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Chapter 1: Literature review 1.1 Malaria

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Malaria, of the genus Plasmodium, is caused by the protozoan parasites. Most of the transmission is through the bite of an infected female anopheline mosquito. More than 500 million people are affected with malaria each year, resulting in 1-2 million fatalities. Falciparum is responsible for the majority of malaria deaths. Pregnant women, children, and anyone who are immunocompromised have the highest rates of morbidity and mortality. Myalgias or arthralgia, malaise or weakness, headache, and chills are the most common symptoms. Microscopy, antigen detection, and polymerase chain reaction (PCR) are among the procedures used to detect malaria parasites. Malaria in pregnancy is a major cause of severe maternal anemia, low birth weight neonates, preterm delivery, and higher infant and maternal death, with primigravidae experiencing these issues more frequently than multigravidae. Chloroquine is the first-line drug for treating three so-called benign malaria, Plasmodium vivax, Plasmodiu...

Thushara Balasuriya

• Malaria is the most important parasitic disease of mankind. It is now confined to the tropical and subtropical areas of Asia, Africa, South and Central America. Even so, nearly half of the population of the world may be exposed to the risk of malaria. • Four different species of malaria parasites infecting man, • Plasmodium vivax, • P. malariae • P.falciparum • P.ovale o Two species, P.vivax and P.falciparum account for about 95 % of all malaria worldwide, the other two being of relatively minor importance. Vectors o Human malaria is transmitted by the female Anopheles mosquito. The male mosquito feeds exclusively on fruit juices, but the female needs at least two blood meals before the first batch of eggs can be laid.

this is for malaria basic knowledge

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Renu Tuteja

Dr. Gourab Biswas

Malaria has both socioeconomic and geo-ecological impact. The evidence of malaria incidences were documented about 2500 years before the birth of Christ and after that investigations are going onto fight against this evil fever. According to World Health Organization (WHO) more than 200 million populations are exposed to health risk by malaria parasite and hence imposed a burden to our society. This paper is a review of the journey of malaria researches over the globe which now becomes a subject of concern both for control and awareness of the disease.

melita jukić

Malaria is a severe disease caused by parasites of the genus Plasmodium, which is transmitted to humans by a bite of an infected female mosquito of the species Anopheles. Malaria remains the leading cause of mortality around the world, and early diagnosis and fast-acting treatment prevent unwanted outcomes. It is the most common disease in Africa and some countries of Asia, while in the developed world malaria occurs as imported from endemic areas. The sweet sagewort plant was used as early as the second century BC to treat malaria fever in China. Much later, quinine started being used as an antimalaria drug. A global battle against malaria started in 1955, and Croatia declared 1964 to be the year of eradication of malaria. The World Health Organization carries out a malaria control program on a global scale, focusing on local strengthening of primary health care, early diagnosis of the disease, timely treatment, and disease prevention. Globally, the burden of malaria is lower than ...

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savita pohekar

Introduction: Malaria is caused by the parasitic protozoan Plasmodium. It is a vector-borne disease which is transmitted from person to person via bites from infected mosquitoes. Following a mosquito bite the parasites multiply in the liver and subsequently infect red blood cells. It is a mosquito-borne illness. Fever or flu symptoms include shivering chills, headaches, and muscle pains. Anemia, jaundice, nausea, and diarrhea are some of the symptoms of malaria. Main Symptoms and Important Clinical Findings: A 24-year-old woman was admitted in. Acharya vinoba bhave rural hospital with chief complaint of stomach pain as her primary complaint. Then after several days Fever, pain, fatigue, headache occur. Several diagnostic evaluations done which shows total Red blood cells count: 4.8 million cu mm; white cell count: 11.810 cells mm3; lymphocytes: 11.2% platelets drop on smear, RBCs are moderated. The Main Diagnoses, Therapeutic Interventions, and Outcomes: 24 years old women admitted ...

SAFIYANU HAMISU

Malaria parasite and and their infection

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Prof. Ganesh D . Barkade

Millions of people die from the parasitic disease malaria each year. This illness is difficult to diagnose in a clinical environment and arises when the red blood cells in the blood are harmed. Malaria is caused by Plasmodium parasites, which are the main global cause of mortality and morbidity. Both in their hosts, the vertebrates, and their carriers, the mosquitoes, these parasites have a complicated life cycle.

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  • Published: 03 August 2017
  • Margaret A. Phillips 1 ,
  • Jeremy N. Burrows 2 ,
  • Christine Manyando 3 ,
  • Rob Hooft van Huijsduijnen 2 ,
  • Wesley C. Van Voorhis 4 &
  • Timothy N. C. Wells 2  

Nature Reviews Disease Primers volume  3 , Article number:  17050 ( 2017 ) Cite this article

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Malaria is caused in humans by five species of single-celled eukaryotic Plasmodium parasites (mainly Plasmodium falciparum and Plasmodium vivax ) that are transmitted by the bite of Anopheles spp. mosquitoes. Malaria remains one of the most serious infectious diseases; it threatens nearly half of the world's population and led to hundreds of thousands of deaths in 2015, predominantly among children in Africa. Malaria is managed through a combination of vector control approaches (such as insecticide spraying and the use of insecticide-treated bed nets) and drugs for both treatment and prevention. The widespread use of artemisinin-based combination therapies has contributed to substantial declines in the number of malaria-related deaths; however, the emergence of drug resistance threatens to reverse this progress. Advances in our understanding of the underlying molecular basis of pathogenesis have fuelled the development of new diagnostics, drugs and insecticides. Several new combination therapies are in clinical development that have efficacy against drug-resistant parasites and the potential to be used in single-dose regimens to improve compliance. This ambitious programme to eliminate malaria also includes new approaches that could yield malaria vaccines or novel vector control strategies. However, despite these achievements, a well-coordinated global effort on multiple fronts is needed if malaria elimination is to be achieved.

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Introduction

Malaria has had a profound effect on human lives for thousands of years and remains one of the most serious, life-threatening infectious diseases 1 – 3 . The disease is caused by protozoan pathogens of the Plasmodium spp.; Plasmodium falciparum and Plasmodium vivax , for which humans are the exclusive mammalian hosts, are the most common species and are responsible for the largest public health burden. Malaria is transmitted by the bite of Plasmodium spp.-infected female mosquitoes of the Anopheles genus 1 – 3 . During a blood meal, infected mosquitoes inject — along with their anticoagulating saliva — sporozoites, which are the infective, motile stage of Plasmodium spp. Sporozoites journey through the skin to the lymphatics and into hepatocytes in the liver ( Fig. 1 ). Inside the hepatocyte, a single sporozoite can generate tens of thousands of merozoites (the stage that results from multiple asexual fissions (schizogony) of a sporozoite within the body of the host), which are released into the bloodstream where they enter red blood cells to replicate (erythrocytic schizogony). A fraction of merozoites (those that are sexually committed) also differentiate and mature into male and female gametocytes, which is the stage that infects the mosquito host when it takes a blood meal 4 , 5 . The onset of clinical symptoms generally occurs 7–10 days after the initial mosquito bite. P. vivax and Plasmodium ovale also have dormant forms, called hypnozoites, which can emerge from the liver years after the initial infection 6 , leading to relapse if not treated properly.

figure 1

The mosquito vector transmits the Plasmodium spp. parasite in the sporozoite stage to the host during a blood meal. Within 30–60 minutes, sporozoites invade liver cells, where they replicate and divide as merozoites. The infected liver cell ruptures, releasing the merozoites into the bloodstream, where they invade red blood cells and begin the asexual reproductive stage, which is the symptomatic stage of the disease. Symptoms develop 4–8 days after the initial red blood cell invasion. The replication cycle of the merozoites within the red blood cells lasts 36–72 hours (from red blood cell invasion to haemolysis). Thus, in synchronous infections (infections that originate from a single infectious bite), fever occurs every 36–72 hours, when the infected red blood cells lyse and release endotoxins en masse 70 – 72 . Plasmodium vivax and Plasmodium ovale can also enter a dormant state in the liver, the hypnozoite. Merozoites released from red blood cells can invade other red blood cells and continue to replicate, or in some cases, they differentiate into male or female gametocytes 4 , 5 . The transcription factor AP2-G (not shown) has been shown to regulate the commitment to gametocytogenesis. Gametocytes concentrate in skin capillaries and are then taken up by the mosquito vector in another blood meal. In the gut of the mosquito, each male gametocyte produces eight microgametes after three rounds of mitosis; the female gametocyte matures into a macrogamete. Male microgametes are motile forms with flagellae and seek the female macrogamete. The male and female gametocytes fuse, forming a diploid zygote, which elongates into an ookinete; this motile form exits from the lumen of the gut across the epithelium 254 as an oocyst. Oocysts undergo cycles of replication and form sporozoites, which move from the abdomen of the mosquito to the salivary glands. Thus, 7–10 days after the mosquito feeds on blood containing gametocytes, it may be ‘armed’ and able to infect another human with Plasmodium spp. with her bite. Drugs that prevent Plasmodium spp. invasion or proliferation in the liver have prophylactic activity, drugs that block the red blood cell stage are required for the treatment of the symptomatic phase of the disease, and compounds that inhibit the formation of gametocytes or their development in the mosquito (including drugs that kill mosquitoes feeding on blood) are transmission-blocking agents. *Merozoite invasion of red blood cells can be delayed by months or years in case of hypnozoites. ‡ The number of days until symptoms are evident. § The duration of gametogenesis differs by species. || The maturation of sporozoites in the gut of the mosquito is highly temperature-dependent. Adapted with permission from Ref. 255 , Macmillan Publishers Ltd.

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The consequences of Plasmodium spp. infection vary in severity depending on the species and on host factors, including the level of host immunity, which is linked to the past extent of parasite exposure 7 , 8 . Malaria is usually classified as asymptomatic, uncomplicated or severe (complicated) 9 ( Box 1 ). Typical initial symptoms are low-grade fever, shaking chills, muscle aches and, in children, digestive symptoms. These symptoms can present suddenly (paroxysms), and then progress to drenching sweats, high fever and exhaustion. Malaria paroxysmal symptoms manifest after the haemolysis of Plasmodium spp.-invaded red blood cells. Severe malaria is often fatal, and presents with severe anaemia and various manifestations of multi-organ damage, which can include cerebral malaria 8 ( Box 1 ). Severe malaria complications are due to microvascular obstruction caused by the presence of red blood cell-stage parasites in capillaries 8 , 10 , 11 . This Primer focuses on our understanding of malaria pathology in the context of parasite and vector biology, progress in diagnostics and new treatments (drugs and vaccines), chemoprotection and chemoprevention.

Box 1: Malaria key terms

Asymptomatic malaria: can be caused by all Plasmodium spp.; the patient has circulating parasites but no symptoms.

Uncomplicated malaria: can be caused by all Plasmodium spp. Symptoms are nonspecific and can include fever, moderate-to-severe shaking chills, profuse sweating, headache, nausea, vomiting, diarrhoea and anaemia, with no clinical or laboratory findings of severe organ dysfunction.

Severe (complicated) malaria: usually caused by infection with Plasmodium falciparum , although less frequently it can also be caused by Plasmodium vivax or Plasmodium knowlesi . Complications include severe anaemia and end-organ damage, including coma (cerebral malaria), pulmonary complications (for example, oedema and hyperpnoeic syndrome 228 ), and hypoglycaemia or acute kidney injury. Severe malaria is often associated with hyperparasitaemia and is associated with increased mortality.

Placental malaria: parasites are present in the placenta, leading to poor outcomes for the fetus and possibly for the mother.

Epidemiology

Human malaria parasites are transmitted exclusively by ∼ 40 species of the mosquito genus Anopheles 12 . During Anopheles spp. mating, males transfer high levels of the steroid hormone 20-hydroxyecdysone to the females, and the presence of this hormone has been associated with favourable conditions for Plasmodium spp. development 13 . Malaria-competent Anopheles spp. are abundant and distributed all over the globe, including the Arctic. However, the efficacy of malaria transmission depends on the vector species and, therefore, varies considerably worldwide; for example, in tropical Africa, Anopheles gambiae is a major and highly efficient vector 14 . The first WHO Global Malaria Eradication Programme (1955–1972) involved, in addition to chloroquine-based treatments, large-scale insecticide campaigns using dichlorodiphenyltrichloroethane (DDT) 15 . This strategy was quite effective against P. falciparum ; although the mosquitoes gradually repopulated DDT-treated areas (because they developed resistance to the insecticide, and the use of DDT itself waned owing to its costs and increasing environmental concerns), these areas have often remained malaria-free and in some cases still are. More-selective vector control approaches, such as the use of insecticide-treated bed nets and indoor residual spraying, have eliminated malaria from several areas (see Diagnosis, screening and prevention, below). However, mosquito resistance to insecticides is a growing concern. Of the 78 countries that monitor mosquito resistance to insecticides, 60 have reported resistance to one or more insecticides since 2010 (Ref. 16 ).

The parasite

Plasmodium spp. are single-celled eukaryotic organisms 17 – 19 that belong to the phylum Apicomplexa, which is named for the apical complex that is involved in host cell invasion. A discussion of the parasite genome and the genetic approaches used to study parasite biology is provided in Box 2 . Of the five human-infective Plasmodium spp., P. falciparum causes the bulk of malaria-associated morbidity and mortality in sub-Saharan Africa, with mortality peaking in the late 1990s at over 1 million deaths annually in the continent 20 ( Fig. 2 ). P. falciparum is associated with severe malaria and complications in pregnancy ( Box 3 ); most malaria-related deaths are associated with this species, which kills ∼ 1,200 African children <5 years of age each day 21 . However, P. falciparum is also found in malarious tropical areas around the world. P. vivax is found in malarious tropical and temperate areas, primarily Southeast Asia, Ethopia and South America, and generally accounts for the majority of malaria cases in Central and South America and in temperate climates. This distribution can be explained by the fact that P. vivax can survive in climatically unfavourable regions and can stay dormant in a hypnozoite form in its human host's liver for many years. Furthermore, many Africans are negative for the Duffy antigen (also known as atypical chemokine receptor 1) on the surface of red blood cells, and this genotype provides protection from P. vivax malaria, as it makes it more difficult for P. vivax to bind to and penetrate red blood cells 22 . However, some cases of P. vivax transmission to Duffy antigen-negative individuals have been reported, which suggests that alternative mechanisms of invasion might be present in some strains, and this might portend the escalation of P. vivax malaria to Africa 23 , 24 . P. ovale is also found in Africa and Asia, but is especially prevalent in West Africa. Two sympatric species exist: P.o. curtisi and P.o. wallikeri 25 . Plasmodium malariae — which can be found worldwide but is especially prevalent in West Africa — causes the mildest infections, although it has been associated with splenomegaly or renal damage upon chronic infection. Plasmodium knowlesi — which was initially considered as a parasite of non-human primates — can not only cause malaria in humans but can also lead to severe and even fatal malaria complications 26 , 27 . The reasons for the emergence of P. knowlesi in humans are not yet fully understood but are possibly linked to land-use changes that have brought humans into close contact with P. knowlesi -infected mosquitoes 28 . Regardless, the possible recent emergence of a form of malaria as a zoonosis poses obvious complications for elimination. In addition, co-infections between P. falciparum and P. vivax have been well-documented and have been reported to occur in up to 10–30% of patients living in areas where both parasites are prevalent 29 , 30 . Mixed infections can also include other species such as P. ovale and P. malariae , and newer diagnostic methods are being developed that will enable better assessment of the frequency and distribution of these types of co-infection (for example, Ref. 31 ).

figure 2

The most-deadly malaria parasite, Plasmodium falciparum , is only found in tropical areas because its gametocytes require 10–18 days at a temperature of >21°C to mate and mature into infectious sporozoites inside the vector 256 . This development timeline is only possible in hot, tropical conditions; where the ambient temperature is lower, mosquitoes can still propagate, but sporozoite maturation is slowed down and, therefore, incomplete, and parasites perish without progeny when the mosquitoes die. Thus, P. falciparum is quite temperature-sensitive; a global temperature rise of 2–3 °C might result in an additional 5% of the world population (that is, several hundred million people) being exposed to malaria 257 . Of note, Plasmodium vivax and Plasmodium ovale can develop in mosquitoes at ambient temperatures as low as 16 °C. The abilities of these parasites to propagate at subtropical temperatures and to remain in the hypnozoite state in the liver are likely to explain their ability to survive dry or cold seasons, and the broader global distribution of these parasites 258 . Countries coded ‘not applicable’ in the Figure were not separately surveyed. Figure based on data from Ref. 16 , WHO.

