Tropical Health Matters

Adegbola and colleagues note that “the efficacy of SP-IPTp is threatened by the emergence of sulfadoxine-pyrimethamine resistant malaria parasites, “which has been observed in East Africa. They therefore, studied the situation in Nigeria, the country with the highest malaria burden in the continent. Their study showed that “the prevalence of VAGKGS haplotype seems to be increasing in prevalence.”

In conclusion, they worried that, “If this is similar in effect to the emergence of 581G in East Africa, the efficacy of SP-IPTp in the presence of these novel Pfdhps mutants should be re-assessed” in Nigeria. This situation threatens the use of sulfadoxine-pyrimethamine (SP) in two major prevention programs including intermittent preventive treatment during pregnancy (IPTp) and seasonal malaria chemoprevention (SMC) for children.

The benefits of IPTp using SP is the ability to administer chemoprevention in a single directly observed dose. Alternative medications are being explored, but from the behavioral intervention perspective, the low cost and simplicity afforded by SP is ideal.

The IPTp strategy had been modified a decade ago from requiring 2 doses, to monthly doses from the second trimester onwards because of parasite resistance or what is also termed drug tolerance by the parasite. Tolerance implies that the drug may still work, but at higher or more frequent doses. Such changes have cost and behavior change implications. Many country reports from the Malaria Indicator Surveys show an expected drop-off in uptake of SP between the first and third doses. For example in the 2021 Nigeria MIS IPTp1 uptake was 58%, while IPTp3 had reduced to 31%.

A related problem in Nigeria is the ubiquitous availability of SP in medicine shops across the country in contrast to official policy limiting it to use in IPTp and SMC. The challenge is finding affordable and feasible alternative medicines for IPTp. In the meantime, we have not even reached coverage targets using SP nor fully achieved rollout of companion interventions such as the use of Insecticide Treated Nets. Much work is still needed to protect pregnant women and fetuses from the malaria induced problems of anemia, low-birth-weight, stillbirth, and more.

A related study from Cameroon: The occurrence of sub-microscopic P. falciparum parasites resistant to SP and intense malaria transmission poses persistent risk of malaria infection during pregnancy in the area. ITN usage and 
monitoring spread of resistance are critical.

https://malariajournal.biomedcentral.com/articles/10.1186/s12936-023-04485-7

Abigail Arthur has contributed this posting to the Blog site for the JHU site for the course Social and Behavioral Foundations of Primary Health Care. Antibiotics are designed after years of research to determine which specific organisms they target, and at which doses they are effective. Hence, they must be used with strict adherence to prescription instructions to ensure maximum effectiveness. Unfortunately, there is a trend here in Lagos showing the gross misuse of antibiotics. Adapted from https://www.downtoearth.org.in/news/health/antibiotic-resistance-nigeria-stares-at-a-major-catastrophe-68915 The factors driving this phenomenon range from the misconceptions and practices of individuals and their contacts to factors associated with the communities and institutions within, same as well as the policies governing both. In Lagos, much of the misuse is fostered by extremely easy access to antibiotic medications aided by poorly implemented drug regulation policies. For instance, in 2005, there were 100 times more basic drug stores (patent and proprietary medicine vendors) than licensed pharmacy shops in Nigeria. ? While the operators of these basic drug stores have very little to no pharmaceutical knowledge, they are the first point of call for medications in the community.

The effect?

The next time you use the red and black tablet(ampicillin) for a skin infection, or an upper respiratory tract infection, it may not work due to the resistance built by microbes to these abused antimicrobials. ? Antimicrobial resistance (AMR) leads make treatments dear as newer generation (and pricier!) medication is then needed. Unfortunately, AMR can also lead to fatalities.

The way forward:

Antimicrobial Stewardship Programs (AMS) instituted by the Ministry of Health was implemented across only 6 health facilities in Lagos state in 2021. ? Our focus of advocacy is to encourage policy makers to consider antimicrobial resistance as an upcoming emergency following the progressive misuse of antimicrobials in the country. We call for proper control on the sale and advertisement of antimicrobials, an improvement in the patient to prescriber ratio and a strengthening of the Antimicrobial Stewardship Program already in place.

