Tropical Health Matters

Ironically, blood transfusion helps with severe malaria, but can be dangerous in mild cases. And with severe malaria delay in treatment is a major risk. Malaria parasites can be surprisingly diverse, even in one home. Health system performance, drug quality and patient adherence are key factors in the effectiveness of anti-malarials. Read more on each article or abstract in the links provided.

The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria

Mousa A et al. conducted a systematic review and a pooled multicentre individual-patient meta-analysis in PLoS Medicine. Despite the reported association of delay in receiving treatment for uncomplicated malaria (UM) with an increased risk of developing severe malaria (SM), access to treatment remains low in most high-burden areas. Researchers performed a pooled individual-participant meta-analysis with the aim to ascertain the correlation between treatment delay and presenting with SM using Ovid MEDLINE and Embas.

Findings revealed significantly higher risk of severe disease in children and adults who had longer delays from symptom onset to treatment-seeking; this relationship was noted to be the strongest for progression to severe malarial anaemia. Per estimates, nearly half of the severe anaemia cases in both children and adults could be averted if they presented within the first 24 hours of symptom onset.

Malaria parasites in Nigeria are genetically diverse: a danger but also a useful tool

Segun Isaac Oyedeji notes that his team’s research has already confirmed that in malaria-endemic countries such as Nigeria, infected individuals carry P. falciparum parasites that are genetically complex or diverse. What we didn’t know was how diverse the parasites are in the micro environment, such as within households and among children of the same family.

Oyedeji thought that knowing the population structure within households could help us understand more about the pattern and development of the disease. It could also inform development of appropriate guidelines and control measures. He found that even in the micro environment, P. falciparum parasites exhibit high genetic diversity. This finding was similar to results from larger communities in malaria endemic regions and has the same important implications. The implication is that a one-size fits all intervention or approach against the parasites may not be effective. There were children living under the same roof and infected by parasites that were genetically different.

New evidence to guide the practice of blood transfusions in children with severe malaria

The Barcelona Institute for Global Health (ISGlobal) described a new study that shows that transfusions could help increase survival, even at higher haemoglobin levels than those currently recommended. The results show that blood transfusion increased the survival of patients with severe disease.

In cases with complications, such as impaired consciousness or elevated lactate in blood, transfusion improved survival even in children whose levels of haemoglobin were higher the recommended threshold of 60g /l. For example, among patients with impaired consciousness, the authors observed improved survival upon transfusion with haemoglobin levels as high as 105 g / l. However, in the case of mild cases, transfusion was associated with an increase in mortality.

Global estimation of anti-malarial drug effectiveness for the treatment of uncomplicated Plasmodium falciparum malaria 1991–2019

Giulia Rathmes and colleagues note that anti-malarial drugs play a critical role in reducing malaria morbidity and mortality, but their role is mediated by their effectiveness. Effectiveness is defined as the probability that an anti-malarial drug will successfully treat an individual infected with malaria parasites under routine health care delivery system. Anti-malarial drug effectiveness (AmE) is influenced by drug resistance, drug quality, health system quality, and patient adherence to drug use; its influence on malaria burden varies through space and time. This study used data from 232 efficacy trials.

The global effectiveness of artemisinin-based drugs was 67.4% (IQR: 33.3–75.8), 70.1% (43.6–76.0) and 71.8% (46.9–76.4) for the 1991–2000, 2006–2010, and 2016–2019 periods, respectively. The use of artemisinin-based combination therapy (ACT) with a competent partner drug and having multiple ACT as first-line treatment choice sustained high levels of effectiveness. High levels of access to healthcare, human resource capacity, education, and proximity to cities were associated with increased effectiveness. Effectiveness of non-artemisinin-based drugs was much lower than that of artemisinin-based.

This study provides evidence that health system performance, drug quality and patient adherence influence the effectiveness of anti-malarials used in treating uncomplicated falciparum malaria. These results provide guidance to countries’ treatment practices and are critical inputs for malaria prevalence and incidence models used to estimate national level malaria burden.

Recent publications in Malaria Journal, The Lancet and eLife tackle several challenges to saving lives and malaria elimination. Problems include low access to bednets for children in Ethiopia, high prevalence of asymptomatic malaria in Ghanaian adults, risk of co-infection with other infectious diseases, and gaps in current interventions to prevent malaria in pregnancy and children. On the hopeful side, new targets for drug therapy are being identified. Read more on each by following the links below.

Long-lasting insecticide-treated bed net ownership, utilization and associated factors among school-age children in Southern Ethiopia

Zerihun Zerdo and colleagues examined net use among children in malaria-prone areas of

Dara Mallo and Uba Debretsehay districts because malaria is one of the major causes of morbidity and mortality among school-age children (SAC) in sub-Saharan Africa. This study was part of a baseline assessment in a cluster-randomized controlled trial.

The ownership of at least one LLIN by households of school-aged children (SAC) was about 19.3% (95% CI 17.7–21.0%) but only 10.3% % (95% CI 7.7–13.7%) of these households had adequate access of bed nets to the household members. Ownership of bed net was lower than universal coverage of at least one bed net for two individuals. It is important to monitor replacement needs and educate mothers with low education level with their SAC on the benefit of consistent utilization of bed nets.