Box 2: The Plasmodium spp. genome and genomic tools for understanding gene function

Characteristics of the Plasmodium spp. genome

Each haploid genome comprises 23 Mb, which encode the programme for the complex life cycle of the parasite within ∼ 5,500 genes 17 – 19 .

Many genes encode proteins that have similarities to host proteins, many are novel, and many (approximately half) remain annotated as genes with hypothetical or of unknown function.

The Plasmodium spp. genome includes an essential plastid, the apicoplast, which is derived from two sequential endosymbiotic events, and encodes genes from both plant (red algal) and bacterial (cyanobacterium) origin 229 . The bacterial origin of some enzymes encoded by the plastid makes Plasmodium spp. sensitive to some antibacterial agents, whereas the plant-like pathways can be targeted by some herbicides. This plastid is one source of genes that differ from the host and that have been considered as potential drug targets.

Gene transcription across the Plasmodium spp. intra-red blood cell life cycle follows a preprogrammed cyclic cascade during which most genes are expressed at peak levels only once per life cycle 230 – 232 . Genes that encode cell surface proteins involved in host–parasite interactions are the exception.

Gene expression patterns have been reported to lack responses to perturbations. Minimal changes were observed after treatment with antifolates and chloroquine; however, larger changes have been observed for other drug classes 233 , 234 . Species-specific differences in transcription have been observed that seem to be linked to the mammalian host 235 .

Ribosome profiling has demonstrated that transcription and translation are tightly coupled for 90% of genes 236 . Exceptions of translationally upregulated genes are typically found for proteins involved in merozoite egress and invasion.

Epigenetic mechanisms to control gene expression include post-translational histone modifications (methylation and acetylation of the amino terminus are the best-characterized). Many of these modifications have been linked to parasite development 63 , 237 .

Genomic tools

Gene knockouts are possible, but RNA interference-mediated knockdown mechanisms do not function in Plasmodium spp. 238 , 239 .

Regulated RNA aptamer-based approaches have led to methods that enable gene knockouts to be functionally rescued; these methods are key for studying essential genes 238 , 239 .

CRISPR–Cas9-directed genome editing has greatly facilitated the genetic manipulation of Plasmodium falciparum 238 , 239 .

Barcoded mutant Plasmodium berghei libraries have been developed to screen for competitive fitness across tens of mutants in a single mouse 240 .

The in vitro selection of drug-resistant mutant parasites followed by whole-genome sequencing has also become a well-established method for revealing candidate drug targets 241 .

Metabolomics approaches facilitate the understanding of Plasmodium spp. biology, and have been used to profile several antimalarial compounds that have both known and unknown mechanisms of action 242 .

Box 3: Malaria and pregnancy

Pregnant women are more susceptible to Plasmodium spp. infection, particularly in their first pregnancy, as the mother-to-be has not yet acquired immunity to parasites that express the protein variant surface antigen 2-CSA (VAR2CSA) 35 . VAR2CSA on the surface of infected red blood cells facilitates adhesion to chondroitin sulfate A (which is part of placental proteoglycans), leading to red blood cell sequestration in the placenta 7 , 64 . The risk of placental malaria is reduced in multigravid women from endemic areas, who generally have antibodies against VAR2CSA 65 – 67 .

Malaria during pregnancy leads to increased risks to the mother and fetus 36 , 243 . Most studies have focused on sub-Saharan Africa; however, pregnancy-related risks are a problem throughout the world, including in Latin America, where Plasmodium vivax is the dominant causative agent 244 .

Placental malaria might be asymptomatic or clinically mild, but it also leads to an increased risk of death for both the fetus and the mother. It predisposes to miscarriage, stillbirth, preterm delivery and babies with low birth weight whose quality of life will probably be poor because of cognitive, mobility, self-care and sensation limitations; such babies also have a high mortality rate 36 , 243 .

Intermittent preventive treatment with sulfadoxine–pyrimethamine in endemic regions is recommended and is generally administered at each antenatal visit following quickening 108 , although the emergence of resistance is threatening its efficacy 245 .

Treatments for pregnant women must take into account the availability of safety data for the fetus. As a consequence, newer treatments require time to obtain sufficient confirmation of their tolerability in the different trimesters. The WHO recommends quinine sulfate and clindamycin in the first trimester. One study has shown that artemisinin derivatives provide comparable safety to quinine 246 , but, at the time of publication, the results of this study have not yet been incorporated into the WHO guidelines. In the second or third trimester, the WHO recommends artemisinin-based combination therapies 108 .

The treatment of pregnant women with P. vivax , Plasmodium ovale or Plasmodium malariae infection can also include chloroquine, unless resistance is suspected 108 . Women who are at a high risk of relapse can be given weekly chloroquine chemoprophylaxis until after delivery. Follow-up therapy with primaquine against P. vivax and P. ovale hypnozoites is not thought to be safe during pregnancy.

The disease

Malaria remains a major burden to people residing in resource-limited areas in Africa, Asia and Central and South America ( Fig. 2 ). An estimated 214 million cases of malaria occurred in 2015 (Ref. 16 ). Africa bears the brunt of the burden, with 88% of the cases, followed by Southeast Asia (10%), the eastern Mediterranean region (2%) and Central and South America (<1%). Malaria continues to kill over three-times as many people as all armed conflicts; in 2015, there were an estimated 438,000 (Ref. 16 ) — 631,000 (Ref. 20 ) deaths resulting from malaria, compared with an estimated 167,000 deaths due to armed conflicts 32 , 33 . In areas of continuous transmission of malaria, children <5 years of age and the fetuses of infected pregnant women experience the most morbidity and mortality from the disease. Children >6 months of age are particularly susceptible because they have lost their maternal antibodies but have not yet developed protective immunity. In fact, adults and children >5 years of age who live in regions of year-round P. falciparum transmission develop a partial protective immunity owing to repeated exposure to the parasite. There is evidence that immunity against P. vivax is acquired more quickly 34 . Individuals with low protective immunity against P. falciparum are particularly vulnerable to severe malaria. Severe malaria occurs in only 1% of infections in African children and is more common in patients who lack strong immune protection (for example, individuals who live in low-transmission settings, children <5 years of age and naive hosts). Severe malaria is deadly in 10% of children and 20% of adults 7 . Pregnant women are more susceptible to Plasmodium spp. infection because the placenta itself selects for the emergence of parasites that express receptors that recognize the placental vasculature; these receptors are antigens to which pregnant women have not yet become partially immune 7 ( Box 3 ). This vulnerability increases the risk of miscarriage; parasitaemia in the placenta can have adverse effects on the fetus 35 – 37 ( Box 3 ).

Co-infection of Plasmodium spp. with other pathogens — including HIV, Mycobacterium tuberculosis and helminths — is common. HIV-infected adults are at an increased risk of severe malaria and death 38 . The overall prevalence of helminth infection is very high (>50% of the population) in malaria-endemic regions and is associated with increased malaria parasitaemia 39 . Surprisingly, naturally occurring iron deficiency and anaemia protect against severe malaria, which was an unexpected finding 40 , as numerous clinical studies have aimed to fortify children and prevent anaemia by distributing iron supplements 41 .

From 2000 to 2015, the incidence of malaria fell by 37% and the malaria mortality rate fell by 60% globally 16 . The WHO attributes much of this reduction of malaria-associated morbidity and mortality to the scale-up of three interventions: insecticide-treated bed nets (69% of the reduction), artemisinin-based combination therapies (ACTs; 21%) and indoor residual insecticide spraying (10%) 16 (see Diagnosis, screening and prevention, below). Until ACT was introduced, progress in malaria control in most malarious countries was threatened or reversed by the nearly worldwide emergence of chloroquine-resistant and sulfadoxine–pyrimethamine-resistant P. falciparum strains and, more recently, of other resistant Plasmodium spp. ACT has become the antimalarial medicine of choice in most malarious areas, and demonstrates rapid parasite clearance, superior efficacy (compared with other clinically approved drugs) and >98% cure rates (typically defined as the percentage of patients who remain malaria-free for 28 days; re-infection events do not count as a recurrence). ACTs achieve these results even in strains that are resistant to older antimalarials, effectively turning the tide against antimalarial drug resistance. However, the emergence of artemisinin-resistant strains in Southeast Asia threatens the usefulness of ACTs 42 – 45 (see Drug resistance, below).

Mechanisms/pathophysiology

The red blood cell stage.

As previously mentioned, the red blood cell stage of Plasmodium spp. infection is the cause of symptomatic malaria, as red blood cells are the site of abundant parasite replication.

Invasion . Plasmodium spp. parasites gain entry into the red blood cell through specific ligand–receptor interactions mediated by proteins on the surface of the parasite that interact with receptors on the host erythrocyte (mature red blood cell) or reticulocyte (immature red blood cell) 46 ( Fig. 3 ). Whereas P. falciparum can invade and replicate in erythrocytes and reticulocytes, P. vivax and other species predominantly invade reticulocytes, which are less abundant than erythrocytes 47 . Most of the parasite erythrocyte-binding proteins or reticulocyte-binding proteins that have been associated with invasion are redundant or are expressed as a family of variant forms; however, for P. falciparum , two essential red blood cell receptors (basigin and complement decay-accelerating factor (also known as CD55)) have been identified ( Fig. 3 ).

figure 3

Invasion occurs through a multistep process 259 . During pre-invasion, low-affinity contacts are formed with the red blood cell membrane. Reorientation of the merozoite is necessary to enable close contact between parasite ligands and host cell receptors, and this is then followed by tight junction formation. In Plasmodium falciparum , a forward genetic screen has shown that complement decay-accelerating factor (not shown) on the host red blood cell is essential for the invasion of all P. falciparum strains 260 . The interaction of a complex of P. falciparum proteins (reticulocyte-binding protein homologue 5 (PfRH5), PfRH5-interacting protein (PfRipr) and cysteine-rich protective antigen (PfCyRPA)) with basigin on the red blood cell surface is also essential for the invasion in all strains 261 , 262 . PfRH5 has been studied as a potential vaccine candidate 46 , and antibodies against basigin have been considered as a potential therapeutic strategy 263 . During the PfRH5–PfRipr–PfCyRPA–basigin binding step, an opening forms between the parasite and the red blood cell, and this triggers Ca 2+ release and enables parasite-released proteins to be inserted into the red blood cell membrane. These proteins are secreted from the micronemes (the small secretory organelles that cluster at the apical end of the merozoite) and from the neck of the rhoptries, and include rhoptry neck protein 2 (PfRON2). Binding between PfRON2 and apical membrane antigen 1 (PfAMA1) on the merozoite surface is required to mediate tight junction formation before the internalization process 264 , and PfAMA1 is also being evaluated as a vaccine candidate 265 . Parasite replication within the red blood cell requires the synthesis of DNA, which can be blocked by several antimalarials: pyrimethamine (PYR), P218 and cycloguanil target P. falciparum dihydrofolate reductase (PfDHFR) 266 , and atovaquone (ATO) blocks pyrimidine biosynthesis by inhibiting the expression of the mitochondrial gene pfcytb (which encodes P. falciparum cytochrome b ) and by preventing the formation of oxidized coenzyme Q, which is needed to enable the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (PfDHODH) to perform its reaction within the mitochondria 50 . The phase II clinical candidate DSM265 also blocks pyrimidine biosynthesis by directly inhibiting PfDHODH 186 . In addition to DNA synthesis, other processes can be targeted by antimalarial drugs. Chloroquine (CHQ) inhibits haem polymerization in the food vacuole 52 but can be expelled from this compartment by the P. falciparum chloroquine-resistance transporter (PfCRT) 267 . The phase II clinical candidate KAE609 and the preclinical candidate SJ(557)733 both inhibit P. falciparum p-type ATPase 4 (PfATP4), which is required for Na + homeostasis during nutrient acquisition 57 , 183 , 184 . The phase I clinical candidate MMV(390)048 (Ref. 191 ) inhibits P. falciparum phosphatidylinositol 4-kinase (PfPI(4)K), which is required for the generation of transport vesicles that are needed to promote membrane alterations during ingression 58 . Hb, haemoglobin.

Replication . Once Plasmodium spp. gain entry into the red blood cell, they export hundreds of proteins into the host cell cytoplasm and cell surface that modulate the acquisition of nutrients, cell adhesion and sequestration in tissues, and pathogenesis 3 , 48 , 49 . Molecular and cell biology approaches are expanding our understanding of the molecular machinery that is required for the export, as well as the identification and function of the exported proteins.

In the red blood cell, Plasmodium spp. replicate rapidly, and during symptomatic disease the parasites may replicate exponentially to >10 12 parasites per patient. This rapid growth requires sustained pools of nucleotides for the synthesis of DNA and RNA, and as a consequence, many antimalarials target pyrimidine biosynthesis 50 ( Fig. 3 ). Plasmodium spp. are auxotrophic for all of the amino acids they need (that is, they must acquire all of these from food because they cannot synthesize them from precursors). Haemoglobin digestion (in a specialized food vacuole) supplies all amino acids except isoleucine, which must be obtained from other host cell components 51 . Haemoglobin digestion also releases haem, which is toxic to the parasite and, therefore, is polymerized into haemozoin (often called malaria pigment, which is visible as a blue pigment under light microscopy), which is an insoluble crystal that sequesters the toxic metabolite 52 . How haem polymerization is facilitated by the parasite remains unclear. A complex of several proteases and haem detoxification protein (HDP) have been identified in the food vacuole; follow-up in vitro studies have shown that components of this complex (for example, falcipain 2, HDP and lipids) were able to catalyse the conversion of haem into haemozoin 53 . The importance of understanding this mechanism is highlighted by the finding that chloroquine and other antimalarials act by inhibiting haem polymerization 54 ( Fig. 3 ). There is also evidence that the iron (haem-bound or free) liberated in the food vacuole during haemoglobin digestion plays a part in activating the toxicity to the parasite of artemisinin derivatives 42 .

Nutrient uptake by the parasite is coupled to the detrimental accumulation of Na + ; however, the parasite expresses an essential plasma membrane Na + export pump (the cation ATPase P. falciparum p-type ATPase 4 (PfATP4)) that can maintain Na + homeostasis 55 – 57 ( Fig. 3 ). The remodelling of the plasma membrane (membrane ingression) to generate daughter merozoites in the late schizont stage requires P. falciparum phosphatidylinositol 4-kinase (PfPI(4)K) 58 . Both PfPI(4)K and PfATP4 are targets of new drugs that are under development ( Fig. 3 ).