The search for adjunctive therapy to aid in recovery from cerebral malaria is explored in Malaria Journal. A faster acting crystalline form of an insecticide is studied. In Nigeria the National Malaria Elimination Program advocates for equal footing with COVID-19 action. Links to full stories and abstracts are found below.

Dimethyl fumarate reduces TNF and Plasmodium falciparum induced brain endothelium activation in vitro

Neida K. Mita-Mendoza, and colleagues studied Cerebral malaria (CM) which is associated with morbidity and mortality despite the use of potent anti-malarial agents. Brain endothelial cell activation and dysfunction from oxidative and inflammatory host responses and products released by Plasmodium falciparum-infected erythrocytes (IE), are likely the major contributors to the encephalopathy, seizures, and brain swelling that are associated with CM. The development of adjunctive therapy to reduce the pathological consequences of host response pathways could improve outcomes.

To accurately reflect clinically relevant parasite biology a unique panel of parasite isolates derived from patients with stringently defined CM was developed. The effect of TNF and these parasite lines on primary human brain microvascular endothelial cell (HBMVEC) activation in an in vitro co-culture model was tested. HBMVEC activation was measured by cellular release of IL6 and nuclear translocation of NF?B. The transcriptional and functional effects of dimethyl fumarate (DMF), an FDA approved drug which induces the NRF2 pathway, on host and parasite induced HBMVEC activation was characterized. In addition, the effect of DMF on parasite binding to TNF stimulated HBMVEC in a semi-static binding assay was examined.

The findings provide evidence that targeting the nuclear factor E2-related factor 2 ( NRF2) pathway in tumour necrosis factor (TNF) and parasite activated human brain microvascular endothelial cell (HBMVEC) mediates multiple protective pathways and may represent a novel adjunctive therapy to improve infection outcomes in CM.

Fast-acting insecticide polymorph could boost malaria-control efforts

Chemistry World reports on a faster-acting version of a common insecticide could boost malaria control efforts. The new crystalline form of deltamethrin is absorbed by mosquitoes 12 times faster than commercial forms and could help to limit malaria transmission despite growing rates of insecticide resistance.

Microcystals of contact insecticides like deltamethrin are crucial ingredients in indoor sprays and treated bed nets used to combat malaria-spreading mosquitoes. But many mosquito populations are developing resistance to these compounds, which is harming efforts to control the disease.

Treat Malaria as National Health Emergency, NEMP tells Federal Government

The Coordinator of National Malaria Elimination Programme (NEMP), has asked the federal government to tackle malaria as a national health emergency in the same manner COVID-19 pandemic is being handled. Against the background of increasing poverty in the country, Civil Society in Malaria Control, Immunisation and Nutrition (ACOMIN) has said there is a direct linkage between malaria scourge and the level of poverty in communities.

Speaking at a meeting with the civil society group involved in anti malaria advocacy, Coordinator of NEMP, said the current level of funding of the health sector by government is unacceptably low.

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.

Leading off our news update are findings from eastern Kenya about a genetic blood grouping that may help prevent malaria. While government leaders in the Asia-Pacific region committed to eliminating malaria, a report from the Gates Foundation explains how COVID-19 has set progress back and without new tools it may take more than 25 years to rid the world of the disease. In that light, Novartis is staking its finances on being able to make medicines that will be accessible and fight malaria. More details and the Gates video can be seen by clicking the links below.

How Dantu Blood Group protects against malaria

The secret of how the Dantu genetic blood variant helps to protect against malaria has been revealed for the first time by scientists at the Wellcome Sanger Institute, the University of Cambridge and the KEMRI-Wellcome Trust Research Programme, Kenya. The team found that red blood cells in people with the rare Dantu blood variant have a higher surface tension that prevents them from being invaded by the world’s deadliest malaria parasite, Plasmodium falciparum. The findings were published in Nature and could be significant in the wider battle against malaria.

