assigned to stop (n=87) or continue (n=98) co-trimoxazole up to age 2 years. At age 2 years, 91 HIV-exposed children who had remained on co-trimoxazole prophylaxis were randomly assigned to discontinue (n=46) or continue (n=45) co-trimoxazole from age 2 years to age 4 years. We recorded 243 malaria episodes (2·91 per person-years) in the 45 HIV-exposed children assigned to continue cotrimoxazole until age 4 years compared with 503 episodes (5·60 per person-years) in the 46 children assigned to stop co-trimoxazole at age 2 years (incidence rate ratio 0·53, 95% CI 0·39–0·71; p<0·0001). There was no evidence of malaria incidence rebound in the year after discontinuation of co-trimoxazole in the HIV-exposed children who stopped co-trimoxazole at age 2 years, but incidence increased signifi cantly in HIV-exposed children who stopped co-trimoxazole at age 4 years (odds ratio 1·78, 95% CI 1·19–2·66; p=0·005). Incidence of grade 3 or 4 serious adverse events, hospital admissions, or deaths did not signifi cantly diff er between HIV-exposed, HIV-unexposed, and HIV-infected children. Interpretation Continuation of co-trimoxazole prophylaxis up to 4 years of age seems safe and effi cacious to protect HIV-exposed children living in malaria-endemic areas

Safety and tolerability of artemether-lumefantrine versus dihydroartemisinin-piperaquine for malaria in young HIV-infected and uninfected children

BACKGROUND: Artemisinin combination therapy has become the standard of care for uncomplicated malaria in most of Africa. However, there is limited data on the safety and tolerability of these drugs, especially in young children and patients co-infected with HIV. METHODS: A longitudinal, randomized controlled trial was conducted in a cohort of HIV-infected and uninfected children aged 4-22 months in Tororo, Uganda. Participants were randomized to treatment with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) upon diagnosis of their first episode of uncomplicated malaria and received the same regimen for all subsequent episodes. Participants were actively monitored for adverse events for 28 days and then passively for up to 63 days after treatment. This study was registered in ClinicalTrials.gov (registration # NCT00527800). RESULTS: A total of 122 children were randomized to AL and 124 to DP, resulting in 412 and 425 treatments, respectively. Most adverse events were rare, with only cough, diarrhoea, vomiting, and anaemia occurring in more than 1% of treatments. There were no differences in the risk of these events between treatment groups. Younger age was associated with an increased risk of diarrhoea in both the AL and DP treatment arms. Retreatment for malaria within 17-28 days was associated with an increased risk of vomiting in the DP treatment arm (HR = 6.47, 95% CI 2.31-18.1, p < 0.001). There was no increase in the risk of diarrhoea or vomiting for children who were HIV-infected or on concomitant therapy with antiretrovirals or trimethoprim-sulphamethoxazole prophylaxis. CONCLUSION: Both AL and DP were safe and well tolerated for the treatment of uncomplicated malaria in young HIV-infected and uninfected children. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00527800; http://clinicaltrials.gov/ct2/show/NCT00527800

Estimating malaria incidence from routine health facility-based surveillance data in Uganda.

BACKGROUND: Accurate measures of malaria incidence are essential to track progress and target high-risk populations. While health management information system (HMIS) data provide counts of malaria cases, quantifying the denominator for incidence using these data is challenging because catchment areas and care-seeking behaviours are not well defined. This study's aim was to estimate malaria incidence using HMIS data by adjusting the population denominator accounting for travel time to the health facility. METHODS: Outpatient data from two public health facilities in Uganda (Kihihi and Nagongera) over a 3-year period (2011-2014) were used to model the relationship between travel time from patient village of residence (available for each individual) to the facility and the relative probability of attendance using Poisson generalized additive models. Outputs from the model were used to generate a weighted population denominator for each health facility and estimate malaria incidence. Among children aged 6 months to 11 years, monthly HMIS-derived incidence estimates, with and without population denominators weighted by probability of attendance, were compared with gold standard measures of malaria incidence measured in prospective cohorts. RESULTS: A total of 48,898 outpatient visits were recorded across the two sites over the study period. HMIS incidence correlated with cohort incidence over time at both study sites (correlation in Kihihi = 0.64, p < 0.001; correlation in Nagongera = 0.34, p = 0.045). HMIS incidence measures with denominators unweighted by probability of attendance underestimated cohort incidence aggregated over the 3 years in Kihihi (0.5 cases per person-year (PPY) vs 1.7 cases PPY) and Nagongera (0.3 cases PPY vs 3.0 cases PPY). HMIS incidence measures with denominators weighted by probability of attendance were closer to cohort incidence, but remained underestimates (1.1 cases PPY in Kihihi and 1.4 cases PPY in Nagongera). CONCLUSIONS: Although malaria incidence measured using HMIS underestimated incidence measured in cohorts, even when adjusting for probability of attendance, HMIS surveillance data are a promising and scalable source for tracking relative changes in malaria incidence over time, particularly when the population denominator can be estimated by incorporating information on village of residence

Malaria Diagnosed in an Urban Setting Strongly Associated with Recent Overnight Travel: A Case-Control Study from Kampala, Uganda.