Immune evasion and host immunity

Malaria parasites first encounter the host immune system when sporozoites are injected in the skin (measured to be ∼ 15 per mosquito bite in one study 59 ), where they may be phagocytosed by dendritic cells for antigen presentation in the lymph node draining the skin inoculation site 60 . The chances of transmission are increased when the host is bitten by mosquitoes that carry a larger number of sporozoites, despite the fact that the number of sporozoites that can simultaneously pass through the mosquito's proximal duct is limited by the duct diameter 61 . Sporozoites encounter several other effectors of the immune system, and how a minority of them can reach the liver and infect the hepatocytes is not well understood. Immune evasion in the liver could be in part explained by the ability of sporozoites to suppress the function of Kupffer cells (also known as stellate macrophages, which are the resident macrophages of the liver) and repress the expression of genes that encode MHC class I molecules 62 . Our understanding of the host immunity associated with the red blood cell stage is more complete. Virulence genes in Plasmodium spp. are part of large expanded multigene families that are found in specialized (for example, subtelomeric) regions of the chromosomes 7 , 63 , 64 . These gene families (for example, var genes in P. falciparum ) encode variants of cell surface proteins that function in immune evasion through antigenic variation and also are involved in mediating cytoadherence of infected red blood cells to endothelial cells, which leads to red blood cell sequestration in tissues.

Malaria disease severity — in terms of both parasite burden and the risk of complicated malaria — is dependent on the levels of protective immunity acquired by the human host 65 – 67 , which can help to decrease the severity of symptoms and reduce the risk of severe malaria. Immunity is thought to result from circulating IgG antibodies against surface proteins on sporozoites (thereby blocking hepatocyte invasion) and merozoites (thereby blocking red blood cell invasion). In high-transmission areas where malaria is prevalent year-round, adults develop partially protective immunity. Young infants (<6 months of age) are also afforded some protection, probably from the antibodies acquired from their mother, whereas children from 6 months to 5 years of age have the lowest levels of protective immunity and are the most susceptible to developing high parasitaemia with risks for complications and death (for example, see the study conducted in Kilifi, Kenya 68 ). In low-transmission areas or areas that have seasonal malaria, individuals develop lower levels of protective immunity and typically have worse symptomatic malaria upon infection. This correlation between protective immunity and malaria severity poses a challenge for successful malaria treatment programmes; as the number of infections and the transmission rates decrease, increasing numbers of patients will lose protective immunity and become susceptible to severe disease. The re-introduction of malaria in areas that had been malaria-free for many years could be devastating in the short term and, therefore, well-organized surveillance is required.

Pathogenesis

The predominant pathogenic mechanism is the haemolysis of Plasmodium spp.-infected red blood cells, which release parasites and malaria endotoxin — understood to be a complex of haemozoin and parasite DNA, which trigger Toll-like receptor 9 (TLR9), a nucleotide-sensing receptor involved in the host immune response against pathogens 69 — that leads to high levels of tumour necrosis factor (TNF) production and to clinical symptoms such as fever 70 – 72 . In addition, the membrane of infected red blood cells stiffens, and this loss of deformability contributes to the obstruction of capillaries, which has life-threatening consequences in severe malaria when vital organs are affected 73 .

Parasite factors that influence disease severity . Disease severity and pathogenesis are linked to surface proteins that are expressed by the parasite. In P. falciparum , a major surface antigen is encoded by the var gene family, which contains ∼ 60 members 7 , 11 , 63 , 64 . The majority of the var genes are classified into three subfamilies — A, B and C — on the basis of their genomic location and sequence: the B and C groups mediate binding to host cells via CD36 (also known as platelet glycoprotein 4), whereas the A group genes mediate non-CD36 binding interactions that have been linked to severe malaria, including cerebral malaria 7 , 64 . The var genes encode P. falciparum erythrocyte membrane protein 1 (PfEMP1), with the B and C groups accounting for >80% of PfEMP1 variants. PfEMP1 is the major protein involved in cytoadherence and mediates the binding of infected erythrocytes to the endothelial vasculature. In cerebral malaria, A group PfEMP1 variants mediate the binding of infected erythrocytes to endothelial protein C receptor (EPCR) and intercellular adhesion molecule 1 (ICAM1) in the brain, causing pathology 8 , 11 , 74 , 75 . However, our knowledge of the host cell receptors that are involved in interactions with the infected erythrocytes is probably incomplete. For example, thrombin — which regulates blood coagulation via vitamin K-dependent protein C — can cleave PfEMP1, thereby reversing and preventing the endothelial binding of infected erythrocytes 74 . In pregnancy, the expression of a specific PfEMP1 variant, variant surface antigen 2-CSA (VAR2CSA) — which is not encoded by one of the three main subfamilies — leads to an increased risk of placental malaria 7 , 64 ( Box 3 ).

High parasitaemia levels also seem to correlate with poor outcomes 7 , 75 , and the circulating levels of P. falciparum histidine-rich protein 2 (which is encoded by pfhrp2 ) have been used as a biomarker of parasitaemia that predicts the risks for microvascular obstruction and severe disease 76 . The brain pathology in children with severe malaria has recently been described in detail 77 .

Additionally, P. vivax does not express the same family of var genes that have been found to be strongly associated with endothelium binding and tissue sequestration, which drives severe disease in P. falciparum , and the ability of P. vivax to only invade reticulocytes leads to lower parasite levels 7 .

Host traits that influence disease severity . Malaria has exerted a strong selection pressure on the evolution of the human genome 78 , 79 . Some haemoglobin-encoding alleles that in homozygous genotypes cause severe blood disorders (such as thalassaemia, the earliest described example, and sickle cell disease) have been positively selected in populations living in malaria-endemic areas because heterozygous genotypes protect against malaria 80 . Other inherited haemoglobin abnormalities (for example, mutations affecting haemoglobin C and haemoglobin E) can also provide protection against malaria 81 .

In addition, genetic polymorphisms that affect proteins expressed by red blood cells or that lead to enzyme deficiencies can also be protective against severe disease. The red blood cell Duffy antigen is a key receptor that mediates the invasion of P. vivax through interaction with the Duffy antigen-binding protein on the parasite surface 46 . The genetic inheritance of mutations in ACKR1 (which encodes the Duffy antigen) in Africa is credited with reducing the spread of P. vivax in this continent, although the finding of Duffy antigen-negative individuals who can be infected with P. vivax suggests that we still have an incomplete understanding of the factors involved in P. vivax invasion 82 , 83 . Glucose-6-phosphate dehydrogenase (G6PD) deficiency 78 , 79 provides protection against severe malaria through an unknown mechanism, at least in hemizygous males 84 , but unfortunately also leads to haemolytic anaemia in patients treated with primaquine, which is an 8-aminoquinoline antimalarial and the only agent currently approved for the treatment of latent (liver-stage) P. vivax malaria. The mode of action of primaquine, which is a prodrug, remains unknown.

The mechanisms of malaria protection in these varied genetic disorders have been widely studied 81 . Common findings include increased phagocytosis and elimination by the spleen of infected mutant erythrocytes, which reduces parasitaemia; reduced parasite invasion of mutant red blood cells; reduced intracellular growth rates; and reduced cytoadherence of infected mutant red blood cells. All of these effects increase protection against severe malaria, which is the main driver of human evolution in this case. Some point mutations in the gene that encodes haemoglobin alter the display of PfEMP1 on the surface of infected red blood cells, thereby diminishing cytoadherence to endothelial cells 85 , 86 . This finding highlights the crucial role of cytoadherence in promoting severe disease.

Finally, variability in the response to TNF, which is secreted from almost all tissues in response to malaria endotoxins, has also been proposed as a factor that mediates differential host responses and contributes to severe malaria when levels are high 7 .

Diagnosis, screening and prevention

The WHO criteria for the diagnosis of malaria consider two key aspects of the disease pathology: fever and the presence of parasites 87 . Parasites can be detected upon light microscopic examination of a blood smear ( Fig. 4 ) or by a rapid diagnostic test (RDT) 87 . The patient's risk of exposure (for example, whether the patient lives in an endemic region or their travel history) can assist in making the diagnosis. Furthermore, the clinical expression of Plasmodium spp. infection correlates with the species’ level of transmission in the area. The symptoms of uncomplicated malaria include sustained episodes of high fever ( Box 1 ); when high levels of parasitaemia are reached, several life-threatening complications might occur (severe malaria) ( Box 1 ).

figure 4

Thin blood films showing Plasmodium falciparum (upper panel) and Plasmodium vivax (lower panel) at different stages of blood-stage development. The images are from methanol-fixed thin films that were stained for 30 minutes in 5% Giemsa. The samples were taken from Thai and Korean patients with malaria: Ethical Review Committee for Research in Human Subjects, Ministry of Public Health, Thailand (reference no. 4/2549, 6 February 2006). The sex symbols represent microgametes (male symbol) and macrogametes (female symbol). ER, early ring stage; ES, early schizont stage; ET, early trophozoite stage; FM, free merozoites; LR, late ring stage; LS, late schizont stage; LT, late trophozoite stage; U, uninfected red blood cell. The slides used were from a previously published study 268 but the images shown have not been previously published. Images courtesy of A.-R. Eruera and B. Russell, University of Otago, New Zealand.

The complications of severe malaria mostly relate to the blocking of blood vessels by infected red blood cells, with the severity and symptoms depending on what organ is affected ( Box 1 ) and to what extent, and differ by age; lung and kidney disease are unusual in children in Africa but are common in non-immune adults.

Parasitaemia . Patients with uncomplicated malaria typically have parasitaemia in the range of 1,000–50,000 parasites per microlitre of blood (however, non-immune travellers and young children who have parasite numbers <1,000 can also present with symptoms). The higher numbers tend to be associated with severe malaria, but the correlation is imprecise and there is no cut-off density. In a pooled analysis of patient data from 61 studies that were designed to measure the efficacy of ACTs (throughout 1998–2012), parasitaemia averaged ∼ 4,000 parasites per microlitre in South America, ∼ 10,000 parasites per microlitre in Asia and ∼ 20,000 parasites per microlitre in Africa 88 . The limit of detection by thick-smear microscopy is ∼ 50 parasites per microlitre 89 . WHO-validated RDTs can detect 50–1,000 parasites per microlitre with high specificity, but many lack sensitivity, especially when compared with PCR-based methods 90 . The ability to detect low levels of parasitaemia is important for predicting clinical relapses, as parasitaemia can increase 20-fold over a 48-hour cycle period. These data are based on measurements in healthy volunteers (controlled human infection models) who were infected at a defined time point with a known number or parasites, and in whom the asymptomatic parasite reproduction was monitored by quantitative PCR up to the point at which the individual received rescue treatment 91 .

In hyperendemic areas (with year-round disease transmission), often many children and adults are asymptomatic carriers of the parasite. In these individuals, the immune system maintains parasites at equilibrium levels in a ‘tug-of-war’. However, parasitaemia in asymptomatic carriers can be extremely high, with reports of levels as high as 50,000 parasites per microlitre in a study of asymptomatic pregnant women (range: 80–55,400 parasites per microlitre) 92 . In addition to the obvious risks for such people, they represent a reservoir for infecting mosquitoes, leading to continued transmission. In clinical studies, the parasitaemia of asymptomatic carriers can be monitored using PCR-based methods, which can detect as few as 22 parasites per millilitre 93 . However, the detection of low-level parasitaemia in low-resource settings requires advanced technology. Loop-mediated isothermal amplification (LAMP) 94 is one promising approach. This type of PCR is fast (10 9 -fold amplification in 1 hour) and does not require thermal cycling, which reduces the requirement for expensive hardware. Versions of this method that do not require electricity are being developed 95 . Nucleic acid-based techniques such as LAMP and PCR-based methods also have the advantage that they can be used to detect multiple pathogens simultaneously and, in theory, identify drug-resistant strains 96 . This approach enables the accurate diagnosis of which Plasmodium spp. is involved, and in the future could lead to the development of multiplexed diagnostics that enable differential diagnosis of the causative pathogens (including bacteria and viruses) in patients who present with fever 97 .

RDTs . RDTs are based on the immunological detection of parasite antigens (such as lactate dehydrogenase (LDH) or histidine-rich protein 2) in the blood, have sensitivities comparable to that of light microscopy examination and have the advantage that they do not require extensive training of the user. These tests provide rapid diagnosis at a point-of-care level in resource-limited settings and can, therefore, substantially improve malaria control. However, occasionally, false-positive results from RDTs can be problematic because they could lead to the wrong perception that antimalarial medicines are ineffective. False-negative test results have been reportedly caused by pfhrp2 gene deletions in P. falciparum strains in South America 98 – 103 . Current data indicate that LDH-targeting RDTs are less sensitive for P. vivax than for P. falciparum 104 , and limited information on the sensitivity of these tests for the rarer species, such as P. ovale or P. malariae , is available. RDTs also offer a great opportunity to track malaria epidemiology; photos taken with mobile phones of the results of the tests can be uploaded to databases (even using cloud-based data architecture 105 ) and provide an automated collection of surveillance data 106 .

Prevention in vulnerable populations

The prevention of Plasmodium spp. infection can be accomplished by different means: vector control, chemoprevention and vaccines. Mosquito (vector) control methods include the following (from the broadest to the most targeted): the widespread use of insecticides, such as DDT campaigns; the use of larvicides; the destruction of breeding grounds (that is, draining marshes and other breeding reservoirs); indoor residual spraying with insecticides (that is, the application of residual insecticide inside dwellings, on walls, curtains or other surfaces); and the use of insecticide-treated bed nets. The use of endectocides has also been proposed; these drugs, such as ivermectin, kill or reduce the lifespan of mosquitoes that feed on individuals who have taken them 107 . However, this approach is still experimental; individuals would be taking drugs that have no direct benefit to themselves (as they do not directly prevent human illness), and so the level of safety data required for the registration of endectocides for this purpose will need to be substantial. Vector control approaches differ in terms of their efficacy, costs and the extent of their effect on the environment. Targeted approaches such as insecticide-treated bed nets have had a strong effect. Chemoprevention is an effective strategy that has been used to reduce malaria incidence in campaigns of seasonal malaria chemoprevention, in intermittent preventive treatment for children and pregnant women, and for mass drug administration 108 . Such antimalarials need to have an excellent safety profile as they are given to large numbers of healthy people. Vaccines excel in eradicating disease, but effective malaria vaccines are challenging because — unlike viruses and bacteria, against which effective vaccines have been developed — protist pathogens (such as Plasmodium spp.) are large-genome microorganisms that have evolved highly effective immune evasion strategies (such as encoding dozens or hundreds of cell surface protein variants). Nevertheless, the improved biotechnological arsenal to generate antigens and improved adjuvants could help to overcome these issues.