In 2017, researchers discovered that the rare Dantu blood variant, which is found regularly only in parts of East Africa, provides some degree of protection against severe malaria. The intention behind this new study was to explain why. Red blood cell samples were collected from 42 healthy children in Kilifi, Kenya, who had either one, two or zero copies of the Dantu gene. The Dantu variant created cells with a higher surface tension—like a drum with a tighter skin. At a certain tension, malaria parasites were no longer able to enter the cell.

Novartis ties bond sale to malaria treatment access in sustainability push

Novartis raised 1.85 billion euros on Wednesday from the sale of a bond on which interest payments will rise if the drugmaker fails to expand access to medicines and programmes to combat malaria and leprosy in a number of developing countries.

Investors are increasingly pushing companies to improve their track record on environmental, social and governance (ESG) issues while sustainable investing grows in popularity, spurring an increase in sustainable debt issuance year after year. Novartis’ bond is only the third issue to date to link payments to creditors to company-wide sustainable development targets. By Yoruk Bahceli

Commitment to make Asia Pacific a malaria free region

Government officials from across Asia Pacific have come together during virtual Malaria Week 2020, to reaffirm their commitment to eliminating malaria and strengthening health systems to keep the region safe from health threats. Embracing the theme of “Inclusion. Integration. Innovation.”, officials called for increased collaboration and action to accelerate towards the goal of ending malaria in the region by 2030, at a time when major gains and regional progress are under threat due to disruptions caused by Covid-19.

It could take up to 25 years to eradicate malaria from Africa – Bill Gates

Bill Gates said: “Moving to malaria which is a very awful disease not just to the kids it kills but many kids whose brains are permanently damaged, the economic effects you have with malaria. If we don’t have new tools like vaccines or new ways of killing mosquitoes, it would probably take more than 25 years to get rid of malaria. If we get the new tools and they work, we think it can be done in under 20 years. So the malaria field is both trying to keep the number of deaths down, and we have to deal with the resistance that comes up, that the mosquitoes develop.”

Gates Foundation Report notes that, “We’ve been set back about 25 years in about 25 weeks.” Extreme poverty increased 7% because of COVID-19. In a video included in the Foundation’s report, Bill Gates explains how COVID-19 disrupts the fight against malaria.

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.

Various updates were found in newsletters and journal abstracts online today. These looked at mosquitoes – what attracts them to people, how ookinetes move in the midgut, and how perlite from volcanic rock may be a barrier repellent. Nigeria reports that there is no ACT resistance – so far.  And malaria partners join to coordinate actions in Uganda.  Click on links to read details.

Nigeria yet to detect resistance of malaria parasite to ACTs, says ministe

Contrary to reports that Africa has for the first time identified resistance strain of the malaria parasite to the drug of choice, Artemisinin Combination Therapy (ACT), the Minister of Health, Dr. Osagie Emmanuel Ehanire, on Monday said a study conducted in three states of the country showed there is no such phenomenon in Nigeria.  “However, we are still monitoring the situation. We insist that people should conduct a malaria test before using the drug of choice. This we hope will help prevent any kind of resistance of the malaria parasite to ACTs.”

Ministry of Health launches the Malaria Free Uganda Fund

Health Minister Dr Jane Ruth Aceng told journalists in Kampala today that the idea of having this new board was reached after realizing that different entities have been conducting the same malaria control related work. She said that the ministry resolved that mainstreaming responsibility will remove financial and operational bottlenecks that deter them from achieving set targets for elimination of the disease. The fund with a board of 11 members is chaired by Kenneth Wycliffe Mugisha of the Rotarian Malaria Partners-Uganda.

