LLIN Evaluation in Uganda Project (LLINEUP): factors associated with childhood parasitaemia and anaemia 3 years after a national long-lasting insecticidal net distribution campaign: a cross-sectional survey

Over the past 20 years, substantial progress on malaria has been achieved worldwide, following heavy investment in control measures [1]. In Africa, much of the decline in malaria morbidity has been attributed to the widespread use of long-lasting insecticidal nets (LLINs) [2]. However, recent data suggest that progress on malaria control may have plateaued, particularly in Africa [1]. In 2017, the World Health Organization (WHO) reported that malaria cases were rising in ten high burden African countries, including Uganda [1]. The estimated number of malaria cases in Uganda increased from 7 million in 2014 to 8.6 million in 2017 [1], raising questions about the coverage and effectiveness of malaria control measures, including LLINs [3, 4].

Measuring the burden of malaria and evaluating the impact of control interventions remains a major challenge [5]. Although the WHO calls for strengthening malaria surveillance within national health management and information systems (HMIS) as a pillar of the Global Technical Strategy for Malaria (2016–2030) [6], the potential limitations of HMIS data collected at health centres are well-recognized [7, 8]. Instead, large cross-sectional surveys are often used to measure key malaria indicators, including the prevalence of parasitaemia and anaemia, on a national scale [9]. However, such surveys are expensive and are done infrequently in some low-resource countries, such as Uganda [10‐12]. In 2009, the Uganda Ministry of Health (MOH) conducted its first national Malaria Indicator Survey [10]. At that time, household ownership of at least one LLIN was less than 50%, and the prevalence of parasitaemia and severe anaemia (defined as haemoglobin < 8 g/dL) in children under-five were 42% and 10%, respectively [10]. As a part of Uganda’s strategic effort to control malaria, the first national LLIN campaign was carried out in 2013–2014, distributing 22.2 million LLINs free-of-charge [3, 11]. The next Malaria Indicator Survey conducted in 2014–2015 approximately 6 months after the LLIN campaign, found that overall, household ownership of at least one LLIN had increased to 94%, while prevalence of parasitaemia among children under-five had decreased to 19% [11].

Despite attempts to intensify malaria control, malaria remains a major problem in much of Uganda [13, 14], and data on the longer-term impact of LLINs nation-wide are lacking. To assess whether the effect of LLINs distributed in the 2013–2014 campaign on malaria indicators has been sustained, a cross-sectional community survey was conducted in 2017 in 48 districts in Eastern and Western Uganda. This is the first large-scale survey in Uganda since the 2014–2015 Malaria Indicator Survey and will serve as the baseline for an ongoing cluster-randomized trial to evaluate the impact of LLINs with, and without, piperonyl butoxide (PBO) distributed in Uganda’s 2017–2018 LLIN campaign on parasite prevalence in community children aged 2–10 years (ISRCTN 17516395) [15‐17].

Over the past 10 years, Uganda’s Ministry of Health has intensified malaria control efforts, scaling-up proven interventions including LLINs, which are a key component of Uganda’s malaria control strategy. These efforts successfully reduced Uganda’s malaria burden between 2009 and 2015 [10, 11]. However, in 2017 reports suggested that the number of malaria cases in Uganda was rising [23]. The cross-sectional community survey reported here, which covered 48 districts of Uganda (approximately 40% of the country), provided an opportunity to assess the prevalence of parasitaemia and anaemia in 2017. The results of this survey suggest that approximately 3 years after LLINs were distributed nationwide in Uganda, adequate coverage of LLINs had fallen to unacceptable levels, while parasite prevalence in children aged 2–4 years appeared to be rising. Parasite prevalence varied widely across the country, and was highest in the East-Central region, where over half of children were parasitaemic. The risk of parasitaemia was highest in older children and those living in poorer households, houses constructed of traditional materials, or without adequate LLIN coverage, while the risk of anaemia was highest in younger children, those with malaria parasitaemia, and those living in a traditional house. Although changes in parasite prevalence may be due to multiple factors, these findings highlight the important issue of net attrition and the substantial heterogeneity of the malaria burden across Uganda. The WHO recommends that mass LLIN campaigns be repeated every 3 years [24]. However, these results contribute to a growing body of evidence that calls the 3-year lifespan of LLINs into question [25‐29]. LLINs may need to be distributed more frequently in Uganda [16], and continuous distribution channels may need to be explored to sustain LLIN coverage in between mass campaigns [30]. Strategies to target malaria control interventions to specific areas of the country, and to high-risk populations, should also be considered. ‘One size’ may not ‘fit all’ for malaria control in Uganda, and other high-burden countries [31].

Parasite prevalence is commonly used as a measure of malaria burden and transmission intensity in endemic areas [2, 32]. The last Uganda Malaria Indicator Survey, conducted in 2014–2015 soon after the LLIN distribution campaign in 2013–2014, reported a substantial decrease in parasite prevalence nationwide, suggesting encouraging progress in malaria control. In contrast, the 2017 survey results, which suggest that parasitaemia had increased, raise concerns about the sustainability of malaria control gains. These recent trends in parasite prevalence could be attributable to net attrition, poor LLIN coverage and use, and the spread of pyrethroid resistance [16, 17]. However, trends over time in parasite prevalence estimated from large cross-sectional surveys, such as the Malaria Indicator Survey, should be interpreted with caution [33]. Malaria Indicator Surveys are conducted infrequently (approximately every 5 years) [10, 11], and provide only a snap-shot of parasite prevalence at a single timepoint. Estimates of parasite prevalence measured in such surveys are affected by survey timing and seasonal variation in transmission intensity [34, 35]. Moreover, parasite prevalence has a complex relationship with age and host immunity [36, 37], patterns of anti-malarial drug use, and estimates are influenced by the diagnostic tests used [38]. Interpreting trends in parasite prevalence is further challenged by the heterogeneous nature of malaria transmission and fluctuations in climate patterns [39‐41]. Thus, national estimates of parasite prevalence, measured infrequently in Malaria Indicator or similar surveys, are not ideal for capturing the full spectrum of malaria transmission or tracking temporal changes and the impact of interventions. Conducting surveys of parasite prevalence more frequently, on a rolling basis [42], or within easy-to-access subgroups [43], should be considered, along with strengthening health facility surveillance to better capture longitudinal estimates of test positivity rates or malaria incidence [6].