Vector control measures . The eradication of mosquitoes is no longer considered an option to eliminate malaria; however, changing the capacity of the vector reservoir has substantial effects on malaria incidence. Long-lasting insecticide-treated bed nets and indoor residual spraying have been calculated to be responsible for two-thirds of the malaria cases averted in Africa between 2000 and 2015 (Ref. 12 ). Today's favoured and more-focused vector control approach involves the use of fine-mazed, sturdy, long-lasting and wash-proof insecticide-treated bed nets 109 . The fabric of these nets is impregnated with an insecticide that maintains its efficacy after ≥20 standardized laboratory washes, and these nets have a 3-year recommended use. Insects are attracted by the person below the net but are killed as they touch the net. However, the efficacy of bed nets is threatened by several factors, including their inappropriate use (for example, for fishing purposes) and behavioural changes in the mosquitoes, which have also begun to bite during the day 110 . The main problem, however, is the increasing emergence of vector resistance to insecticides, especially pyrethroids 110 and, therefore, new insecticides with different modes of action are urgently needed. New insecticides have been identified by screening millions of compounds from the libraries of agrochemical companies, but even those at the most advanced stages of development are still 5–7 years from deployment (see the International Vector Control Consortium website ( http://www.ivcc.com ) and Ref. 111 ) ( Fig. 5 ). Few of these new insecticides are suitable for application in bed nets (because of high costs or unfavourable chemical properties), but some can be used for indoor residual spraying. New ways of deploying these molecules are also being developed, such as improved spraying technologies 112 , timed release to coincide with seasonal transmission and slow-release polymer-based wall linings 113 , 114 .

figure 5

The categories of compounds that are currently under study are defined in the first column on the left; compounds belonging to these categories have advanced to phase I trials or later stages. New screening hits (developed by Syngenta, Bayer, Sumitomo and the Innovative Vector Control Consortium (IVCC)) are at early research stages and are not expected to be deployed until 2020–2022. Similarly, species-specific approaches to the biological control of mosquitoes are not expected to move forward before 2025. The main data source for this Figure was the IVCC; for the latest updates visit the IVCC website ( www.ivcc.com ). Note that not all compounds listed on the IVCC website are shown in this Figure. The dates reflect the expected deployment dates. AI, active ingredient; CS, capsule suspension; IRS, indoor residual spray; LLIN, long-lasting insecticidal mosquito net; LLIRS, long-lasting indoor residual spray; LSHTM, London School of Hygiene and Tropical Medicine (UK); PAMVERC, Pan-African Malaria Vector Research Consortium. *Clothianidin and chlorfenapyr.

Genetic approaches, fuelled by advances in the CRISPR–Cas9 gene editing technology, represent an exciting area of development for novel insect control strategies. There are currently two main approaches: population suppression, whereby mosquitoes are modified so that any progeny are sterile; and population alteration, whereby mosquitoes are modified so that the progeny are refractory to Plasmodium spp. infection 115 , 116 . Initial approaches to population suppression involved releasing sterile male insects 117 . These strategies have now been developed further, with the release of male insects carrying a dominant lethal gene that kills their progeny 118 , 119 . Gene drive systems can be used for both population suppression and population alteration. These systems use homing endonucleases, which are microbial enzymes that induce the lateral transfer of an intervening DNA sequence and can, therefore, convert a heterozygote individual into a homozygote. Homing endonucleases have been re-engineered to recognize mosquito genes 120 and can rapidly increase the frequency of desirable traits in a mosquito population 121 . Gene drive systems have now been used in feasibility studies to reduce the size of mosquito populations 122 or to make mosquitoes less able to transmit malaria-causing parasites 123 . Another approach is inspired by the finding that Aedes aegypti mosquitoes (the vector for Dengue, yellow fever and Zika viruses) infected with bacteria of the Wolbachia spp. (a parasite that naturally colonizes numerous species of insects) cannot transmit the Dengue virus to human hosts 124 . Symbiont Wolbachia spp. can be modified to make them deleterious to other parasites in the same host, and progress has been made in finding symbionts that can colonize Anopheles spp. mosquitoes 125 , 126 . Although all of the above approaches are very promising, they are still at a very early stage, and the environmental uncertainties associated with the widespread distribution of such technologies, as well as the complex regulatory requirements, provide additional hurdles that will need to be overcome.

Chemoprotection and chemoprevention . Chemoprotection describes the use of medicines (given at prophylactic doses) to temporarily protect subjects entering an area of high endemicity — historically, tourists and military personnel — and populations at risk from emergent epidemics, but is also being increasingly considered for individuals visiting areas that have recently become malaria-free. Chemoprevention, which is often used in the context of seasonal malaria, describes the use of medicines with demonstrated efficacy that are given regularly to large populations at full treatment doses (as some of the individuals treated will be asymptomatic carriers).

Currently, there are three ‘gold-standard’ alternatives for chemoprotection: daily atovaquone–proguanil, daily doxycycline and weekly mefloquine. Mefloquine is the current mainstay drug used to prevent the spread of multidrug-resistant Plasmodium spp. in the Greater Mekong subregion of Southeast Asia, despite having a ‘black box warning’ for psychiatric adverse events; however, an analysis of pooled data from 20,000 well-studied patients found that this risk was small (<12 cases per 10,000 treatments) 127 . An active search to find new medicines that could be useful in chemoprotection, in particular medicines that can be given weekly or even less frequently, is underway. One interesting possibility is the use of long-acting injectable intramuscular combination chemoprotectants, which, if effective, could easily compete with vaccination, if they provided protection with 3–4 injections per year. Such an approach (called pre-exposure prophylaxis) is being studied for HIV infection (which also poses major challenges to the development of an effective vaccine) 128 and may lead to the development of long-acting injectable drug formulations 129 produced as crystalline nanoparticles (to enhance water solubility) using the milling technique.

Chemoprevention generally refers to seasonal malaria chemoprevention campaigns, which target children <5 years of age 130 . In the Sahel region (the area just south of the Sahara Desert, where there are seasonal rains and a recurrent threat of malaria), seasonal malaria chemoprevention with a combination of sulfadoxine–pyrimethamine plus amodiaquine had a strong effect 131 – 135 , with a >80% reduction in the number of malaria cases among children and a >50% reduction in mortality 136 . Although these campaigns are operationally complex — as the treatment has to be given monthly — >20 million children have been protected between 2015 and 2016, at a cost of ∼ US$1 per treatment. A concern about seasonal malaria chemoprevention is the potential for a rebound effect of the disease. Rebound could occur if children lose immunity to malaria while receiving treatment that is later stopped because they reached the age limit, if campaigns are interrupted because of economic difficulties or social unrest (war), or if drug resistance develops. Owing to the presence of resistant strains, a different approach is needed in African areas south of the Equator 137 , and this led to trials of monthly 3-day courses of ACTs in seasonal chemoprevention 135 ; there is an increasing amount of literature on the impressive efficacy of dihydroartemisinin (DHA)–piperaquine to prevent malaria in high-risk groups 138 . To reduce the potential for the emergence of drug resistance, the WHO good practice standards state that, when possible, drugs used for chemoprevention should differ from the front-line treatment that is used in the same country or region 108 , which emphasizes the need for the development of multiple, new and diverse treatments to provide a wider range of options.

Finally, intermittent preventive treatment is also recommended to protect pregnant women in all malaria-endemic areas 108 ( Box 3 ).

Vaccines . Malaria, along with tuberculosis and HIV infection, is a disease in which all components of the immune response (both cellular, in particular, during the liver stage, and humoral, during the blood stage) are involved yet provide only partial protection, which means that developing an effective vaccine will be a challenge. The fact that adults living in high-transmission malarious areas acquire partial protective immunity indicates that vaccination is a possibility. As a consequence, parasite proteins targeted by natural immunity, such as the circumsporozoite protein (the most prominent surface antigen expressed by sporozoites), proteins expressed by merozoites and parasite antigens exposed on the surface of infected red blood cells 139 have been studied for their potential to be used in vaccine programmes 140 . However, experimental malaria vaccines tend to target specific parasite species and surface proteins, an approach that both restricts their use and provides scope for the emergence of resistance. Sustained exposure to malaria is needed to maintain natural protective immunity, which is otherwise lost within 3–5 years 141 , perhaps as a result of the clearance of circulating antibodies and the failure of memory B cells to develop into long-lived plasma B cells. Controlled human infection models 142 – 144 have started to provide a more precise understanding of the early cytokine and T cell responses in naive subjects, emphasizing the role of regulatory T cells in dampening the response against the parasite, which results in the exhaustion of T cells 145 . Vaccine development is currently focusing on using multiple antigens from different stages of the parasite life cycle. Future work will also need to focus on the nature of the immune response in humans and specifically the factors that lead to diminished T cell responses. New generations of adjuvants are needed, possibly compounds that produce the desired specific response rather than inducing general immune stimulation. This is a challenging area of research, as adjuvants often have a completely different efficacy in humans compared with in preclinical animal models.

Currently, there is no vaccine deployed against malaria. The ideal vaccine should protect against both P. falciparum and P. vivax , with a protective, lasting efficacy of at least 75%. The most advanced candidate is RTS,S (trade name: Mosquirix; developed by GlaxoSmithKline and the Program for Appropriate Technology in Health Malaria Vaccine Initiative), which contains a recombinant protein with parts of the P. falciparum circumsporozoite protein combined with the hepatitis B virus surface antigen and a proprietary adjuvant. RTS,S reduced the number of malaria cases by half in 4,358 children 5–17 months of age during the first year following vaccination 146 , preventing 1,774 cases for every 1,000 children also owing to herd immunity, and had an efficacy of 40% over the entire 48 months of follow-up in children who received four vaccine doses over a 4-year period 147 . The efficacy of RTS,S during the entire follow-up period dropped to 26% when children only received three vaccine doses. The efficacy during the first year in 6–12-week-old children was limited to 33%. Thus, the RTS,S vaccine failed to provide long-term protection. Further studies, as requested by the WHO, will be done in pilot implementations of 720,000 children in Ghana, Kenya and Malawi (240,000 in each country, half of whom will receive the vaccine) before a final policy recommendation is made. However, a vaccine with only partial and short-term efficacy could still be used in the fight against malaria. RTS,S could be combined with chemoprevention to interrupt malaria transmission in low-endemic areas 148 . Thus, vaccines that are unable to prevent Plasmodium spp. infection could be used to prevent transmission (for example, by targeting gametocytes) or used as an additional protective measure in pregnant women.

A large pipeline of vaccine candidates is under evaluation ( Fig. 6 ). These include irradiated sporozoites — an approach that maximizes the variety of antigens exposed 149 — and subunit vaccines, which could be developed into multicomponent, multistage and multi-antigen formulations 150 . Although vaccines are typically designed for children, as the malaria map shrinks, both paediatric and adult populations living in newly malaria-free zones will need protection because they would probably lose any naturally acquired immunity and would, therefore, be more susceptible. Indeed, in recent years, there has been a focus on developing transmission-blocking vaccines to drive malaria elimination. This approach has been labelled altruistic, as vaccination would have no direct benefit for the person receiving it, but it would benefit the community; a regulatory pathway for such a novel approach has been proposed 151 , 152 . The most clinically advanced vaccine candidate that is based on this approach is a conjugate vaccine that targets the female gametocyte marker Pfs25 (Ref. 153 ), and other antigens are being tested preclinically. Monoclonal antibodies are another potential tool to provide protection. Improvements in manufacturing and high-expressing cell lines are helping to overcome the major barrier to the use of monoclonal antibodies (high costs) 154 , and improvements in potency and pharmacokinetics are reducing the volume and frequency of administration 155 . Monoclonal antibodies could be particularly useful to safely provide the relatively short-term protection needed in pregnancy. The molecular basis of the interaction between parasites and the placenta is quite well understood; two phase I trials of vaccines that are based on the VAR2CSA antigen are under way 156 , 157 .

figure 6

The main data source for this Figure was Ref. 269 . Not all vaccines under development are shown in the Figure. AIMV VLP, Alfalfa mosaic virus virus-like particle; AMA1, apical membrane antigen 1; AMANET, African Malaria Network Trust; ASH, Albert Schweitzer Hospital (Gabon); ChAd63, chimpanzee adenovirus 63; CHUV, Centre Hospitalier Universitaire Vaudois (Switzerland); CNRFP, Centre National de Recherche et de Formation sur le Paludisme (Burkina Faso); CS, circumsporozoite protein; CSP, circumsporozoite protein; EBA, erythrocyte-binding antigen; ee, elimination eradication; EP, electroporation; EPA, Pseudomonas aeruginosa exoprotein A; EVI, European Vaccine Initiative; CVac, chemoprophylaxis vaccine; FhCMB, Fraunhofer Center for Molecular Biotechnology (USA); GSK, GlaxoSmithKline; IP, Institut Pasteur (France); INSERM, Institut National de la Santé et de la Recherche Médicale (France); JHU, Johns Hopkins University (USA); KCMC, Kilimanjaro Christian Medical College (Tanzania); KMRI, Kenyan Medical Research Institute; LSHTM, London School of Hygiene and Tropical Medicine (UK); M3V.Ad.PfCA, multi-antigen, multistage, adenovirus-vectored vaccine expressing Plasmodium falciparum CSP and AMA1 antigens; mAb, monoclonal antibody; ME-TRAP multiple epitope thrombospondin-related adhesion protein; MRCG, Medical Research Council (The Gambia); MSP, merozoite surface protein; MVA, modified vaccinia virus Ankara; MUK, Makerere University Kampala (Uganda); NHRC, Navrongo Health Research Centre (Ghana); NIAID, National Institute of Allergy and Infectious Diseases (USA); NIMR, National Institute for Medical Research (UK); NMRC, Naval Medical Research Center (USA); PAMCPH, pregnancy-associated malaria Copenhagen; PATH, Program for Appropriate Technology in Health; PfAMA1-DiCo, diversity-covering Plasmodium falciparum AMA1; PfCelTOS, Plasmodium falciparum cell-traversal protein for ookinetes and sporozoites; PfPEBS, Plasmodium falciparum pre-erythrocytic and blood stage; PfSPZ, Plasmodium falciparum sporozoite; PfSPZ-GA1, genetically attenuated PfSPZ; pp, paediatric prevention; PRIMALVAC, PRIMVAC project (INSERM); PRIMVAC, recombinant var2CSA protein as vaccine candidate for placental malaria; Pfs25, Plasmodium falciparum 25 kDa ookinete surface antigen; PvCSP, Plasmodium vivax circumsporozoite protein; PvDBP, Plasmodium vivax Duffy-binding protein; Rh or RH, reticulocyte-binding protein homologue; SAPN, self-assembling protein nanoparticle; SSI, Statens Serum Institut (Denmark); U., University; UCAP, Université Cheikh Anta Diop (Senegal); UKT, Institute of Tropical Medicine, University of Tübingen (Germany); USAMMRC, US Army Medical Research and Materiel Command; WEHI, Walter and Eliza Hall Institute of Medical Research (Australia); WRAIR, Walter Reed Army Institute of Research (USA). *Sponsors of late-stage clinical trials. ‡ Pending review or approval by WHO prequalification, or by regulatory bodies who are members or observers of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

No single drug is ideal against all Plasmodium spp. or all of the manifestations of the disease that occur in different patient populations. Thus, treatment must be tailored to each situation appropriately 108 , 158 . First, the treatment of uncomplicated malaria and that of severe malaria are distinct. In uncomplicated malaria, the treatment of choice is an oral medicine with high efficacy and a low adverse-effect profile. However, the preferred initial therapy in severe malaria requires rapid onset and includes the parenteral administration of an artemisinin derivative, which can rapidly clear the parasites from the blood, and it is also suitable for those patients who have changes in mental status (such as coma) that make swallowing oral medications impossible. For the treatment of malaria during pregnancy, the options are limited to the drugs that are known to be safe for both the expectant mother and the fetus, and different regimens are needed ( Box 2 ). Different drugs are used for different Plasmodium spp., and the choice is usually driven more by drug resistance frequencies (which are lower in P. vivax , P. ovale , P. malariae and P. knowlesi than in P. falciparum ) than by species differences as such. Thus, chloroquine, with its low cost and excellent safety, is used in most cases of non- P. falciparum malaria, where it remains effective, whereas P. falciparum malaria requires newer medicines that overcome resistance issues. The persistence of P. vivax and P. ovale hypnozoites, even after clearance of the stages that cause symptoms, necessitates additional treatments. Only primaquine targets hypnozoites.