Volcanic Rock Yields a New Kind of Insecticide for Mosquitoes

Insecticide resistance to pesticides has become widespread in mosquito populations, making insecticides less effective over time. Therefore, there is an urgent need for insecticides with alternative modes of action. tested a material derived from volcanic rock, perlite, as a potential non-chemical insecticide against Anopheles gambiae, one of the primary mosquitoes that spreads malaria in Africa. In their new report published in August in the Journal of Medical Entomology, they show that perlite has encouraging potential as a mechanical insecticide. Perlite is believed to act by causing dehydration in the mosquitoes. read more…

Mosquitoes love pregnant, beer-drinking exercisers with Type O blood

Mosquitoes spread Zika, West Nile, Chikungunya, Dengue, and Malaria, resulting in 700 million illnesses a year and a million deaths. Even if you don’t get sick from a mosquito bite, the blood thinner they pump into your flesh before draining your blood causes swelling and itching. This article in Smithsonian Magazine lists the factors that make some people more tempting targets than others to mosquito bites. They include:

• Blood type: “One study found that in a controlled setting, mosquitoes landed on people with Type O blood nearly twice as often as those with Type A.”
• Carbon Dioxide: “people who simply exhale more of the gas over time—generally, larger people—have been shown to attract more mosquitoes than others.”
• Exercise: “mosquitoes find victims at closer range by smelling the lactic acid, uric acid, ammonia and other substances expelled via their sweat”
• Skin bacteria: “scientists found that having large amounts of a few types of bacteria made skin more appealing to mosquitoes”
• Beer: “Just a single 12-ounce bottle of beer can make you more attractive to the insects”
• Pregnancy: “pregnant people exhale about 21 percent more carbon dioxide and are on average about 1.26 degrees Fahrenheit warmer than others”
• Clothing color: “wearing colors that stand out (black, dark blue or red) may make you easier to find”
• Genetics: “underlying genetic factors are estimated to account for 85 percent of the variability between people in their attractiveness to mosquitoes”

Live In Vivo Imaging of Plasmodium Invasion of the Mosquito Midgut

Malaria is one of the most devastating parasitic diseases in humans and is transmitted by anopheline mosquitoes. The mosquito midgut is a critical barrier that Plasmodium parasites must overcome to complete their developmental cycle and be transmitted to a new host. Here, we developed a new strategy to visualize Plasmodium ookinetes as they traverse the mosquito midgut and to follow the response of damaged epithelial cells by imaging live mosquitoes. Understanding the spatial and temporal aspects of these interactions is critical when developing novel strategies to disrupt disease transmission.

Today we feature summaries and abstracts concerning Plasmodium malariae, P. knowlesi and monkey models for vaccine testing, clothianidin insecticide resistance, the mosquito immune system and drug interactions between medicines for malaria patients.

Some mosquitoes already have resistance to the latest weapon against malaria

By Munyaradzi Makoni: An insecticide about to be widely deployed inside African homes to combat malaria-carrying mosquitoes is already losing its punch. Two years ago, the World Health Organization (WHO) gave the green light for clothianidin, long used in agriculture to kill crop pests, to be added to the current mainstays of indoor mosquito control, which are losing their effectiveness as the insects develop resistance. Since then, many African countries have been laying plans to spray the walls of homes with the pesticide—it would represent the first new class of chemicals adopted for such use in decades—and looking anxiously for evidence of pre-existing resistance.

Now, scientists at Cameroon’s Centre for Research in Infectious Diseases (CRID) have found it. They recently sampled mosquitoes from rural and urban areas around Yaoundé, the capital, including two key malaria carriers. In one standard susceptibility assay, exposure to clothianidin for 1 hour killed 100% of Anopheles coluzzii. But in some A. gambiae samples as many as 55% of the mosquitoes survived, the group reported in a preprint posted 7 August on the bioRxiv preprint server.

Atlas of Malaria Mosquitoes’ Immune System Assembled

An international team of scientists led by investigators at the Wellcome Sanger Institute and the NIH has created the first cell atlas of mosquito immune cells to understand how the insects fight malaria, as well as other mosquito-borne infections. The mosquito host is essential for the malaria parasite to complete its lifecycle, so any disruption would dramatically reduce the transmission of one of the world’s deadliest diseases.
Findings from the new study—published recently in Science through an article titled “Mosquito cellular immunity at single-cell resolution“—discussed the discovery of new types of mosquito immune cells, including a rare cell type that could be involved in limiting malaria infection. The authors also identified molecular pathways implicated in controlling the malaria parasite.