Prevalence of and risk factors for Plasmodium spp. co-infection with hepatitis B virus: a systematic review and meta-analysis

Kotepui and Kotepui observed that Plasmodium spp. and hepatitis B virus (HBV) are among the most common infectious diseases in underdeveloped countries. Therefore they examined co-infection in people living in endemic areas of both diseases. The PubMed, Web of Science, and Scopus databases were searched. Observational cross-sectional studies and retrospective studies assessing the prevalence of Plasmodium species and HBV co-infection were examined. and found 22 studies to include in a systematic review and meta-analysis. Overall, the pooled prevalence estimate of Plasmodium spp. and HBV co-infection was 6% (95% CI 4–7%, Cochran’s Q statistic?<?0.001, I2: 95.8%).

No difference in age or gender and risk of Plasmodium spp. and HBV co-infection group was found. The present study revealed the prevalence of Plasmodium spp. and HBV co-infection, which will help in understanding co-infection and designing treatment strategies. Future studies assessing the interaction between Plasmodium spp. and HBV are recommended.

High prevalence of asymptomatic malaria infections in adults, Ashanti Region, Ghana, 2018

Melina Heinemann and co-researchers noted that Ghana is among the high-burden countries for malaria infections and recently reported a notable increase in malaria cases. While asymptomatic parasitaemia is increasingly recognized as a hurdle for malaria elimination, studies on asymptomatic malaria are scarce, and usually focus on children and on non-falciparum species. Therefore asymptomatic adult residents from five villages in the Ashanti Region, Ghana, were screened for Plasmodium species by rapid diagnostic test (RDT) and polymerase chain reaction (PCR) during the rainy season. Samples tested positive were subtyped using species-specific real-time PCR.

Molecular prevalence of asymptomatic Plasmodium infection was 284/391 (73%); only 126 (32%) infections were detected by RDT. While 266 (68%) participants were infected with Plasmodium falciparum, 33 (8%) were infected with Plasmodium malariae and 34 (9%) with P. ovale. The sub-species P. ovale curtisi and P. ovale wallikeri were identified to similar proportions. Non-falciparum infections usually presented as mixed infections with P. falciparum.

Most adult residents in the Ghanaian forest zone are asymptomatic Plasmodium carriers. The high Plasmodium prevalence not detected by RDT in adults highlights that malaria eradication efforts must target all members of the population. Beneath Plasmodium falciparum, screening and treatment must also include infections with P. malariae, P. o. curtisi and P. o. wallikeri.

Scientists shed new light on mechanisms of malaria parasite motility

eLife reports a new insight on the molecular mechanisms that allow malaria parasites to move and spread disease within their hosts has just been published. The first X-ray structures of the molecular complex that allows malaria parasites to spread disease highlight a novel target for antimalarial treatments.

The movement and infectivity of the parasite Plasmodium falciparum, and ultimately its ability to spread malaria among humans, rely on a large molecular complex called the glideosome. The new findings provide a blueprint for the design of future antimalarial treatments that target both the glideosome motor and the elements that regulate it.

New Lancet Series: Malaria in early life

Malaria infections are harmful to both the pregnant mother and the developing fetus. Malaria is associated with a 3–4 times increased risk of miscarriage and a substantially increased risk of stillbirth, and it disproportionately affects children younger than 5 years. Falciparum malaria is responsible for more than 200 000 child deaths per year in Africa and vivax malaria causes excess mortality in children in Asia and Oceania. In a duet of papers, we review 1) the deleterious effects of malaria in pregnancy on the developing fetus and 2) the current strategies for prevention and treatment of malaria in children.

Paper 1 is “Deleterious effects of malaria in pregnancy on the developing fetus: a review on prevention and treatment with antimalarial drugs” by Makoto Saito, Valérie Briand, Aung Myat Min, and Rose McGready. The authors are concerned that one in ten maternal deaths in malaria endemic countries may result from Plasmodium falciparum infection, that malaria is associated with a 3–4 times increased risk of miscarriage and a substantially increased risk of stillbirth. While current treatment and prevention strategies reduce, but do not eliminate, malaria’s damaging effects on pregnancy outcomes. They conclude that there is a need for alternative strategies to prevent malaria in pregnancy.

Paper 2 is “Treatment and prevention of malaria in children” by Elizabeth A Ashley and Jeanne Rini Poespoprodjo. They examine the following interventions: Triple antimalarial combination therapies, the RTS,S/AS01 vaccine, seasonal malaria chemoprevention and preventing relapse in Plasmodium vivax infection with primaquine.

The American Journal of Tropical Medicine and Hygiene has several new articles on malaria. Abstracts are shared. Two articles examine the role of travel in malaria transmission, both cross-border and rural-urban. Another considers the effect on pharmacokinetics of lumefantrine due to gut bacteria. In Uganda indoor spraying has reduced transmission, but asymptomatic cases remain among children. The challenges of asymptomatic malaria to elimination efforts is also examined in India. Links to the articles are found below.

Evidence of Microbiome–Drug Interaction between the Antimalarial Lumefantrine and Gut Microbiota in Mice

The antimalarial drug lumefantrine exhibits erratic pharmacokinetics. Intersubject variability might be attributed, in part, to differences in gut microbiome–mediated drug metabolism. We assessed lumefantrine disposition in healthy mice stratified by enterotype to explore associations between the gut microbiota and lumefantrine pharmacokinetics. Gut microbiota enterotypes were classified according to abundance and diversity indices from 16S rRNA sequencing. Pharmacokinetic parameters were computed using noncompartmental analysis. Two distinct enterotypes were identified.