P. falciparum malaria

The mainstay treatments for uncomplicated P. falciparum malaria are ACTs: fixed-dose combinations of two drugs, an artemisinin derivative and a quinine derivative 108 ( Box 4 ; Table 1 ).

Owing to its high lipophilicity, artemisinin itself is not the molecule of choice in any stringent regulatory authority-approved combination. Instead, semisynthetic derivatives are used: namely, DHA (the reduced hemiacetal of the major active metabolite of many artemisinin derivatives), artesunate (a succinate prodrug of DHA that is highly water-soluble) or artemether (a methylether prodrug of DHA).

Quinine has been used in medicine for centuries 159 , but it was only in the mid-20th century that a synthetic form was made and the emerging pharmaceutical and government research sectors delivered the next-generation medicines that built on it. The combination partners of choice are 4-aminoquinolines (for example, amodiaquine, piperaquine and pyronaridine) and amino-alcohols (such as mefloquine or lumefantrine); these molecules are believed to interfere with haemozoin formation. There are now five ACTs that have been approved or are close to approval by the FDA, the European Medicines Agency (EMA) or WHO prequalification ( Figs 7 , 8 ; Table 1 ). In pivotal clinical studies, these combinations have proven extremely effective (achieving an adequate clinical and parasitological response (that is, the absence of parasitaemia at day 28 in >94% of patients; for example, see Ref. 160 ), are well-tolerated (as they have been given to >300 million paediatric patients), are affordable (typically under US$1 per dose) and, thanks to ingenious formulations and packaging, are stable in tropical climate conditions.

figure 7

a | Preclinical candidates. b | Compounds or compound combinations that are in clinical development. The multitude of molecules that target only the asexual blood stages reflects the fact that many of these compounds are at an early stage of development, and further assessment of their Target Candidate Profile is still ongoing. KAF156 and KAE609 were discovered in a multiparty collaboration between the Novartis Institute for Tropical Disease (Singapore), the Genomics Institute of the Novartis Research Foundation (GNF; USA), the Swiss Tropical and Public Health Institute, the Biomedical Primate Research Centre (The Netherlands), the Wellcome Trust (UK) and Medicines for Malaria Venture (MMV). DSM265 was discovered through a collaboration involving the University of Texas Southwestern (UTSW; USA), the University of Washington (UW; USA), Monash University (Australia), GlaxoSmithKline (GSK) and MMV. MMV(390)048 was discovered through a collaboration involving the University of Cape Town (UCT; South Africa), the Swiss Tropical and Public Health Institute, Monash University, Syngene and MMV. SJ(557)733 was discovered in a collaboration involving St Jude Children's Research Hospital (USA), Rutgers University (USA), Monash University and MMV. Note that not all compounds are shown in this Figure, and updates can be found on the MMV website ( www.mmv.org) . CDRI, Central Drug Research Institute (India); ITM, Institute of Tropical Medicine; MRC, Medical Research Council; HKUST, Hong Kong University of Science and Technology; U., University. *Part of a combination that aims to be a new single-exposure radical cure (Target Product Profile 1). ‡ Product that targets the prevention of relapse in Plasmodium vivax malaria. § 3-day cure, artemisinin-based combination therapy. || Severe malaria and pre-referral treatment.

figure 8

See the Medicines for Malaria Venture (MMV) website ( www.mmv.org ) for updates. CDRI, Central Drug Research Institute (India); GSK, GlaxoSmithKline; ITM, Institute of Tropical Medicine; U., University; UCT, University of Cape Town (South Africa); UTSW, University of Texas Southwestern (USA); UW, University of Washington (USA). *Part of a combination that aims to be a new single-exposure radical cure (Target Product Profile 1). ‡ Product that targets the prevention of relapse in Plasmodium vivax malaria. § 3-day cure, artemisinin-based combination therapy.

Following the results of comprehensive studies in Africa and Asia, the injectable treatment of choice for severe P. falciparum malaria is artesunate 161 – 163 . In the United States, artesunate for intravenous use is available as an Investigational New Drug (IND) through the Centers for Disease Control and Prevention (CDC) malaria hotline and shows efficacies of >90% even in patients who are already unconscious 161 . Sometimes, however, in low-income countries, it is necessary to administer intravenous quinine or quinine while awaiting an artesunate supply. Suppositories of artesunate are in late-stage product development 164 and are already available in Africa as a pre-referral treatment to keep patients alive while they reach a health clinic.

Box 4: Artemisinin

Artemisinin (also known as qinghaosu in China; see the structure) is extracted from the leaves of the Artemisia annua plant.

literature review on malaria pdf

Youyou Tu was recognized by the 2015 Nobel Prize committee for her contribution to medicine for the discovery of artemisinin, which she achieved by retrieving and following instructions from ancient Chinese texts 247 . Owing to the ability of artemisinin to rapidly reduce parasitaemia and fever, the effect that artemisinin and its derivatives has had on the management of malaria cannot be overstated; since their introduction in the 1970s and their subsequent wider implementation — which was possible particularly owing to the work of Nicholas White and colleagues 248 – 251 — millions of lives have been saved. These drugs seem to be activated by haem-derived iron, and their toxicity is probably mediated through the formation of reactive oxidative radicals 42 . Data indicate that they interfere with phosphatidylinositol-3-phosphate metabolism (which is thought to be involved in the trafficking of haemoglobin to the digestive vacuole 252 ) and provide possible mechanistic insights into the nature of clinically observed artemisinin resistance 253 .

P. vivax malaria

Chloroquine or ACTs are WHO-recommended for uncomplicated P. vivax malaria 108 (although chloroquine is no longer used in several countries, such as Indonesia). As chloroquine-resistant P. vivax is becoming increasingly widespread, particularly in Asia, the use of ACTs is increasing; although only artesunate–pyronaridine is approved for the treatment of blood-stage P. vivax malaria, the other ACTs are also effective and are used off-label. Relapses of P. vivax malaria present a problem in malaria control. Relapse frequencies differ among P. vivax strains; they are high (typically within 3 weeks) in all-year transmission areas, such as Papua New Guinea, but relapse occurs on average after 7 months in areas with a dry or winter season. Some P. vivax strains, such as the Moscow and North Korea strains, are not, in most cases, symptomatic at the time of first infection but become symptomatic only following reactivation of the hypnozoites 165 . Primaquine needs to be administered in addition to the primary treatment to prevent relapse and transmission, which can occur even years after the primary infection. Primaquine treatment, however, requires 14 days of treatment, has gastrointestinal adverse effects in some patients, and is contraindicated in pregnant women and in patients who are deficient in or express low levels of G6PD (as it can cause haemolysis). Tafenoquine 166 , a next-generation 8-aminoquinoline, is currently completing phase III clinical studies. As with patients receiving primaquine, patients receiving tafenoquine will still require an assessment of their G6PD enzyme activity to ensure safe use of the drug and to determine the optimal dose. In phase II studies, tafenoquine was shown to have an efficacy similar to that of primaquine but with a single dose only compared with the 7–14-day treatment with primaquine; higher patient compliance is expected to be a major benefit of a single-dose regimen. The ultimate elimination of P. vivax malaria will be dependent on the availability of safe and effective anti-relapse agents, and is, therefore, a major focus of the drug discovery community.

Drug resistance

The two drugs in ACTs have very different pharmacokinetic profiles in patients. The artemisinin components have a plasma half-life of only a few hours yet can reduce parasitaemia by three-to-four orders of magnitude. By contrast, the 4-aminoquinolines and amino-alcohols have long terminal half-lives (>4 days), providing cure (defined as an adequate clinical and parasitological response) and varying levels of post-treatment prophylaxis. The prolonged half-life of the non-artemisinin component of ACTs has raised concerns in the research community owing to the risk of drug resistance development. However, the effectiveness of the ACTs in rapidly reducing parasitaemia suggests that any emerging resistance has arisen largely as a result of poor clinical practice, including the use of artemisinin derivatives as monotherapy, a lack of patient compliance and substandard medicine quality (including counterfeits); these are all situations in which large numbers of parasites are exposed to a single active molecule 167 . However, resistance to piperaquine 168 and partial resistance to artemisinin 169 (which manifests as a reduced rate of parasite clearance rate rather than a shift in the half-maximal inhibitory concentration (IC 50 )) has been confirmed in the Greater Mekong subregion, as well as resistance to mefloquine and amodiaquine in various parts of the world 170 . Africa has so far been spared, but reports of treatment failure for either artemisinin 171 or ACT 172 in African isolates of P. falciparum have raised concerns. Thus, artemisinin-resistant Plasmodium spp. and insecticide-resistant mosquitoes are major threats to the progress that has been made in reducing the number of malaria-related deaths through current control programmes. It is important to emphasize that progress against malaria has historically been volatile; in many areas, the disease has re-emerged as the efficacy of old drugs has been lost in strains that developed resistance.

Many advances have been made in identifying genetic markers in Plasmodium spp. that correlate with resistance to clinically used drugs ( Table 2 ). These markers enable the research and medical communities to proactively survey parasite populations to make informed treatment choices. Cross-resistance profiles reveal reciprocity between 4-aminoquinolines and amino-alcohols (that is, parasites resistant to one class are also less sensitive to the other). In addition, a drug can exert two opposite selective pressures: one towards the selection of resistant mutants and the other towards the selection of strains that have increased sensitivity to a different drug, a phenomenon known as ‘inverse selective pressure’ (Refs 173 , 174 ). These findings support the introduction of treatment rotation or triple combination therapies as potential future options. Finally, the drug discovery and development pipeline is delivering not only new compounds that have novel modes of action and overcome known resistant strains but also chemicals that have the potential to be effective in a single dose, which could overcome compliance issues. Nevertheless, policymakers need to be on high alert to prevent or rapidly eliminate outbreaks of resistant strains, and to prioritize the development of new treatments.

The drug discovery and development pipeline

The most comprehensive antimalarial discovery portfolio has been developed by the not-for-profit product development partnership Medicines for Malaria Venture (MMV) in collaboration with its partners in both academia and the pharmaceutical industry, with support from donors (mainly government agencies and philanthropic foundations) ( Fig. 7 ). Promising compound series have been identified from three approaches: hypothesis-driven design to develop alternatives to marketed compounds (for example, synthetic peroxides such as ozonides); target-based screening and rational design (for example, screening of inhibitors of P. falciparum dihydroorotate dehydrogenase (PfDHODH)); and phenotypic screening 175 . Phenotypic screening has been the most successful approach to date, in terms of delivering preclinical candidates and identifying — through the sequencing of resistant mutants — novel molecular targets. However, with advances in the understanding of parasite biology and in molecular biology technology, target-based approaches will probably have a substantial role in coming years.

Two combinations — OZ439 (also known as artefenomel) with ferroquine (Sanofi and MMV) and KAF156 with lumefantrine (Novartis and MMV) — are about to begin phase IIb development to test the efficacy of single-dose cure and, in the case of KAF156–lumefantrine, also 2-day or 3-day cures. OZ439 is a fully synthetic peroxide for which sustained plasma exposure is achieved by a single oral dose in humans 176 , 177 ; the hope is that it could replace the three independent doses required for artemisinin derivatives. Ferroquine is a next-generation 4-aminoquinoline without cross-resistance to chloroquine, amodiaquine or piperaquine 178 , 179 . KAF156 is a novel imidazolopiperazine that has an unknown mechanism of action 180 – 182 , but its resistance marker — P. falciparum cyclic amine resistance locus ( pfcarl ) — seems to encode a transporter on the endoplasmic reticulum membrane of the parasite. Interestingly, whereas OZ439 and ferroquine principally affect the asexual blood stages, KAF156 also targets both the asexual liver stage and the sexual gametocyte stage and, therefore, could have an effect on transmission.

Two other compounds, KAE609 (also known as cipargamin 183 , 184 ) and DSM265 (Refs 185 – 188 ), are poised to begin phase IIb and are awaiting decisions on combination partners. KAE609 is a highly potent spiroindolone that provides parasite clearance in patients even more rapidly than peroxides; its assumed mode of action is the inhibition of PfATP4 ( Fig. 3 ), which is encoded by its resistance marker and is a transporter on the parasite plasma membrane that regulates Na + and H + homeostasis. Inhibition of this channel, which was identified through the sequencing of resistant mutants, increases Na + concentrations and pH, resulting in parasite swelling, rigidity and fragility, thereby contributing to host parasite clearance in the spleen in addition to intrinsic parasite killing. In addition, effects on cholesterol levels in the parasite plasma membrane have been noted that are also likely to contribute to parasite killing by leading to an increased rigidity that results in more rapid clearance in vivo 189 . DSM265 is a novel triazolopyrimidine that has both blood-stage and liver-stage activity, and that selectively inhibits PfDHODH ( Fig. 3 ). It was optimized for drug-like qualities from a compound that was identified from a high-throughput screen of a small-molecule library 186 , 190 . DSM265 maintains a serum concentration that is above its minimum parasiticidal concentration in humans for 8 days, and has shown efficacy in both treatment and chemoprotection models in human volunteers in phase Ib trials 185 , 188 .

Within phase I, new compounds are first assessed for safety and pharmacokinetics, and then for efficacy against the asexual blood or liver stages of Plasmodium spp. using a controlled human malaria infection model in healthy volunteers 144 . This model provides a rapid and cost-effective early proof of principle and, by modelling the concentration–response correlation, increases the accuracy of dose predictions for further clinical studies. The 2-aminopyridine MMV(390)048 (also known as MMV048 (Refs 191 , 192 )), SJ(557)733 (also known as (+)-SJ733 (Refs 57 , 193 )) and P218 (Ref. 194 ) are currently progressing through phase I. MMV(390)048 inhibits PfPI(4)K ( Fig. 3 ), and this inhibition affects the asexual liver and blood stages, as well as the sexual gametocyte stage. MMV(390)048 has good exposure in animal models 192 , suggesting that it could potentially be used in a single dose in combination with another drug. SJ(557)733, which is a dihydroisoquinoline, inhibits PfATP4 and is an alternative partner that has a completely different structure from that of KAE609, and it has excellent preclinical safety and development potential. P218 is currently being evaluated for testing in controlled human malaria infection cohorts.

A further eight compounds are undergoing active preclinical development 195 . Of these compounds, four are alternatives to the leading compounds that target established mechanisms: the aminopyrazole PA92 (also known as PA-21A092 (Ref. 196 )) and the thiotriazole GSK030 (also known as GSK3212030A) both target PfATP4; DSM421 (Ref. 197 ) is a triazolopyrimidine alternative to DSM265; and UCT943 (also known as MMV642943) 198 is an alternative to MMV(390)048. Three compounds show novel mechanisms of action or resistance markers: M5717 (also known as DDD498 or DDD107498 (Ref. 199 )) inhibits P. falciparum elongation factor 2 (and, therefore, protein synthesis) and has outstanding efficacy against all parasite life-cycle stages; MMV253 (also known as AZ13721412) 200 is a fast-acting triaminopyrimidine with a V-type ATPase as resistance marker; and AN13762 (also known as AN762) is a novel oxaborole 201 with a novel resistance marker. All of these compounds have been developed through collaborations with MMV.