Genetic analysis of the orthologous crt and mdr1 genes in Plasmodium malariae from Thailand and Myanmar

Plasmodium malariae is a widely spread but neglected human malaria parasite, which causes chronic infections. The observed polymorphisms in pmcrt and pmmdr1 genes are unlikely to affect protein function and unlikely related to chloroquine drug pressure. Similarly, the absence of pmmdr1 copy number variation suggests limited mefloquine drug pressure on the P. malariae parasite population, despite its long time use in Thailand for the treatment of falciparum malaria.

Quantification of Plasmodium knowlesi versus Plasmodium falciparum in the rhesus liver: implications for malaria vaccine studies in rhesus models

Rhesus macaques are valuable pre-clinical models for malaria vaccine development. The Plasmodium knowlesi/rhesus and Plasmodium falciparum/rhesus models are two established platforms for malaria vaccine testing… Detection of 18S rRNA in the liver following high dose intravenous PfSPZ confirmed that rhesus are modestly susceptible to wild-type P. falciparum sporozoites. However, comparison of 18S rRNA RT-PCR biomarker signal indicates that the P. falciparum liver burden was 3–5 logs lower than in PkSPZ-infected animals. Quantification of this difference in liver stage burden will help guide and interpret data from pre-clinical studies of live-attenuated sporozoite vaccines in rhesus models.

Potential drug–drug interactions associated with adverse clinical outcomes and abnormal laboratory findings in patients with malaria

Hospitalized patients with malaria often present with comorbidities or associated complications for which a variety of drugs are prescribed. Multiple drug therapy often leads to drug–drug interactions (DDIs). The following drug pairs reported the highest frequency of adverse events associated with the interactions; calcium containing products-ceftriaxone, isoniazid–rifampin, pyrazinamide–rifampin, isoniazid–acetaminophen, and ciprofloxacin–metronidazole.

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.

Aline Uwimana, Noella Umulisa, Meera Venkatesan, Eric S. Halsey, Tharcisse Munyaneza, Rafiki Madjid Habimana, Ryan Sandford, Leah F. Moriarty, Emily Piercefield, Zhiyong Zhou, Samaly Souza, Ira Goldman, Naomi Lucchi, Brian Ezema, Eldin Talundzic, Daniel Ngamije, Jean-Louis N Mangala, William Brieger, Venkatachalam Udhayakumar, and Aimable Mbituyumuremyi presented a poster on “Presence of k13 561H artemisinin resistance mutations in Plasmodium falciparum infections from Rwanda” at the 68th Annual Meeting of the American Society of Tropical Medicine and Hygiene. Their findings follow.

Artemisinin-based combination therapy (ACT) is the recommended first-line antimalarial for uncomplicated Plasmodium falciparum infection in Rwanda. With the emergence of artemisinin and partner drug resistance in the Greater Mekong sub-region, it is important to characterize the presence of polymorphisms in k13, a gene associated with artemisinin resistance, and in pfmdr1, a gene associated with susceptibility to partner drugs including lumefantrine.

To date, there have been sporadic reports of validated k13 markers in Africa. Adequate efficacy (94-97%) for the ACT artemether-lumefantrine (AL) was found in a therapeutic efficacy study (TES) conducted in three Rwandan sites (Masaka, Rukara and Bugarama) in 2018. TES clinical results are presented in poster LB-5134. Dried blood spots collected from the 2018 TES were characterized for artemisinin resistance-associated k13 molecular markers and 8 flanking microsatellites to assess genetic profile and diversity, along with mutations in pfmdr1.

Methods: DNA was isolated from day 0 and day of recurrence dried blood spots from a 2018 TES of AL conducted in 3 sites in Rwanda and analyzed by Sanger sequencing for resistance markers in the k13 and pfmdr1 genes.