Maximal concentration (C max) and total drug exposure measured as the area under the drug concentration–time curve (AUC0–24) differed significantly between the groups. The mean and standard deviation of C max were 660 ± 220 ng/mL versus 390 ± 59 ng/mL (P = 0.02), and AUC0–24 was 9,600 ± 2,800 versus 5,800 ± 810 ng × h/mL (P = 0.01). In healthy mice intragastrically dosed with the antimalarial drug lumefantrine in combination with artemether, lumefantrine exposure was associated with gut bacterial community structure. Studies of xenobiotic–microbiota interactions can inform drug posology and elucidate mechanisms of drug disposition.

Malaria Transmission, Infection, and Disease following Sustained Indoor Residual Spraying of Insecticide in Tororo, Uganda

Tororo, a district in Uganda with historically high malaria transmission intensity, has recently scaled up control interventions, including universal long-lasting insecticidal net distribution in 2013 and 2017, and sustained indoor residual spraying (IRS) of insecticide since December 2014. We describe the burden of malaria in Tororo 5 years following the initiation of IRS. We followed a cohort of 531 participants from 80 randomly selected households in Nagongera subcounty, Tororo district, from October 2017 to October 2019. Mosquitoes were collected every 2 weeks using CDC light traps in all rooms where participants slept, symptomatic malaria was identified by passive surveillance, and microscopic and submicroscopic parasitemia were measured every 4 weeks using active surveillance. Over the 2 years of follow-up, 15,780 female anopheline mosquitos were collected, the majority (98.0%) of which were Anopheles arabiensis.

The daily human biting rate was 2.07, and the annual entomological inoculation rate was 0.43 infective bites/person/year. Only 38 episodes of malaria were diagnosed (incidence 0.04 episodes/person/year), and there were no cases of severe malaria or malarial deaths. The prevalence of microscopic parasitemia was 1.9%, and the combined prevalence of microscopic and submicroscopic parasitemia was 10.4%, each highest in children aged 5–15 years (3.3% and 14.0%, respectively). After 5 years of intensive vector control measures in Tororo, the burden of malaria was reduced to very low transmission levels. However, a significant proportion of the population remained parasitemic, primarily school-aged children with submicroscopic parasitemia, providing a potential reservoir for malaria transmission.

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.

Prevalence of Asymptomatic Malaria Parasitemia in Odisha, India: A Challenge to Malaria Elimination

The prevalence of malaria in India is decreasing, but it remains a major concern for public health administration. The role of submicroscopic malaria and asymptomatic malaria parasitemia and their persistence is being explored. A cross-sectional survey was conducted in the Kandhamal district of Odisha (India) during May–June 2017. Blood samples were collected from 1897 individuals for screening of asymptomatic parasitemia. Samples were screened using rapid diagnostic tests (RDTs) and examined microscopically for Plasmodium species. Approximately 30% of randomly selected samples (n = 586) were analyzed using real-time PCR (qPCR), and the genetic diversity of Plasmodium falciparum was analyzed.

The prevalence of Plasmodium species among asymptomatic individuals detected using qPCR was 18%, which was significantly higher than that detected by microscopy examination (5.5%) or RDT (7.3%). Of these, 37% had submicroscopic malaria. The species-specific prevalence among asymptomatic malaria-positive cases for P. falciparum, Plasmodium vivax, and mixed infection (P. falciparum and P. vivax) by qPCR was 57%, 29%, and 14%, respectively. The multiplicity of infection was 1.6 and 1.2 for the merozoite surface protein-1 gene (msp1) and (msp2), respectively. Expected heterozygosity was 0.64 and 0.47 for msp1 and msp2, respectively. A significant proportion of the study population, 105/586 (18%), was found to be a reservoir for malaria infection, and identification of this group will help in the development of elimination strategies.

Travel Is a Key Risk Factor for Malaria Transmission in Pre-Elimination Settings in Sub-Saharan Africa: A Review of the Literature and Meta-Analysis

By sustaining transmission or causing malaria outbreaks, imported malaria undermines malaria elimination efforts. Few studies have examined the impact of travel on malaria epidemiology. We conducted a literature review and meta-analysis of studies investigating travel as a risk factor for malaria infection in sub-Saharan Africa using PubMed. We identified 22 studies and calculated a random-effects meta-analysis pooled odds ratio (OR) of 3.77 (95% CI: 2.49–5.70), indicating that travel is a significant risk factor for malaria infection.

Odds ratios were particularly high in urban locations when travel was to rural areas, to more endemic/high transmission areas, and in young children. Although there was substantial heterogeneity in the magnitude of association across the studies, the pooled estimate and directional consistency support travel as an important risk factor for malaria infection.

Differentiating malaria parasite species is something science can do today, but in the 1800s the debate was over what actually caused the disease.  This ability to test and diagnose gives us an important surveillance tool, the 3Ts. News from Ghana is that malaria deaths are reducing, and Guatemala is focusing on elimination. Read more at the links in each section.

Wyss Researchers Develop Malaria Diagnostic Procedure Capable of Differentiating Malaria Species

Researchers at Harvard’s Wyss Institute have developed a new malaria diagnostic test that efficiently detects and can distinguish between species of malaria parasites,
the new procedure significantly improves upon current diagnostic methods, which fail to differentiate between types of malaria. Procedures that only identify Plasmodium falciparum can lead to severe consequences for patients, since other types of malaria are resilient to therapies designed to treat Plasmodium falciparum because they enter a dormant stage in the human liver.

These genes help explain how malaria parasites survive treatment with common drug.