The eighth compound in active preclinical development, led by Jacobus Pharmaceuticals, is JPC3210 (Ref. 202 ), which is a novel aminocresol that improves upon the historical candidate (WR194965) that was developed by the Walter Reed Army Institute of Research and tested in patients at the time of the development of mefloquine in the 1970s. JPC3210 has an unknown mechanism of action and has potent, long-lasting efficacy in preclinical models, suggesting its potential to be used in a single dose for both treatment and prophylaxis 202 .

Quality of life

Malaria is one among the diseases of poverty. The WHO website states the following: “There is general agreement that poverty not only increases the risk of ill health and vulnerability of people, it also has serious implications for the delivery of effective health-care such as reduced demand for services, lack of continuity or compliance in medical treatment, and increased transmission of infectious diseases” (Ref. 203 ). The socioeconomic burden of malaria is enormous, and although the disease predominantly affects children, it is a serious obstacle to a country's development and economy 204 . Malaria is responsible for annual expenses of billions of euros in some African countries 205 . In many endemic areas, each individual suffers multiple episodes of malaria per year, with each episode causing a loss of school time for children and work time for their parents and guardians. Despite the declining trends in malaria morbidity and mortality, the figures are still disconcertingly high for a disease that is entirely preventable and treatable 16 .

Malaria also has long-term detrimental effects on the non-health-related quality of life of the affected population; it intensifies poverty by limiting education opportunities, as it leads to absenteeism in schools and reduced productivity at work 16 . The effects of acute illness normally drive families to seek urgent attention, which may consist of self-medication, if the disease is familiar to the household. Yet, even an episode of uncomplicated malaria can be potentially fatal, owing to a delay in promptly accessing efficacious antimalarial drugs. As malaria is so familiar to many households, patients — especially children — may be presented late for early diagnosis and treatment in health facilities. Late presentation prolongs morbidity, increases the risk of severe malaria, and deprives the families of income through direct expenses and reduced productivity. Frequent disease episodes experienced in the endemic areas as well as their possible complications can negatively affect child growth and nutrition, shortening the lives of children and family members. The neurological consequences can affect a child's ability to learn and become a self-reliant adult 206 – 208 , as they often occur during an important brain growth phase, when brain areas involved in higher learning (such as planning, decision-making, self-awareness and social sensitivity) mature. Cognitive deficits occurring during the early education years affect the entire family, as they impair the ability of the child to contribute to the well-being of the family as they grow and put additional strain on the parents, who may sometimes have to care for a substantially disabled child and, later, a disabled adult 209 .

The agenda set by the WHO aims for malaria incidence and mortality to decrease by 90% over the next 15 years, with increasing numbers of countries that eliminate the disease 210 . Even if we achieve the ambitious goals set by the WHO, there will still be a child dying of malaria every 10 minutes in 2030. The ACTs are extraordinarily effective, and much of the disease burden could be reduced by the complete deployment and availability of these medicines. There are now two approved ACTs that are specifically designed (taste-masked and sweetened) for paediatric use.

However, the emergence of drug-resistant Plasmodium spp. and insecticide-resistant mosquitoes is a major concern. The first clinical reports of artemisinin resistance came from the Thai–Cambodian border region in the mid-2000s 211 . So far, resistant strains have not spread to Africa, and the severity of the malaria caused by artemisinin-resistant parasites is not different from that of disease caused by wild-type strains. However, if artemisinin derivatives became ineffective, no alternative first-line treatments would be available, as new therapies are still only in phase II clinical trials, and their safety and efficacy will need to be effectively assessed in the field before they can be deployed for widespread clinical use.

Diagnostics

Future diagnostics should address two main issues. First, new diagnostic tests would ideally be non-invasive and not require a blood sample. Many approaches have been piloted, including parasite antigen detection in saliva 212 or urine 213 , the detection of specific volatile chemicals in breath 214 , and direct non-invasive measurements of iron-rich haemozoin in skin blood vessels 215 . Second, diagnostic tests should be able to detect drug-resistant strains directly in the point-of-care setting, rather than in sentinel sites, to provide better treatment and generate more-detailed epidemiological maps 216 . A next-generation amplicon-sequencing method suitable for use in endemic countries would enable the high-throughput detection of genetic mutations in six P. falciparum genes that are associated with resistance to antimalarial drugs, including ACTs, chloroquine and sulfadoxine–pyrimethamine 217 .

Malaria challenges

In addition to the length of the process of discovering and developing new drugs, insecticides and vaccines, in malaria there is the hurdle of the delivery of these new compounds, which first need to obtain approval from all local regulatory authorities. There is a trend for harmonization of the approval requirements among different authorities, with an initiative involving several regional African organizations, for example, to review data on behalf of many countries, similarly to the EMA reviewing files on behalf of all of the European Union countries. These events are paving the way to shorten the time from the end of clinical studies to the day of large-scale deployment, when affected populations will start to reap the benefits.

The move towards elimination and eradication

High-content cellular assays have become available to test inhibitors of transmission and compounds that target hypnozoites 218 , 219 . Discovery efforts for treatment and chemoprotection combinations conform to the malaria Target Product Profiles — a planning tool for therapeutic candidates that is based on FDA guidelines — to ensure that what is delivered has clinical relevance. The MMV has defined 220 and updated 221 Target Candidate Profiles (TCPs), which define the attributes that are required for the ideal medicines and have proven invaluable in guiding single-molecule optimization and decision-making.

The current focus is moving beyond TCP1 (which includes molecules that clear asexual blood-stage parasitaemia); the goal is to deliver compounds that do not simply treat patients and control symptoms but that also have biological activity that disrupts the life cycle of the parasite and hence break the transmission cycle, a step that is necessary in the move towards elimination. Particular areas of interest are anti-relapse agents for P. vivax malaria (TCP3; compounds that target hypnozoites), compounds that kill hepatic schizonts (TCP4) and protect against the onset of symptoms, and gametocytocidal compounds to block transmission (TCP5). Future projects include work on long-lasting endectocides (TCP6), such as ivermectin 107 . The MMV Discovery Portfolio also includes alternative compounds to the clinical frontrunners, molecules with new mechanisms of action (which target, for example, N -myristoyltransferase 222 , coenzyme A biosynthesis 223 , phenylalanyl tRNA synthetase 224 , prolyl 225 tRNA synthetase, plasmepsin V 226 and the Q i site of cytochrome bc 1 (Ref. 227 )) and compounds that seem to be resistance-proof (at least in vitro ).

In conclusion, while much progress has been made towards reducing the burden of malaria, much work remains to be done if these gains are to bring lasting relief to those living under the threat of infection. Without a continued focus on developing new antimalarials and new approaches for diagnosis and vector control, malaria will continue to exert an unacceptable toll on people living in disease endemic areas.

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Acknowledgements

The authors thank R. Bryant, A. Hill, S. Rees and S. L. Hoffman for their help with the content of Figure 4 and Figure 6 , and S. Duparc for critical reading of the clinical sections of the manuscript.

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Introduction (M.A.P., J.N.B. and W.C.V.V.); Epidemiology (M.A.P. and W.C.V.V.); Mechanisms/pathophysiology (M.A.P.); Diagnosis, screening and prevention (M.A.P., J.N.B., R.H.v.H. and T.N.C.W.); Management (J.N.B., R.H.v.H. and T.N.C.W.); Quality of life (C.M.); Outlook (R.H.v.H. and T.N.C.W.); Overview of Primer (M.A.P.).

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Phillips, M., Burrows, J., Manyando, C. et al. Malaria. Nat Rev Dis Primers 3 , 17050 (2017). https://doi.org/10.1038/nrdp.2017.50

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Diagnosis, Treatment, and Prevention of Malaria in the US : A Review

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Importance   Malaria is caused by protozoa parasites of the genus Plasmodium and is diagnosed in approximately 2000 people in the US each year who have returned from visiting regions with endemic malaria. The mortality rate from malaria is approximately 0.3% in the US and 0.26% worldwide.

Observations   In the US, most malaria is diagnosed in people who traveled to an endemic region. More than 80% of people diagnosed with malaria in the US acquired the infection in Africa. Of the approximately 2000 people diagnosed with malaria in the US in 2017, an estimated 82.4% were adults and about 78.6% were Black or African American. Among US residents diagnosed with malaria, 71.7% had not taken malaria chemoprophylaxis during travel. In 2017 in the US, P falciparum was the species diagnosed in approximately 79% of patients, whereas P vivax was diagnosed in an estimated 11.2% of patients. In 2017 in the US, severe malaria, defined as vital organ involvement including shock, pulmonary edema, significant bleeding, seizures, impaired consciousness, and laboratory abnormalities such as kidney impairment, acidosis, anemia, or high parasitemia, occurred in approximately 14% of patients, and an estimated 0.3% of those receiving a diagnosis of malaria in the US died. P falciparum has developed resistance to chloroquine in most regions of the world, including Africa. First-line therapy for P falciparum malaria in the US is combination therapy that includes artemisinin. If P falciparum was acquired in a known chloroquine-sensitive region such as Haiti, chloroquine remains an alternative option. When artemisinin-based combination therapies are not available, atovaquone-proguanil or quinine plus clindamycin is used for chloroquine-resistant malaria. P vivax, P ovale, P malariae, and P knowlesi are typically chloroquine sensitive, and treatment with either artemisinin-based combination therapy or chloroquine for regions with chloroquine-susceptible infections for uncomplicated malaria is recommended. For severe malaria, intravenous artesunate is first-line therapy. Treatment of mild malaria due to a chloroquine-resistant parasite consists of a combination therapy that includes artemisinin or chloroquine for chloroquine-sensitive malaria. P vivax and P ovale require additional therapy with an 8-aminoquinoline to eradicate the liver stage. Several options exist for chemoprophylaxis and selection should be based on patient characteristics and preferences.

Conclusions and Relevance   Approximately 2000 cases of malaria are diagnosed each year in the US, most commonly in travelers returning from visiting endemic areas. Prevention and treatment of malaria depend on the species and the drug sensitivity of parasites from the region of acquisition. Intravenous artesunate is first-line therapy for severe malaria.

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Daily JP , Minuti A , Khan N. Diagnosis, Treatment, and Prevention of Malaria in the US : A Review . JAMA. 2022;328(5):460–471. doi:10.1001/jama.2022.12366

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  • Published: 29 October 2018

Complex interactions between malaria and malnutrition: a systematic literature review

  • D Das 1 , 2 ,
  • R F Grais 4 ,
  • E A Okiro 7 ,
  • K Stepniewska 1 , 2 ,
  • R Mansoor 1 , 2 ,
  • S van der Kam 5 ,
  • D J Terlouw 6 , 10 , 11 ,
  • J Tarning 1 , 2 , 3 ,
  • K I Barnes 8 , 9 &
  • P J Guerin 1 , 2  

BMC Medicine volume  16 , Article number:  186 ( 2018 ) Cite this article

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Despite substantial improvement in the control of malaria and decreased prevalence of malnutrition over the past two decades, both conditions remain heavy burdens that cause hundreds of thousands of deaths in children in resource-poor countries every year. Better understanding of the complex interactions between malaria and malnutrition is crucial for optimally targeting interventions where both conditions co-exist. This systematic review aimed to assess the evidence of the interplay between malaria and malnutrition.

Database searches were conducted in PubMed, Global Health and Cochrane Libraries and articles published in English, French or Spanish between Jan 1980 and Feb 2018 were accessed and screened. The methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale and the risk of bias across studies was assessed using the GRADE approach. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guideline were followed.

Of 2945 articles screened from databases, a total of 33 articles were identified looking at the association between malnutrition and risk of malaria and/or the impact of malnutrition in antimalarial treatment efficacy. Large methodological heterogeneity of studies precluded conducting meaningful aggregated data meta-analysis. Divergent results were reported on the effect of malnutrition on malaria risk. While no consistent association between risk of malaria and acute malnutrition was found, chronic malnutrition was relatively consistently associated with severity of malaria such as high-density parasitemia and anaemia. Furthermore, there is little information on the effect of malnutrition on therapeutic responses to artemisinin combination therapies (ACTs) and their pharmacokinetic properties in malnourished children in published literature.

Conclusions

The evidence on the effect of malnutrition on malaria risk remains inconclusive. Further analyses using individual patient data could provide an important opportunity to better understand the variability observed in publications by standardising both malaria and nutritional metrics. Our findings highlight the need to improve our understanding of the pharmacodynamics and pharmacokinetics of ACTs in malnourished children. Further clarification on malaria-malnutrition interactions would also serve as a basis for designing future trials and provide an opportunity to optimise antimalarial treatment for this large, vulnerable and neglected population.

Trial registration

PROSPERO CRD42017056934 .

Peer Review reports

Malaria and malnutrition in children (refers to all forms of undernutrition) are reported independently to be major causes of morbidity and mortality in low- and middle-income countries. About 3.2 billion people remained at risk of malaria with an estimated 216 million new cases (95% confidence interval 196–263 million) and 445,000 deaths worldwide in 2016; the majority of deaths occur in children under 5 years in sub-Saharan Africa [ 1 ]. Approximately 3.1 million deaths in children under five are attributed to malnutrition each year, representing 45% of all childhood deaths [ 2 ]. The interaction between malaria and childhood malnutrition has been studied for many years and complex interactions between these high-burden conditions are now increasingly recognised. Understanding the consequences of malnutrition on malaria and vice versa is crucial and may help guide the choice of public health interventions and research priorities where significant co-morbidity exists.

Malnutrition is a complex phenomenon due to its multifactorial aetiology and diverse clinical presentation. Acute malnutrition manifests with wasting (low weight for height) and chronic malnutrition as stunting (low height for age). Being underweight (low weight for age) can result from either chronic or acute malnutrition or both. Assessment of malnourishment can be conducted using anthropometric indicators which compare child’s weight and height to the standardised age- and sex-specific growth reference derived from the international reference population of children between 6 and 59 months of age (World Health Organization (WHO) Child Growth Standards 2006) [ 3 ]. The anthropometric indicators are expressed as a number of standard deviations (SDs) below or above the reference mean or median value, Z-score. Cutoffs of − 3 are used to indicate severe malnutrition and values between − 2 and − 3 are considered to be moderate malnutrition. Weight-for-height Z-score (WHZ) is the indicator used to classify a child with wasting. Mid-Upper Arm Circumference (MUAC) is another frequently used indicator for wasting. Severe acute malnutrition (SAM) is defined as MUAC < 115 mm and/or WHZ < − 3 and/or bilateral pitting oedema. Stunting is defined by the measure of height-for-age Z-score (HAZ) and a child is considered as being underweight based on low weight-for-age Z-score (WAZ). These definitions do not take micronutrient malnutrition into account, which can occur even if the person is getting enough energy and they are not thin or short.