Prevalence of k13 candidate and validated artemisinin resistance markers was calculated using day 0 samples. Presence of k13 markers post-treatment was determined using samples collected on the day of recurrence. 8 flanking microsatellite markers downstream and upstream of k13 were evaluated and compared with previously published results from samples from Thailand1.

Results of Prevalence of k13 561 were derived from HDNA from 219 of 228 day 0 samples and all 37 post-treatment samples were successfully isolated from dried blood spots. 26 of 219 day 0 samples showed presence of the 561H mutation in the k13 gene, a World Health Organization validated marker of artemisinin resistance (ref). 3 of the 26 were mixed infections with wild type (561R/H).

*WHO definitions2: Suspected endemic artemisinin resistance is defined as

• • ? 10% of patients with a half-life of the parasite clearance slope ? 5 hours after treatment with ACT or artesunate monotherapy; or
• • ? 5% of patients carrying k13 resistance-confirmed mutations; or
• • ? 10% of patients with persistent parasitaemia by microscopy at 72 hours
  Confirmed endemic artemisinin resistance is defined as
• • ? 5% of patients carrying k13 resistance-confirmed mutations, all of whom have been found to have either persistent parasitaemia by microscopy on day 3 or a half-life of the parasite clearance slope ? 5 hours after treatment

Additional k13 data found 8 of 37 post-treatment samples with k13 561H in 4 recrudescences (all also with 561H on day 0) and in 4 reinfections. Candidate k13 resistance marker 469F found in 3 day 0 samples (2 in Rukara, 1 in Bugarama) Candidate k13 resistance markers 441L and 449A found in 1 day 0 sample each (Masaka and Rukara, respectively)

In conclusion, k13 561H, a validated marker of artemisinin resistance, was found at a prevalence of 1-20% amongst 3 TES sites in Rwanda. This is the highest proportion of artemisinin resistance-confirmed k13 mutations reported to date in Africa. The overall efficacy of AL was high in all sites (>90%; see poster LB-5134). However, parasitemia on day 3, a proxy for delayed parasite clearance, ranged from 0-15% across sites. Together with the presence of k13 561H, our results indicate confirmed artemisinin resistance in one site, Masaka, and suspected resistance in another, Rukara.

Flanking microsatellites indicate that the k13 561H mutation likely arose locally as opposed to being introduced from Southeast Asia. k13 mutations are present against a high background prevalence of pfmdr1 N86 and D1246, associated with reduced susceptibility to lumefantrine4.

These results indicate that although AL remains an effective treatment of uncomplicated malaria in Rwanda, artemisinin resistance may be emerging. Continued monitoring and confirmation of suspected resistance is critical. Future studies will include an expansion of TES sites and frequent parasite sampling to assess parasite clearance rates, in addition to molecular analysis.

References

1. Talundzic et al 2015. Selection and Spread of Artemisinin-Resistant Alleles in Thailand Prior to the Global Artemisinin Resistance Containment Campaign PLoS Pathogens 11(4)
2. WHO 2017. Status report on artemisinin and ACT resistance
3. Ishengoma et al 2019. Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated malaria and prevalence of Pfk13 and Pfmdr1 polymorphisms after a decade of using artemisinin-based combination therapy in mainland Tanzania Malaria Journal 18(1):88.
4. Venkatesan et al 2014 . Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine. AJTMH 91(4)

Contact information: Dr. Aline Uwimana <aline.uwimana@rbc.gov.rw> and Dr. Meera Venkatesan <mvenkatesan@usaid.gov>

Affiliations: Malaria and Other Parasitic Diseases Division, Rwanda Biomedical Centre, Kigali, Rwanda; Maternal and Child Survival Program/JHPIEGO, Baltimore MD, USA; US President’s Malaria Initiative, Washington DC, USA; US President’s Malaria Initiative, Atlanta, Georgia, USA; Malaria Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, 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