The essential malaria drug artemisinin acts like a “ticking time bomb” in parasite cells—but in the half a century since the drug was introduced, malaria-causing parasites have slowly grown less and less susceptible to the treatment, threatening attempts at global control over the disease.

In a paper published September 23 in Nature Communications, Whitehead Institute Member Sebastian Lourido and colleagues use genome screening techniques in the related parasite Toxoplasma gondii (T. gondii) to identify genes that affect the parasites’ susceptibility to artemisinin. Two genes stood out in the screen: one that makes the drug more lethal, and another that helps the parasite survive the treatment…

Test, Treat, and Track: Strengthening Malaria Response Capabilities in Sierra Leone

A public-private partnership in Sierra Leone aimed to build capacity for testing, treating, and tracking malaria. The post notes the “public-private partnership in Sierra Leone was a collaboration between USAID’s Human Resources for Health in 2030 (HRH2030) program; the U.S. President’s Malaria Initiative (PMI), the Global Fund to Fight AIDS, Tuberculosis and Malaria; the Pharmacy Consultancy of Sierra Leone; and the Sierra Leone National Malaria Control Program”.

NMCP partnered with pharmacies to strengthen their malaria case management capabilities. Anitta and her colleague Brenda Stafford, a trained pharmacist and Procurement and Supply Management officer, led the initiative, going pharmacy-to-pharmacy to train staff on the NMCP’s “Three T” approach: Test, Treat, and Track.

To address the first T, private pharmacies were given free malaria rapid diagnostic tests. According to 2016 data, only half of children under-five with fever received appropriate malaria testing. For the second T, the pharmacists were trained on malaria prevention, treating patients with uncomplicated malaria, and referring patients with severe malaria to health facilities. As for the last T, tracking malaria test results is key in forecasting the spread of disease. NMCP provided pharmacies with two forms that track results: a registry form to track patient information and a summary form which aggregates that into monthly data reports

Miasma War over cause of malaria was heated

Nicole Layton of the Chowan Herald reported that in the 1850s, two North Carolina doctors had a heated and protracted battle over the cause of malaria in the state. This Miasma War is so famous. So what the heck is Miasma? Those fans of Charles Dickens can tell you that at one point miasmas were thought to be the main vector for disease transmission.

During Dickens’ time in London the air was very foul and rather visible because of wood and coal and it smelled bad due to the lack of indoor plumbing. It was thought that this foul air was the cause of disease. Because our part of North Carolina had a lot of rotting vegetation and swamps there was certainly foul air about and very noticeable illness. So the general thought was that malaria was a result of this bad air.

Escuintla, Guatemala: Clinton Health Access Initiative (CHAI)

CHAI’s Guatemala Malaria Team is supporting the Ministry of Health’s National Malaria Program by providing technical assistance and supporting programmatic planning, execution, monitoring and evaluation of effective interventions in the department of Escuintla in southern Guatemala. Over the past five years, CHAI has engaged in the country and helped them make meaningful steps towards orienting their national strategic plans and systems towards the historical goal of malaria elimination.

CHAI’s Guatemala team works in close coordination with the Ministry of Health and other international partners to design, plan, execute and evaluate the impact of the country´s elimination-focused interventions in Escuintla.

Ghana: Malaria deaths in children under five reduce

Ghana has recorded a reduction in malaria deaths in children under five by 83 per cent over the last eight years, the National Malaria Control Programme (NMCP) has said. The rate of malaria-related deaths reduced from 0.6 per cent in 2012 to 0.1 per cent in 2019, showing significant inroads in malaria-related deaths among children. Malaria-related deaths of all ages also reduced by 2,799 in 2012 to 333 by end of 2019, representing an 88 per cent reduction.

Malaria Journal released three articles ranging from the relation between malaria and agricultural irrigation, artemisinin resistance on the Myanmar-China border, and efforts at costing malaria elimination interventions. PLoS Medicine examined the quality of malaria clinical management in children. Finally, Frontiers in Cellular and Infection Microbiology reported on a new drug against malaria and toxoplasmosis. Click on links to read more details.

Minimal tillage and intermittent flooding farming systems show a potential reduction in the proliferation of Anopheles mosquito larvae in a rice field in Malanville, Northern Benin

Irrigation systems have been identified as one of the factors promoting malaria disease around agricultural farms in sub-Saharan Africa. However, if improved water management strategy is adopted during rice cultivation, it may help to reduce malaria cases among human population living around rice fields.

A clear reduction of larva density was observed with both intermittent flooding systems applied to minimal tillage (MT?+?IF?+?NL) and intermittent flooding applied to deep tillage (DT?+?IF?+?AL), showing that intermittent flooding could reduce the abundance of malaria vector in rice fields. Recommending intermittent flooding technology for rice cultivation may not only be useful for water management but could also be an intentional strategy to control mosquitoes vector-borne diseases around rice farms.

No evidence of amplified Plasmodium falciparum plasmepsin II gene copy number in an area with artemisinin-resistant malaria along the China–Myanmar border

The emergence and spread of artemisinin resistance in Plasmodium falciparum poses a threat to malaria eradication, including China’s plan to eliminate malaria by 2020. Piperaquine (PPQ) resistance has emerged in Cambodia, compromising an important partner drug that is widely used in China in the form of dihydroartemisinin (DHA)-PPQ. Several mutations in a P. falciparum gene encoding a kelch protein on chromosome 13 (k13) are associated with artemisinin resistance and have arisen spread in the Great Mekong subregion, including the China–Myanmar border. Multiple copies of the plasmepsin II/III (pm2/3) genes, located on chromosome 14, have been shown to be associated with PPQ resistance.