The exact relationship between childhood malnutrition and malaria remains complex, controversial, and poorly understood. One of the key questions is, to what extent the burden of malaria is attributable to wasting and stunting? In regard to the impact of malaria on malnutrition, some evidence suggests malaria has adverse effects on nutritional status of young children [ 4 , 5 , 6 , 7 , 8 , 9 ]. On the other hand, whether and how malnutrition influences malaria morbidity and mortality is debated. Some studies have reported that malnutrition is associated with a higher risk of malaria [ 10 , 11 , 12 , 13 ], others have suggested a protective effect [ 14 , 15 , 16 , 17 ], or no differential risk [ 18 , 19 ]. Similarly, there is very limited evidence on the relationship between nutritional status and antimalarial drug efficacy. Clinical efficacy of the current first-line malaria treatment, the artemisinin combination therapies (ACTs), in malnourished children has been rarely explored [ 20 , 21 , 22 ]. Understanding the complex relationship of the immune response of individuals infected with malaria and suffering of malnutrition is crucial to guide specific antimalarial therapeutic approaches in this vulnerable sub-population. There are key knowledge gaps in defining the complex relationship between malnutrition and malaria, which need to be identified and addressed. We aimed to conduct a systematic review of the current understanding of interactions between acute or chronic malnutrition and the risk of developing malarial infection. A further objective was to explore published literature on the impact of malnutrition on the efficacy of antimalarial treatment.

We conducted a systematic literature review of manuscripts published between Jan 1, 1980, and Feb 19, 2018. PubMed, Global Health and Cochrane Libraries were searched using key terms (Additional file  1 ), and articles published in English, French or Spanish were accessed. Two reviewers identified relevant articles of interest, as per criteria listed below, by screening titles and abstracts of publications retrieved. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guideline [ 23 ] was followed. The PRISMA checklist is provided as Additional file  2 and the review is registered in international prospective register of systematic reviews (PROSPERO Registration No. CRD42017056934).

Eligibility screening

For the selected articles, full text was obtained and assessed for relevance to any of the following topics of interest: (1) association between malnutrition and risk of malaria and (2) malnutrition and antimalarial treatment efficacy. We excluded studies primarily focused on non-malarial conditions such as TB, HIV, neglected tropical diseases, pneumonia or diarrhoeal diseases; non-clinical studies (systematic reviews, opinion pieces, editorials, modelling studies, economic evaluations, guidelines, protocols, book chapters) and in vitro, animal, plant or molecular studies; studies on malaria in pregnancy and placental malaria; demographic and health surveys, mortality surveys, qualitative studies; case reports or series; vaccine studies; and studies primarily focused only on malaria or malnutrition or micronutrient deficiencies or anaemia. For this review, observational and interventional studies in non-pregnant populations with malnutrition assessed by anthropometric measurements as exposure and risk of malaria infection (whether asymptomatic parasitemia or uncomplicated malaria) as outcome were included.

Data extraction

From each of the included studies in this review, the following variables were extracted: authors, year of publication, country, study design, age (range or median/mean), sex (ratio), sample size, growth standards, malaria transmission intensity, definition of malaria and the reported risk estimates. The methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS) [ 24 ] and the risk of bias across studies was assessed using the GRADE approach [ 25 ]. The risk of bias assessment within and across studies is presented as Additional file  3 .

Aggregated data meta-analysis was not possible due to the heterogeneity of studies in respect to study design, definition of malnutrition, definition of malaria, study population, e.g. age group target, analysis conducted and effect measures presented. Only summaries of study findings are presented in this review. Association between malnutrition and risk of malaria was deemed to be statistically significant if either the P value was < 0.05 and/or the 95% confidence intervals (CIs) did not include 1. The risk of malaria was classified as “increased” or “decreased” according to the interpretation of the effect estimates provided (i.e. incidence risk ratio (IRR), odds ratio (OR), risk ratio (RR) or hazard ratio (HR)) if statistical significance was achieved as described above.

The literature search identified 2945 articles. A total of 32 articles identified through the search and 1 article obtained through citation tracking were included, describing cross-sectional surveys ( n  = 16), longitudinal studies ( n  = 12), interventional studies ( n  = 3), case-control study ( n  = 1) and individual patient data meta-analysis ( n  = 1) (Fig.  1 ). Details of the 33 studies included in this review are given in Table  1 , while the study characteristics are summarised in Additional file  4 .

figure 1

Flow diagram of study selection

Association between malnutrition and risk of malaria

In total, 29 studies assessed the association between malnutrition and risk of malaria (Tables  2 ,  3 and  4 ).

Risk of malaria infection in children with stunting (chronic malnutrition)

Twenty-three studies explored the relationship between stunting and risk of malaria infection (Table  2 ). Overall results were conflicting, with 15 studies showing that stunting was associated with an increased malaria risk, 11 studies showing no association and 2 studies showing a protective effect of stunting (Table  2 ).

A prospective cohort study of 487 children under 5 years of age in rural Gambia by Deen et al. reported that being stunted increased the risk of malaria infection significantly (RR = 1.35 (95% CI = 1.08–1.69)) [ 10 ]. The authors hypothesised that the observed association between malnutrition and malaria infection might be influenced by confounding factors such as HIV co-infection or socio-economic factors. Similarly, in a cross-sectional survey in children < 3 years in Kenya, Friedman and colleagues found an increased malaria risk in stunted children, showing a trend towards an increased risk of clinical malaria (OR = 1.77, P  = 0.06), and significantly increased risk of any malaria parasitemia (OR = 1.98, P  < 0.0001), high-density parasitemia (any species, > 1500–7000/μL; OR = 1.84, P  < 0.0001) and severe anaemia (OR = 2.65, P  < 0.0001) [ 26 ]. In contrast, a longitudinal study from the Gambia by Snow et al. in children aged 1–4 years reported only a minor (non-significant) impact of stunting on clinical and asymptomatic malaria episodes [ 17 ]. Two longitudinal malaria surveillance reports, one in Senegal with 874 children aged 12 months–5 years and the other in Burkina Faso with 685 children aged 6–30 months did not show any association between a low HAZ and subsequent malaria attacks [ 18 , 27 ]. Similarly, Verhoef et al. in Kenya did not observe an association between being stunted and the risk of malaria infection; however, they showed that stunting might determine the severity of malaria-associated anaemia in African children [ 13 ]. Verret et al. found that in chronically malnourished children in a high-transmission setting in Uganda, children with mild (HAZ [≥ − 2 and < − 1]) to moderate (HAZ < − 2) stunting not given trimethoprim-sulfamethoxazole prophylaxis were at higher risk for recurrent parasitemia [ 22 ]. Contrary to this, in a cohort survey of 790 children under 5 years in the Kivu province, Democratic Republic of Congo (DRC), Mitangala and colleagues found that being severely stunted was protective of subsequent malaria parasitemia [ 21 ]. This finding was supported by Genton et al. in a prospective cohort of 136 children aged 10–120 months in Papua New Guinea showing that lower HAZ had a protective effect against falciparum malaria [ 14 ].

Risk of malaria infection in children with wasting

Eighteen studies explored the relationship between wasting and risk of malaria infection (Table  3 ). Overall, results were again conflicting, with three studies showing that wasting was associated with an increased malaria risk, two studies showing a protective effect and most studies showing no association (Table  3 ).

Takakura et al. [ 29 ], Ehrhardt et al. [ 11 ] and Shikur et al. [ 28 ] found an increased risk of P. falciparum malaria in children with wasting. In a case-control study involving 428 under-five children in Ethiopia, Shikur and colleagues found that severely wasted children were three times more likely to have malaria episode than non-wasted children (adjusted OR = 2.90 (95% CI = 1.14–7.61) [ 28 ]. In 2006, Ehrhardt et al. reported a survey involving 2905 children in Ghana aged 6–108 months in which wasting was significantly associated with a higher risk of clinical malaria (OR = 1.86, 95% CI = 1.14–3.02) [ 11 ]. Takakura et al. in a cross-sectional study of 309 children and adolescents (aged 2 to 18 years) in the Lao PDR showed that P. falciparum infection was associated with wasting [ 29 ]. However, Fillol and colleagues reported a significant protective association between being wasted (WHZ < − 2) at the onset of the rainy season and the risk of a clinical malaria episode (OR = 0.33, 95% CI = 0.13–0.81) in 874 preschool children (between 12 months and 5 years of age) in Senegal [ 27 ]. Similarly, in a cross-sectional survey of 1862 very young children (from 0 to 36 months age) in western Kenya, Friedman et al. showed that wasting decreased the risk of concurrent malaria (OR = 0.75, P  = 0.18) and high-density parasitemia (OR = 0.96, P  = 0.88), although increased the risk of severe malarial anaemia (OR = 2.0, P  = 0.04) [ 26 ]. In contrast, two other longitudinal studies conducted in the Gambia [ 17 ] and in Burkina Faso [ 18 ] and a few cross-sectional surveys from Equatorial Guinea [ 30 ], Eastern Kenya [ 13 ] and Ghana [ 11 ] reported no association between being wasted and the risk of malaria infections.

Risk of malaria infection in underweight children

Nineteen studies explored the relationship between being underweight-for-age and risk of malaria infection (Table  4 ). Overall, results were again conflicting, with five studies showing that underweight children carried a higher malaria risk, and the remaining studies showing no association (Table  4 ).

In 2006, Ehrhardt et al. using cross-sectional surveys in Ghana found that being underweight was significantly associated with a higher risk of having fever of any cause (OR = 1.59, 95% CI = 1.13–2.23), clinical malaria (OR = 1.67, 95% CI = 1.10–2.50) and anaemia (OR = 1.68, 95% CI = 1.38–2.04) [ 11 ]. This was confirmed by Sumbele et al. [ 57 ] who found that 21.6% of underweight children but only 8.2% of adequately nourished children developed clinical malaria ( P  = 0.007) in Cameroon. In a series of cross-sectional surveys conducted in the South Pacific island of Vanuatu in 1997, Williams et al. found a strong association between the incidence of P. vivax malaria and subsequently becoming underweight (IRR = 2.6, 95% CI = 1.5–4.4) but no significant effect of P. falciparum malaria (IRR = 1.1, 95% CI = 0.57–2.1) [ 31 ]. On the other hand, Tonglet et al. reported a non-significant protective association between being underweight and the risk of clinical malaria in children between 9 months and 2 years of age in the DRC (OR = 0.68, 95% CI = 0.24–1.11) [ 32 ].

Malnutrition and anti-malarial drug efficacy

Limited data exist on the effect of malnutrition on response to antimalarial drugs, in particular ACTs. Only five studies were identified in our literature search, and results were again contradictory.

In 2008, Obua et al. explored the impact of nutritional status on the dose, drug concentrations and treatment outcome with co-packaged chloroquine plus sulfadoxine-pyrimethamine in 83 children (6 months–5 years) with uncomplicated falciparum malaria [ 33 ]. The authors found that stunting (height-for-age Z-score < − 2) was associated with higher bodyweight-adjusted (mg/kg) doses of chloroquine and sulfadoxine-pyrimethamine, higher sulfadoxine concentrations on day 1 and chloroquine concentrations on day 3, and better cure rates ( P  = 0.046).

In a longitudinal study of 292 infants (aged 4–12 months) in Uganda, a high malaria transmission intensity setting, ACTs (artemether-lumefantrine and dihydroartemisinin-piperaquine) were generally efficacious with a good early parasitological response (99% of study participants cleared parasites by day 3) for treatment of P. falciparum malaria, including in 43% chronically malnourished children [ 22 ]. However, in this study, stunted children (height-for-age Z-score < − 2) in the dihydroartemisinin-piperaquine arm who were not taking trimethoprim-sulfamethoxazole prophylaxis (given to all HIV-infected and exposed infants) were at higher risk for recurrent parasitaemia (HR 3.18 (95% CI 1.18–8.56); P  = 0.022). Another study carried out in the DRC in 445 children, comparing the efficacy of standard doses of artesunate-amodiaquine between children with and without severe acute malnutrition (SAM), observed no evidence of reduced efficacy in children with SAM, which had an adequate clinical and parasitological cure rate, ACPR, of 91.4% [ 34 ]. A recent multi-centre (Mali and Niger), open-label trial compared the efficacy and pharmacokinetics of artemether-lumefantrine in 399 children with or without SAM. The results of this study showed adequate therapeutic efficacy in both SAM and non-SAM groups (day 42 ACPR 100% vs. 98.3% respectively) with no early treatment failures and no difference in parasite clearance reported. However, a higher risk of reinfection in children older than 21 months suffering from SAM was evident (AHR 2.10 (1.04–4.22); P  = 0.038) [ 35 ]. Similarly in a large pooled analysis of individual pharmacokinetic-pharmacodynamic (PK-PD) data from 2787 patients treated with artemether-lumefantrine for uncomplicated Pf malaria, the WorldWide Antimalarial Resistance Network (WWARN) demonstrated that among children 1–4 years of age in high-transmission areas, the risk of reinfection increased with a decrease in WAZ with a HR of 1.63 (95% CI 1.09 to 2.44) for a child with WAZ of − 3 compared to an adequately nourished child (WAZ = 0) [ 36 ].

Information on the pharmacokinetic properties of ACTs in malnourished children is critically lacking in the published literature. Our search retrieved a study published in 2016 which assessed the efficacy of AL in relation to drug exposure in children with SAM vs. non-SAM in Mali and Niger [ 35 ]. This study measured lumefantrine concentration and showed that despite the administration of 92 g fat with dosing of SAM children (compared to 15 mL milk in non-SAM children), day 7 lumefantrine concentrations were lower in children with SAM compared to non-SAM (median 251 vs. 365 ng/mL, P  = 0.049). In the WWARN pooled analysis of individual PK-PD data from patients treated with artemether-lumefantrine for uncomplicated Pf malaria, underweight-for-age young children (< 3 years) had 23% (95% CI − 1 to 41%) lower day 7 lumefantrine concentrations than adequately nourished children of same age [ 36 ].

The evidence on the effect of malnutrition on malaria risk remains controversial and in many instances contradictory. The current review highlights some key limitations in the way the interaction between malaria and malnutrition has been assessed and reported. First, differences in methodology, study populations, the variability in measures used to define malnutrition (e.g. different growth references, different cut off thresholds), and the heterogeneous malaria transmission intensities with different levels of host immunity within the different studies make the comparison challenging. Second, there is a paucity of information on the effect of malnutrition on therapeutic responses to ACTs and their pharmacokinetic properties in malnourished children in published literature. Generally, vulnerable populations with common co-morbidities such as malnutrition, obesity, HIV or tuberculosis co-infection are excluded from or under-represented in antimalarial drug efficacy trials [ 37 ]. Although weight is documented, height is rarely recorded in ACT efficacy trials (< 20% of 250 trials currently included in the WWARN repository, personal communication Kasia Stepniewska), restricting the possibilities for secondary analyses. Another useful metric, mid-upper arm circumference (MUAC) is also rarely documented in malaria clinical trials despite being relatively easy to measure and low MUAC shown to be associated with increased malaria risk [ 38 ] and decreased lumefantrine bioavailability [ 39 ]. Several confounding factors and effect modifiers have been suggested such as age, co-morbidities (e.g. HIV, tuberculosis co-infection and drug interactions), immunity, socio-economic status, or refeeding practices. However, these confounding factors are poorly documented and controlled for in most of the reported studies in this review.