Malaria is frequently diagnosed in urban Kampala, despite low transmission intensity. To evaluate the association between recent travel out of Kampala and malaria, we conducted a matched case-control study. Cases were febrile outpatients with a positive malaria test; controls were febrile outpatients with a negative test. For every two cases, five controls were selected, matching on age. Data were collected on recent overnight travel out of Kampala (past 60 days), destination and duration of travel, and behavioral factors, including sleeping under an insecticide-treated net (ITN) during travel. From July to August 2019, 162 cases and 405 controls were enrolled. The locations of residence of cases and controls were similar. More controls were female (62.7% versus 46.3%, P < 0.001). Overall, 158 (27.9%) participants reported recent overnight travel. Travelers were far more likely to be diagnosed with malaria than those who did not travel (80.4% versus 8.6%, OR 58.9, 95% CI: 23.1-150.1, P < 0.001). Among travelers, traveling to a district not receiving indoor residual spraying of insecticide (OR 35.0, 95% CI: 4.80-254.9, P < 0.001), no ITN use (OR 30.1, 95% CI: 6.37-142.7, P < 0.001), engaging in outdoor activities (OR 22.0, 95% CI: 3.42-141.8, P = 0.001), and age < 16 years (OR 8.36, 95% CI: 2.22-56.2, P = 0.03) were associated with increased odds of malaria. Kampala residents who traveled overnight out of the city were at substantially higher risk of malaria than those who did not travel. For these travelers, personal protection measures, including sleeping under an ITN when traveling, should be advocated

Protective efficacy of co-trimoxazole prophylaxis against malaria in HIV exposed children in rural Uganda: a randomised clinical trial

Objective To evaluate the protective efficacy of co-trimoxazole prophylaxis against malaria in HIV exposed children (uninfected children born to HIV infected mothers) in Africa

East Africa International Center of Excellence for Malaria Research: Summary of Key Research Findings

The Program for Resistance, Immunology, Surveillance, and Modeling of Malaria (PRISM) has been conducting malaria research in Uganda since 2010 to improve the understanding of the disease and measure the impact of population-level control interventions in the country. Here, we will summarize key research findings from a series of studies addressing routine health facility-based surveillance, comprehensive cohort studies, studies of the molecular epidemiology, and transmission of malaria, evaluation of antimalarial drug efficacy, and resistance across the country, and assessments of insecticide resistance. Among our key findings are the following. First, we found that in historically high transmission areas of Uganda, a combination of universal distribution of long-lasting insecticidal-treated nets (LLINs) and sustained indoor residual spraying (IRS) of insecticides lowered the malaria burden greatly, but marked resurgences occurred if IRS was discontinued. Second, submicroscopic infections are common and key drivers of malaria transmission, especially in school-age children (5–15 years). Third, markers of drug resistance have changed over time, with new concerning emergence of markers predicting resistance to artemisinin antimalarials. Fourth, insecticide resistance monitoring has demonstrated high levels of resistance to pyrethroids, appreciable impact of the synergist piperonyl butoxide to pyrethroid susceptibility, emerging resistance to carbamates, and complete susceptibility of malaria vectors to organophosphates, which could have important implications for vector control interventions. Overall, PRISM has yielded a wealth of information informing researchers and policy-makers on the malaria burden and opportunities for improved malaria control and eventual elimination in Uganda. Continued studies concerning all the types of surveillance discussed above are ongoing

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Mapping malaria incidence using routine health facility surveillance data in Uganda

Introduction Maps of malaria risk are important tools for allocating resources and tracking progress. Most maps rely on cross-sectional surveys of parasite prevalence, but health facilities represent an underused and powerful data source. We aimed to model and map malaria incidence using health facility data in Uganda.Methods Using 24 months (2019–2020) of individual-level outpatient data collected from 74 surveillance health facilities located in 41 districts across Uganda (n=445 648 laboratory-confirmed cases), we estimated monthly malaria incidence for parishes within facility catchment areas (n=310) by estimating care-seeking population denominators. We fit spatio-temporal models to the incidence estimates to predict incidence rates for the rest of Uganda, informed by environmental, sociodemographic and intervention variables. We mapped estimated malaria incidence and its uncertainty at the parish level and compared estimates to other metrics of malaria. To quantify the impact that indoor residual spraying (IRS) may have had, we modelled counterfactual scenarios of malaria incidence in the absence of IRS.Results Over 4567 parish-months, malaria incidence averaged 705 cases per 1000 person-years. Maps indicated high burden in the north and northeast of Uganda, with lower incidence in the districts receiving IRS. District-level estimates of cases correlated with cases reported by the Ministry of Health (Spearman’s r=0.68, p&lt;0.0001), but were considerably higher (40 166 418 cases estimated compared with 27 707 794 cases reported), indicating the potential for underreporting by the routine surveillance system. Modelling of counterfactual scenarios suggest that approximately 6.2 million cases were averted due to IRS across the study period in the 14 districts receiving IRS (estimated population 8 381 223).Conclusion Outpatient information routinely collected by health systems can be a valuable source of data for mapping malaria burden. National Malaria Control Programmes may consider investing in robust surveillance systems within public health facilities as a low-cost, high benefit tool to identify vulnerable regions and track the impact of interventions