DHA-PPQ for uncomplicated P. falciparum infection still showed efficacy in an area with artemisinin-resistant malaria along the China–Myanmar border. There was no evidence to show PPQ resistance by clinical study and molecular markers survey. Continued monitoring of the parasite population using molecular markers will be important to track emergence and spread of resistance in this region.

Costing malaria interventions from pilots to elimination programmes

Malaria programmes in countries with low transmission levels require evidence to optimize deployment of current and new tools to reach elimination with limited resources. Recent pilots of elimination strategies in Ethiopia, Senegal, and Zambia produced evidence of their epidemiological impacts and costs. There is a need to generalize these findings to different epidemiological and health systems contexts. Drawing on experience of implementing partners, operational documents and costing studies from these pilots, reference scenarios were defined for rapid reporting (RR), reactive case detection (RACD), mass drug administration (MDA), and in-door residual spraying (IRS). These generalized interventions from their trial implementation to one typical of programmatic delivery. In doing so, resource use due to interventions was isolated from research activities and was related to the pilot setting. Costing models developed around this reference implementation, standardized the scope of resources costed, the valuation of resource use, and the setting in which interventions were evaluated. Sensitivity analyses were used to inform generalizability of the estimates and model assumptions.

Populated with local prices and resource use from the pilots, the models yielded an average annual economic cost per capita of $0.18 for RR, $0.75 for RACD, $4.28 for MDA (two rounds), and $1.79 for IRS (one round, 50% households). Intervention design and resource use at service delivery were key drivers of variation in costs of RR, MDA, and RACD. Scale was the most important parameter for IRS. Overall price level was a minor contributor, except for MDA where drugs accounted for 70% of the cost. The analyses showed that at implementation scales comparable to health facility catchment area, systematic correlations between model inputs characterizing implementation and setting produce large gradients in costs. Prospective costing models are powerful tools to explore resource and cost implications of policy alternatives. By formalizing translation of operational data into an estimate of intervention cost, these models provide the methodological infrastructure to strengthen capacity gap for economic evaluation in endemic countries. The value of this approach for decision-making is enhanced when primary cost data collection is designed to enable analysis of the efficiency of operational inputs in relation to features of the trial or the setting, thus facilitating transferability.

Quality of clinical management of children diagnosed with malaria: A cross-sectional assessment in 9 sub-Saharan African countries between 2007–2018

Appropriate clinical management of malaria in children is critical for preventing progression to severe disease and for reducing the continued high burden of malaria mortality. This study aimed to assess the quality of care provided to children under 5 diagnosed with malaria across 9 sub-Saharan African countries. We used data from the Service Provision Assessment (SPA) survey. SPAs are nationally representative facility surveys capturing quality of sick-child care, facility readiness, and provider and patient characteristics across 9 countries, including Uganda (2007), Rwanda (2007), Namibia (2009), Kenya (2010), Malawi (2013), Senegal (2013–2017), Ethiopia (2014), Tanzania (2015), and Democratic Republic of the Congo (2018).

In this study, we found that a majority of children diagnosed with malaria across the 9 surveyed sub-Saharan African countries did not receive recommended care. Clinical management is positively correlated with the stocking of essential commodities and is somewhat improved in more recent years, but important quality gaps remain in the countries studied. Continued reductions in malaria mortality will require a bigger push toward quality improvements in clinical care. Despite increases in the distribution of malaria tests and effective antimalarial medications, significant gaps in the quality of care for pediatric malaria are present in these 9 countries. Further improvements in quality of malaria care may require a better understanding of remaining barriers and facilitators to appropriate management.

Novel drug could be a powerful weapon in the fight against malaria and toxoplasmosis

Princeton researchers are making key contributions toward developing a promising new treatment for the widespread and devastating diseases toxoplasmosis and malaria.
The Princeton scientists specialize in preparing the drug compound into a medicine that is both safe and effective for humans and able to reach its intended sites of action in the body in sufficient doses. An international team of scientists found the new drug—designated JAG21—to be highly effective against parasites in cell-based studies in the lab. After the discovery, team representatives contacted Princeton’s Robert Prud’homme for help in translating the JAG21 compound into a deliverable medication. Prud’homme is a co-author of a study, published in June 2020 in Frontiers in Cellular and Infection Microbiology, that describes the compound and its excellent preliminary results in mice.

Recent news over this weekend included efforts at school and peer education on bednets in Ethiopia, gender inequality effects of COVID-19 and pandemics, a reduction in severe malaria in Rwanda and increased use of home based case management, and the altering of scientific reports by political appointees. Links in these summaries take one to the full story.

Effectiveness of peer-learning assisted primary school students educating the rural community on insecticide-treated nets utilization in Jimma-zone Ethiopia

Abstract: Making insecticide-treated nets (ITNs) utilization a social norm would support the global goal of malaria eradication and Ethiopian national aim of its elimination by 2030. Jimma zone is one of the endemic settings in Ethiopia. This study aimed to report effects of malaria education, delivered by students, on community behaviours; particularly ITNs. The intervention engaged students from primary schools in participatory peer education within small groups, followed by exposing parents with malaria messages aimed at influencing perceptions and practices.

Over the intervention periods, the findings showed significant improvement in exposure to and content intensity of malaria messages delivered by students. Socio-demography, access, exposures to messages, and parental perception that students were good reminders predicted ITN utilization over the intervention periods with some changing patterns. Exposing the community to malaria education through students effectively supports behaviour change, particularly ITN usage, to be more positive towards desired malaria control practices. A school-based strategy is recommended to the national effort to combat malaria.