In this survey, increasing age among children aged 2–10 years was strongly associated with malaria parasitaemia, which has been well-described [37]. Anti-malarial immunity is gradually acquired through repeated parasite exposure and increases with age at a rate determined by malaria transmission intensity [37, 44, 45]. In higher transmission areas, young children who lack protective immunity are at highest risk of clinical disease [45], and are more likely to be diagnosed and treated for malaria. However, older children, who have acquired relatively more anti-disease than anti-parasite immunity, are more likely to harbour asymptomatic infections, which often go untreated [37, 46, 47]. School-aged children often have the highest parasite prevalence within populations [36, 48], may be more likely to carry gametocytes [49, 50], and are less likely to use bed nets than other age groups [20, 51]. Thus, school-aged children are likely to be important contributors to the human infectious reservoir for onward transmission of malaria to mosquitoes [48, 52‐54]. Moreover, as malaria control interventions are scaled-up, and transmission intensity and consequently the level of acquired immunity in the population fall, the peak age of clinical malaria may shift from the very young, to include older school-aged children [55, 56]. Thus, as malaria is controlled, malaria morbidity and mortality may paradoxically rise in school-aged children, highlighting the need to monitor this age group as malaria control intensifies. Although parasite prevalence in children aged 2–10 years is a widely used metric [2, 32], the Uganda Malaria Indicator Surveys only assess children under-five. Recognizing the limitations of parasite prevalence as an indicator of malaria burden and transmission, the age-range of the population sampled in the Uganda Malaria Indicator Survey should be reconsidered, to more fully assess the malaria burden and impact of control interventions in Uganda.

In this study, children living in poorer households, and those made of traditional materials, were more likely to be parasitaemic. The complex link between malaria and poverty is well-described [57‐61]. In Uganda, a recent evaluation of the relationship between malaria and poverty found that agricultural success was associated with higher socio-economic position, which was associated with lower human biting rate and lower odds of malaria infection (but not clinical incidence) in children; house type and food security partly explained the effect of socio-economic position on risk of malaria infection [61]. Evidence of the association between house construction on malaria risk is growing, and house design is a promising target for future interventions [22, 62‐64]. A systematic review found that odds of parasitaemia and clinical malaria were lower in residents of modern houses as compared to those living in houses constructed with traditional materials, although the quality of the evidence was low [63]. One randomized controlled trial that evaluated the impact of housing modifications on epidemiological outcomes suggested that a housing intervention (covering doors and windows with netting, screening ceilings and blocking eaves) reduced anaemia in Gambian children by 48% [62]. Improving housing and the built environment is a promising new strategy, but further research is needed to explore the potential role and impact of such interventions [64].

Malaria parasitaemia was the strongest predictor of moderate anaemia in this study. The aetiology of childhood anaemia in low- and middle-income countries is multifactorial and complex [65]. However, Plasmodium falciparum malaria is a well-recognized risk factor for anaemia in malaria-endemic settings [66‐69]. Other major causes of childhood anaemia include iron and other nutritional deficiencies, acute and chronic infections, and genetic haemoglobin disorders [65]. In Uganda, the prevalence of anaemia in children under-five, as measured in the Malaria Indicator and Demographic Health Surveys, appears to be declining. The proportion of children aged 6–59 months with any anaemia (defined as a haemoglobin < 11 g/dL) decreased steadily from 72.6% in 2006 [70], to 61.5% in 2009 [10], and further to 52.8% in 2016 [12]. These results are encouraging and may reflect progress in malaria control in Uganda [66], including use of indoor residual spraying [71], as well as progress in controlling other risk factors for childhood anaemia in Uganda [72, 73].

This study had several limitations. First, estimates of parasite prevalence were based on microscopy and may have underestimated the true prevalence of infection [74]. Indeed, there is an increasing appreciation of the role of asymptomatic carriage in transmission and more sensitive methods, such as loop mediated isothermal amplification (LAMP) and polymerase chain reaction (PCR), have revealed that the proportion of infections due to sub-microscopic parasitaemia is high [75]. Secondly, prevalence of parasitaemia and anaemia were measured cross-sectionally in this study, providing only a snap-shot of the malaria burden at a single point in time. Longitudinal measures of malaria burden, including incidence of clinical malaria, are preferable for monitoring the impact of interventions and trends over time [76]. Finally, variation in reporting haemoglobin values in past Malaria Indicator Surveys limited the comparison of anaemia across severity categories; in the 2014–2015 survey, only haemoglobin values < 8.0 g/dL were reported [11].

In 2017, approximately 3 years after LLINs were distributed in Uganda through a national campaign, adequate coverage with LLINs was low, and parasite prevalence was rising, raising concerns about the sustainability of malaria control gains. Parasitaemia and anaemia were found to vary widely across the country, highlighting the heterogeneity of malaria in Uganda. Strategies to target malaria control interventions to specific geographic areas, and to high-risk populations including older children and poorer households, should be considered.