Melinda Gates calls on Leaders to Ensure that Women, Girls are Not Left Behind in the Global Response to COVID-19

Melinda Gates has launched a paper exploring how the COVID-19 pandemic has exploited pre-existing inequalities and drastically impacted women’s lives and livelihoods. In the paper, titled “The Pandemic’s Toll on Women and Girls,” Melinda makes the case that to recover fully from this pandemic, leaders must respond to the ways that it is affecting men and women differently. She puts forward a set of specific, practical policy recommendations that governments should consider in their pandemic response—to improve health systems for women and girls, design more inclusive economic policies, gather better data, and prioritize women’s leadership.Writing in the paper, Melinda describes how previous disease outbreaks, including AIDS and Ebola, tend to exploit existing forces of inequality, particularly around gender, systemic racism, and poverty.
Melinda concludes, “This is how we can emerge from the pandemic in all of its dimensions: by recognizing that women are not just victims of a broken world; they can be architects of a better one.

Severe malaria drops by 38% in Rwanda

In its annual Malaria and Neglected Tropical Diseases Report, the Ministry of Health says that the national malaria incidence reduced from 401 cases per 1,000-person in 2017-2018 fiscal year to 200 cases per 1,000-person in 2019-2020. According to the report, 4,358 cases of severe malaria (representing a 38 per cent reduction) were reported at the health facility level compared to 7,054 in 2018-2019. The decrease in malaria deaths is attributed to home based management interventions, the free treatment of malaria for Ubudehe Categories I and II and the quality of care at health facility level.

There has also been a steady increase of proportion of children under 5 and above plus adults who are seeking care from 13 per cent to 58 per cent in 2015-2016 and 2019-2020 respectively. “This indicates that interventions such home based treatment of children and adults that contributed to early diagnosis and treatment have been successful in decreasing the number of severe cases and consequently the number of malaria deaths,” the report indicates.

Political appointees sought to alter CDC scientific reports so they don’t contradict or undermine the president

Caputo (a US presidential appointee) and his communications staff have worked to delay CDC reports that contradict President Donald Trump’s rhetoric. One publication was held back for about a month, according to Politico, for recommending against the use of hydroxychloroquine, a malaria drug touted by the White House as a potential cure for COVID-19.

The reports, written by career scientists, are known as the Morbidity and Mortality Weekly Reports, and according to Politico, are used to “inform doctors, researchers, and the general public about how Covid-19 is spreading and who is at risk.” Jennifer Kates, of the Kaiser Family Foundation’s global health work, who has relied on past reports, told Political they are “the go-to place for the public health community to get information that’s scientifically vetted.” Alexander (a presidential appointee), in this missive, said any future reports related to the coronavirus “must be read by someone outside of CDC like myself.”

From time-to-time we will feature a collection of news and abstracts available “today.” Here are five stories available on 31st August 2020.

Med-tech on a leash: The many diseases that can be detected by dogs

Malaria, a parasitic disease, which is transmitted to humans by Anopheles mosquitoes, can also be detected by our canine friends. In 2019, English researchers presented the results of a study conducted in The Gambia, which involved training dogs with socks that had been worn by children infected with malaria, who otherwise had no symptoms.
The experiment proved to be so successful that researchers are now planning on using this method to test for asymptomatic cases of the disease….

New Malaria Transmission Patterns Emerge In Africa.

An international study reveals how future climate change could affect malaria transmission in Africa over the next century. Malaria is a climate sensitive disease; it thrives where it is warm and wet enough to provide surface water suitable for breeding by the mosquitoes that transmit it. For more than two decades now, scientists have suggested that climate change may alter the distribution and length of transmission seasons due to new patterns of temperature and rainfall. The burden of this disease falls primarily on Africa. In 2018, out of an estimated 228 million cases of malaria worldwide, 93% were in the African continent.
Detailed mapping of malaria transmission is vital for the distribution of public health resources and targeted control measures.

In the past, rainfall and temperature observations have been used in malaria climatic suitability models to estimate the distribution and duration of annual transmission, including future projections. But factors affecting how rainfall results in water for mosquito breeding are highly complex, for example how it is absorbed into soil and vegetation, as well as rates of runoff and evaporation. A new study, led by the Universities of Leeds and Lincoln in the UK, for the first time combined a malaria climatic suitability model with a continental-scale hydrological model that represents real-world processes of evaporation, infiltration and flow through rivers. This process-focused approach gives a more in-depth picture of malaria-friendly conditions across Africa….

Covid has spelt a lockdown for routine health services in India

Official data are now available to show the extent to which routine health services in India were unavailable and the scale of its impact. The number of fully immunised children fell by over 15 lakh in the three-month period from April to June compared to the same months last year. The number of institutional deliveries fell by about 13 lakh. The registered number of TB patients undergoing treatment fell to almost half of what it was last year. People seeking cancer treatment as outpatients fell by over 70%. Hard-won progress on several national health goals, including the programme to bring down infant and maternal mortality or those to treat TB, malaria and non-communicable diseases such as heart diseases, diabetes and cancer,

Insecticide resistance in indoor and outdoor-resting Anopheles gambiae in Northern Ghana

The overall results did not establish that there was a significant preference of resistant malaria vectors to solely rest indoors or outdoors, but varied depending on the resistant alleles present. Phenotypic resistance was higher in indoor than outdoor-resting mosquitoes, but genotypic and metabolic resistance levels were higher in outdoor than the indoor populations. Continued monitoring of changes in resting behaviour within An. gambiae s.l. populations is recommended.

Highlighting the burden of malarial infection and disease in the neonatal period: making sense of different concepts

Review of neonates from 14 malaria-endemic countries found pooled prevalence in this specific age group. Importantly, their results suggest a prevalence of congenital malaria of 40.4/1000, and a prevalence of neonatal malaria of 12/1000, Interestingly, the authors also confirmed congenital malaria to be more frequent in settings with unstable malaria transmission, a finding in line with the hypothesis of the importance of the immunity background in the risk of congenital malaria.

Until recently it was thought that the novel coronavirus, COVID-19, was less severe in children. Now as more cases can be studied, that prognosis is less likely to be true. The number of cases overall in Africa is still lower than the rest of the world, with 36,857 cases reported by the Africa CDC as of 29 April 2020, compared to over 3 million globally. One assumes out of this that the number of child cases would also be lower, but there is worry about other indirect effects of the pandemic on children.

Initial beliefs that the young would be less impacted by COVID-19 may have led to complacency. For example, the Atlantic reports that, “Africa will enjoy the advantage of youth. COVID-19 kills mostly the old, and Africans are relatively young, with a median age of 18.9. (The median age in the United States and China is 38.) That means, in effect, that about half of Africans who get COVID-19 will have a low risk of death.” The reality is turning out much different.

First from the medical standpoint, VOA reports that, “Doctors in Britain, Italy, Portugal and Spain are exploring a possible link between a severe inflammatory disease in children and the coronavirus. A growing number of children of various ages in several European countries have been admitted to hospitals with high fever and heart issues. Some also have suffered from gastrointestinal problems, such as vomiting and diarrhea.” There is not enough information disaggregated by age to tell us how coronavirus is affecting children in Africa.

Secondly, UNICEF tells us that, “in any crisis, the young and the most vulnerable suffer disproportionately,” as children suffer from “collateral damage.” Lockdowns reduce access to essential services such as routine immunization, nutritional supplementation and malaria treatment and prevention programs and thus increase morbidity and mortality among children.

Nature published on 7^th April that measles has currently, “killed more than 6,500 children in the Democratic Republic of the Congo (DRC) and is still spreading through the country.” Unfortunately “23 countries have suspended measles vaccination campaigns as they cope with SARS-CoV-2.”

There are groups of children that are especially vulnerable. In Kenya. “Street children are having a rough time during the curfew. Food and water are a real problem as hotels and eating places where they would normally get food have closed down. Movement is restricted,” according to the Guardian. The article goes further to share the concern that, “the virus could drive homeless children back to families where they are at risk of abuse.” Abuse of children during stressful times goes affects many confined to homes with out-of-work parents, not just street children.

We cannot afford to lose more children to direct and collateral mortality from the COVID-19 pandemic as it spreads in Africa. We need to begin with better data to tell us about infection and effects on children. Nigeria has done some reporting on age.  We need to ensure that all countries collect data on children and COVID-19 and also maintain routine child survival services.

The Demographic and Health Survey Program has recently released the 2018 Malaria Indicator Survey for Mozambique. Below is a summary of some of the key findings. These focus on access and use of insecticide-treated nets, intermittent preventive treatment in pregnancy and case management

While “82% of Mozambican households have at least one ITN, and half have at least one ITN for each two people,” these achievements do not reach universal coverage targets. That said, the ownership of at least one net by a household did increase from 51% in 2011 to the recent 82%. Likewise 23% of households met the universal coverage target of one net per two people in a household in 2011 compared to 51% in 2018. The pace of progress may appear good, but this must be seen in light of lack of growth in donor funding and greater calls for countries to assume more financial responsibility for disease control.

Of interest is the fact that net ownership is spread somewhat evenly over the economic class quintiles. Ideally we would want to see better ownership figures for the lower quintiles.

Households obtained their nets from three major sources. “Most ITNs (87%) were obtained in mass distribution campaigns, 4% in prenatal consultations (PNC) and 6% are purchased in stores or markets.” While the proportion getting their nets through PNC may roughly reflect the proportion of the population who are pregnant at a given time, the survey is not specifically a snapshot of this population in real time. Thus, one could question whether distribution of ITNs through routine health services is fully functioning.

Since it was noted that only half of households have the ideal number of ITNs to reach universal coverage of their members, it is not surprising that only, “69% of the population of households’ family members have access to an ITN. This means that 7 in every 10 people could sleep under an ITN if each ITN in a household were used by a maximum of two people.” On the positive side, this represents an approximate doubling of use of ITNs since 2011.

The survey further notes that those segments of the population traditionally viewed as “vulnerable” fared a bit better: “73% of children under 5 years and 76% of pregnant women slept under an ITN the night before investigation.” This too, represents a doubling from 2011. There is also geographical variation where it appears that the more rural provinces have higher rates of use.

It would appear that IRS is not a major component of malaria control. Household coverage with indoor residual spray “decreased from 19% in 2011 to 11% in 2015, and then increased to 16% in 2018.” Urban coverage (23%) of IRS in the twelve months prior to the survey is twice as high as the percentage in rural areas (12%).

Although still not meeting targets, Mozambique has seen major progress in providing IPTp for pregnant women. Over the period from 2011 to 2018 the proportion of pregnant women receiving even one dose rose from 37% to 85%. Since WHO has set targets for at least 3 monthly doses from the 13th week of pregnancy, Mozambique’s coverage of the third dose increased from 10% to 41% with wide variation among provinces.

UNICEF shared data from 2015 to show that 51% of pregnant women in Mozambique attended 4 PNC/ANC visits, implying that there are missed opportunities for achieving at least 3 doses of IPTp. Also, since more women are now getting the first dose of IPTp, hopefully more can also get an ITN at PNC.

These national surveys (MIS, DHS) are invaluable for assessing progress and planning what interventions need to be strengthened where and among whom. They also show that progress is slow, reinforcing global concerns that malaria elimination will still be a challenge by 2050.

The Efficacy of artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum infection in Rwanda, 2018 was investigated by Aline Uwimana, Noella Umulisa, Eric S. Halsey, Meera Venkatesan, Tharcisse Munyaneza, Rafiki Madjid Habimana, Ryan Sandford, Leah Moriarty, Emily Piercefield, Zhiyong Zhou, Samaly Souza, Naomi Lucchi, Daniel Ngamije, Jean-Louis N Mangala, William Brieger, Venkatachalam Udhayakumar, Aimable Mbituyumuremyi.* The results were presented at the 68th Annual Meeting of the American Society of Tropical Medicine and Hygiene and are seen below.

Background: In Rwanda, there were 4,195,013 confirmed malaria cases and 341 malaria-related deaths in 2018[1]. Regular monitoring of artemisinin-based combination therapy efficacy is important to assess drug efficacy and for timely detection of the emergence of antimalarial drug resistance. In Rwanda, national policy is to routinely monitor the first-line antimalarial per World Health Organization (WHO) guidelines[2] The most recent therapeutic efficacy results in Rwanda showed an efficacy of the first-line antimalarial, artemether-lumefantrine (AL), of >97% in Masaka and Ruhuha in a study conducted from 2013 to 2015[3]

Methods: This was an Efficacy trial based on the standard WHO in vivo protocol[2]. Three sites (see map) were selected in Rwanda. Artemether-lumefantrine (AL) was given twice daily; each dose given under observation for 3 days. Participants were treated with AL and followed for 28 days from March 2018 to December 2018.

PCR correction, differentiating recrudescence from reinfection in late treatment failure samples, was performed using genotyping of seven neutral microsatellites. Microsatellite data were analyzed using a previously published algorithm that assigns each late treatment failure a posterior probability of recrudescence[4]

• Primary Endpoint: 28-day PCR-corrected efficacy
• Secondary Endpoints: 28-day uncorrected efficacy, day 3 parasitemia

PCR-corrected and uncorrected efficacies are seen to the left.  Kaplan Meier Curves are presented. Uncorrected (top) and PCR-corrected (bottom) survival functions for time until failure for a 2018 therapeutic efficacy study using artemether-lumefantrine in three Rwandan study sites; ACPR: adequate clinical and parasitological response. Day 3 Parasitemia was identified. Two sites, Masaka and Rukara, had > 10% of subjects with parasites detectable on day 3, a WHO criteria for suspected artemisinin resistance.

With PCR-corrected efficacies greater than the 90% cut-off recommended by WHO, AL remains an effective antimalarial to treat uncomplicated P. falciparum in Rwanda
More than 10% of subjects had day 3 parasitemia at two sites; the relationship with this finding and k13 mutations observed in this study was presented in ASTMH poster LB-5295 (Friday, November 22, 2019).

Periodic antimalarial efficacy monitoring in Rwanda should be maintained, and future studies should incorporate additional methods to assess parasite clearance times and presence of molecular markers of resistance. WHO algorithm indicating that, for this study, even with suspected artemisinin resistance in Rwanda, no change in ACT treatment policy is warranted at this time.

References

1. Rwanda Malaria and Other Parasitic Diseases Division, Rwanda Biomedical Center, HMIS data, 2018.
2. WHO, Methods for Surveillance of Antimalarial Drug Efficacy, 2009.
3. Uwimana A, Efficacy of artemether–lumefantrine versus dihydroartemisinin–piperaquine for the treatment of uncomplicated malaria among children in Rwanda: an open-label, randomized controlled trial, Trans R Soc Trop Med Hyg; doi:10.1093/trstmh/trz009; 2019.
4. Plucinski MM, Morton L, Bushman M, Dimbu PR, Udhayakumar V. Robust algorithm for systematic classification of malaria late treatment failures as recrudescence or reinfection using microsatellite genotyping. Antimicrob Agents Chemother;59:6096–100; 2015.

Contact Information: Aline Uwimana, MD: aline.uwimana@rbc.gov.rw and Eric Halsey, MD: ycw8@cdc.gov

*Affiliations: Malaria and Other Parasitic Diseases Division, Rwanda Biomedical Centre, Kigali, Rwanda; Maternal and Child Survival Program/JHPIEGO, Baltimore MD, USA; The US President’s Malaria Initiative, Atlanta, Georgia, USA; Malaria Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA; US President’s Malaria Initiative, Washington DC, USA; National Reference Laboratory, Rwanda Biomedical Centre, Kigali, Rwanda; US Peace Corps, Kigali, Rwanda; US President’s Malaria Initiative, Kigali, Rwanda; WHO Rwanda Office, Malaria and Neglected Tropical Diseases Programs, Kigali, Rwanda; The Johns Hopkins University, Bloomberg School of Public Health, Department of International Health, Baltimore, MD, USA