This review has several limitations. First, one third of the studies included in this review recruited individuals of all ages, and disaggregating observations by the age of individuals (below and above 5 years) was not possible. Methodologically, the temporal relationship between malnutrition and risk of malaria (and progression from infection to symptomatic malaria) could not be assessed because of cross-sectional study design (50% included studies). It is also limited by the extent to which important confounders (such as differential micronutrient deficiencies, ecological and genetic factors) are measured and reported in the included articles. Finally, the heterogeneity of the selected studies (presented as Additional file 5 ) including variations in measurement of nutritional status, definition of malaria, and statistical approaches adopted in deriving the risk estimates restricted plausible aggregated data meta-analysis in this review.

Interestingly, while no consistent association between risk of malaria and acute malnutrition was found, chronic malnutrition was relatively consistently associated with severity of malaria such as high-density parasitemia and anaemia [ 10 , 26 , 27 ] . The mechanism behind the higher risk of recurrent parasitemia could be explained partially by the impact of chronic malnutrition on the immune system and/or lower antimalarial bioavailability. Likewise, the apparent protection of wasted children from clinical malaria might be caused by their being administered a higher mg/kg antimalarial dose and/or a modulation of their immune response and thus an absence of symptoms, e.g. fever usually associated with malaria as opposed to an absence of malaria infection. Friedman et al. showed high-density parasitemia as a predictor for chronic malnutrition [ 26 ]. Nevertheless, the role of malaria in the aetiology of malnutrition remains unclear. The effect of malaria on nutritional status appeared to be greatest during the first 2 years of life and age acted as an effect modifier in the association between malaria episodes and malnutrition [ 6 ].

ACTs are now recommended for the treatment of uncomplicated falciparum malaria in almost all malaria-endemic countries and the number of children exposed to these antimalarial agents is increasing. A priority area is to identify gaps in our current knowledge in regard to the pharmacokinetic properties of artemisinins and partner drugs in malnourished paediatric populations to optimise dosing in order to ensure efficacy, safety and avoid the selection of parasite resistance [ 40 ]. Exposing pathogens to sub-therapeutic levels of active ingredients is a major driver of resistance. Protein-energy malnutrition, defined as insufficient calorie and protein intake, may have potential physiological effects on the absorption, distribution and metabolism of ACTs and subsequently affect the efficacy and safety of ACTs. Severe acute malnutrition can cause pathophysiological changes, including increasing total body water, leading to greater volume of distribution of drugs, which in turn may cause sub-optimal drug exposure when ACTs are given at standard doses [ 35 , 41 ]. This could be further compounded by malnutrition in paediatric patients leading to dosing inaccuracies of ACTs when dose is calculated by age (over-dosing for actual body weight) or weight (under-dosing for age). Malnutrition can also be associated with intestinal malabsorption and villous atrophy of the jejunal mucosa which may cause impaired drug absorption [ 42 ]. The reduced absorption of lipids and fats has the potential to specifically affect the lipid-soluble ACTs [ 43 ]. The hepatic metabolism of the ACTs may be compromised in malnourished children. For instance, in case of quinine, hepatic metabolism is decreased in protein deficiency and increased in global malnutrition [ 44 ]. Thus, hepatic metabolised drugs should be carefully monitored in children with malnutrition. A recent individual patient data (IPD) meta-analysis conducted by the WWARN to investigate the effect of dosing strategy on efficacy of artemether-lumefantrine showed that the risk of treatment failure was greatest in malnourished children aged 1–3 years in Africa (PCR-adjusted efficacy 94.3%, 95% CI 92.3–96.3) [ 45 ]. Another large WWARN IPD meta-analysis of individual PK-PD data from patients treated with artemether-lumefantrine (AL) for uncomplicated malaria, showed day 7 concentrations adjusted for mg/kg dose were lowest in very young children (< 3 years), among whom underweight-for-age children had 23% (95% CI − 1 to 41%) lower concentrations than adequately nourished children of the same age and 53% (95% CI 37 to 65%) lower concentrations than adults [ 36 ]. This raises the question of whether an adapted dosing regimen is needed in malnourished young children. The PK-PD evaluation of artemisinins and longer-acting partner antimalarials for the treatment of malaria in paediatric populations and the effect of malnutrition on the pharmacological activity of ACTs is a priority area to identify and address key knowledge gaps.

A summary of the remaining knowledge gaps is presented to serve as the basis for prioritising future research strategies and highlights the need for standardising measures and reporting of nutritional status. Further analyses using individual patient data could provide an important opportunity to better understand the variability observed in publications by standardising both malaria nutritional metrics. In an era of emergence and spread of antimalarial drug resistance, it is imperative to improve our understanding of the pharmacodynamics and pharmacokinetics of ACTs in malnourished children to optimise antimalarial treatment of this very large vulnerable population. Pooled analysis, gap analysis and carefully designed prospective, randomised controlled clinical trials can provide strong evidence on the outstanding questions raised in this review related to malaria-malnutrition interactions.

Abbreviations

Artemisinin combination therapy

Adjusted odds ratio

Confidence interval

Democratic Republic of Congo

Grading of Recommendations Assessment, Development, and Evaluation

Height-for-age Z-score

Hazard ratio

Individual patient data

Incidence risk ratio

Mid-Upper Arm Circumference

Newcastle-Ottawa Scale

Plasmodium falciparum

Pharmacokinetic-pharmacodynamic

Severe acute malnutrition

Standard deviation

Weight-for-age Z-score

World Health Organization

Weight-for-height Z-score

WorldWide Antimalarial Resistance Network

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Acknowledgements

The authors gratefully acknowledge the assistance of Eli Harriss with database searches and Per Olav Vandvik for reviewing the methods of the manuscript. The authors are also very grateful to Prabin Dahal, Makoto Saito, Andrea Stewart and Alex Gardiner for their valuable comments on the manuscript.

WorldWide Antimalarial Resistance Network (WWARN) is funded by the Bill and Melinda Gates Foundation. EAO is supported by the Wellcome as an Intermediary Fellow (# 201866) and also acknowledge the support of the Wellcome to the Kenya Major Overseas Programme (# 077092 and 203077).

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All the data used in this review has been presented in the main text either as tables or as supplementary files. Additional requests for the data can be made through the WorldWide Antimalarial Resistance Network ( www.wwarn.org ). Please email: [email protected]

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Das, D., Grais, R.F., Okiro, E.A. et al. Complex interactions between malaria and malnutrition: a systematic literature review. BMC Med 16 , 186 (2018). https://doi.org/10.1186/s12916-018-1177-5

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literature review on malaria pdf

Malaria in pregnancy: a literature review

  • PMID: 18455095
  • DOI: 10.1016/j.jmwh.2008.02.012

Pregnant women are more likely than nonpregnant women to become infected with malaria and to have severe infection. The effects of malaria during pregnancy include spontaneous abortion, preterm delivery, low birth weight, stillbirth, congenital infection, and maternal death. Malaria is caused by the four species of the protozoa of the genus Plasmodium, which is transmitted by the bite of the female Anopheline mosquito, congenitally, or through exposure to infected blood products. This article reviews the epidemiology, pathology, clinical symptoms, diagnosis, and treatment of malaria in pregnant women. Interventions to prevent malaria include intermittent preventive treatment, insecticide-treated nets, and case management of malaria infection and anemia.

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  • Anemia / complications
  • Anopheles / parasitology
  • Antimalarials / therapeutic use
  • Insect Vectors / parasitology
  • Malaria* / diagnosis
  • Malaria* / physiopathology
  • Malaria* / therapy
  • Malaria* / transmission
  • Plasmodium / physiology
  • Pregnancy Complications, Parasitic* / diagnosis
  • Pregnancy Complications, Parasitic* / physiopathology
  • Pregnancy Complications, Parasitic* / therapy
  • Pyrimethamine / therapeutic use
  • Sulfadoxine / therapeutic use
  • Antimalarials
  • Sulfadoxine
  • Pyrimethamine

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An Overview of Malaria in Pregnancy

Melissa bauserman.

1 Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, NC

Andrea L Conroy

2 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN

Krysten North

3 Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, NC

Jackie Patterson

4 Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, NC

5 Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, NC

Steve Meshnick

6 Department of Epidemiology, University of North Carolina Gilligns School of Global Public Health, Chapel Hill, NC

One hundred twenty-five million pregnant women are at risk for contracting malaria, a preventable cause of maternal and infant morbidity and death. Malaria parasites contribute to adverse pregnancy and birth outcomes due to their preferential accumulation in placental intervillous spaces. Pregnant women are particularly vulnerable to malaria infections, and malaria infections during pregnancy put their fetuses at risk. Malaria in pregnancy is associated with anemia, stillbirth, low birth weight and maternal and fetal death. We review the challenges to diagnosing malaria in pregnancy, as well as strategies to prevent and treat malaria in pregnancy. Finally, we discuss the current gaps in knowledge and potential areas for continued research.

Introduction

Globally, an estimated 125 million pregnant women reside in areas where they are at risk of contracting malaria in pregnancy (MIP), and MIP remains an important preventable cause of adverse birth outcomes. 1 Although there are five species of malaria that infect humans, two main species of Plasmodium contribute to adverse maternal and fetal outcomes in pregnancy, P. falciparum and P. vivax. In sub-Saharan Africa, where the majority of adverse birth outcomes attributable to malaria occur, P. falciparum is the dominant species. However, over half of pregnancies that are potentially exposed to malaria occur in Southeast Asia and the Western Pacific where P. falciparum and P. vivax coexist. Co-existence of P. falciparum and P. vivax also occurs in South America, where 3% of the global total of women at risk for MIP reside. 1

Over the past decade, there has been significant progress in reducing the global prevalence of P. falciparum , particularly in Africa. However, women remain at high risk of MIP, with over 50% of women in high transmission areas having P. falciparum detected in peripheral blood at presentation to antenatal care. 2 , 3 This high prevalence of disease results from an increased risk of contracting malaria among pregnant compared to non-pregnant women. Women who are younger, malnourished, primigravidae/secundigravidae, lack immunity to pregnancy-associated malaria, or living with HIV are at the highest risk of malaria-associated adverse pregnancy outcomes. 4 , 5

Pathophysiology of Malaria in Pregnancy

MIP contributes to adverse pregnancy outcomes, at least in part, due to the preferential accumulation of parasites in the placental intervillous space. Placental sequestration is common in infections with P. falciparum because malaria parasites export a protein, VAR2CSA, to the red blood cell membrane that facilitates adherence to chondroitin-sulfate A (CSA) on syndecan-1, which is anchored in placental tissue. 6 This interaction is associated with the recruitment, retention and activation of mononuclear cells in the placenta—and is thought to mediate malaria’s effect on birth outcomes. 7 Maternal antibodies against VAR2CSA are protective. 5 P. vivax can also lead to placental changes, but to date no studies have unequivocally documented the sequestration of P. vivax infected erythrocytes in the placenta. 8

A number of histological changes in P. falciparum infected placentae have been described, including the infiltration of mononuclear cells, deposition of malaria pigment, thickening of the trophoblast basement membrane, syncytial knotting, and complement deposition. 9 – 11 Inflammation in the placenta has been linked to impaired transplacental transport of glucose 12 and amino acids, 13 and disruption of the insulin-like growth hormone axis. 14 Impaired nutrient transport across the placenta may be further exacerbated by altered placental angiogenesis 15 leading to changes in both the villous architecture 16 and surface area for nutrient exchange, as well as impaired uteroplacental blood flow. 15 , 17 These histologic and functional changes likely contribute to impaired fetal growth. Longitudinal Doppler data support the idea that malaria in the first half of pregnancy can lead to changes in umbilical artery blood flow and fetal growth in pregnancy, and this is affected by both gravidity and nutritional status. 18

Risk Factors for Malaria in Pregnancy

Environmental, parasite, and maternal factors influence the severity of MIP. In areas where malaria transmission is high, the primary burden of malaria is in primigravidae, whereas, in areas of low transmission, all gravidities are at risk. In areas of high transmission, primigravidae develop antibodies to VAR2CSA protein produced by malaria parasites, and are partially protected during subsequent pregnancies; this tends not to happen in areas of low transmission. 19 Overall, pregnant women living in areas with low or unstable (episodic) transmission have little or no immunity to malaria and are at a two-to-three times higher risk of severe disease compared to non-pregnant controls. 20 P. falciparum has typically been associated with more severe MIP than P. vivax , although P. vivax is more likely to occur in a mother with little acquired immunity. 21 Maternal age and gravidity also play a role in the severity of MIP. Younger mothers are at greater risk for severe malaria infection compared to older mothers, who appear to have some protection from severe disease. 4 In high transmission areas, such as sub-Saharan Africa, primigravidae and secundigravidae are at greater risk for severe malaria infection compared to multigravidae, but this is not true in areas of low transmission, where multigravidae have not had prior malaria exposure nor developed immunity. 22

Malnourished pregnant women are at increased risk for adverse birth outcomes with MIP. 23 A meta-analysis using individual patient data from 14,633 pregnancies from Africa and the Western Pacific between 1996–2015 showed that malaria and malnutrition are common exposures, with 35% of women having either of those exposures. Pregnant women with malnutrition and malaria were at an increased risk of LBW compared to women with only 1 of those risk factors. 24 Recent data suggests reduced L-arginine intake is one mechanism through which malnutrition contributes to low birth weight with both nutritional survey data 25 and preclinical models 26 suggesting that L-arginine supplementation may reduce preterm birth 25 and increase fetal viability, placental vascularization, and birth weight. 26

Burden of Malaria

Maternal effects.

The clinical effects of malaria on pregnant women vary from no symptoms to severe anemia and death. Women living in areas of low malaria transmission who have a lower degree of acquired immunity are more likely to experience complications such as renal failure, pulmonary edema, and cerebral malaria. 27 Despite this, the overall maternal mortality rate is similar in low-transmission areas (0.6–12.5%) compared to malaria-endemic areas (0.5–23%). 4 More research is warranted on the topic of malaria-related mortality during pregnancy, as the current data are limited and inconsistent.

Maternal anemia is one of the most common symptoms of MIP. Plasmodium causes anemia through hemolysis, increased splenic clearance of erythrocytes, and reduced red blood cell production. While severe anemia during pregnancy (hemoglobin <7 g/dL) is often multifactorial with significant nutritional components, malaria can play an important role. 28 In one estimate in sub-SaharanAfrica, the population attributable fraction of malaria to severe anemia during pregnancy was 26%. 4 For endemic areas with a 5% baseline prevalence of severe anemia, epidemiological modeling predicts malaria-induced anemia to contribute to nine maternal deaths per 100,000 live births. 4 However, in a population-based study in the Democratic Republic of the Congo, malaria played little or no role as a driver of anemia during pregnancy. 29

Pregnant women are three times more likely to be affected by severe malaria. 30 The World Health Organization defines severe malaria as parasitemia with evidence of end organ dysfunction ( Table 1 ). The presenting features of severe malaria can include severe anemia, hypoglycemia, acute respiratory distress syndrome, renal failure and cerebral malaria. 30 The median mortality of severe MIP is 39% (range 8–100%). 30 Severe malaria must be treated promptly with intensive care and parenteral antimalarial medication to reduce mortality. 31

Treatment Strategies for MIP

Fetal Effects

Malaria is an important cause of stillbirth throughout endemic areas ( Figure 1 ). MIP contributes to 12–20% of stillbirths in endemic regions of sub-Saharan Africa, with lower rates if the mother undergoes treatment. 32 P. falciparum detection both in peripheral blood samples or placental samples at delivery nearly doubles the odds of stillbirth (odds ratio 1.81 and 1.5, respectively). 32 Stillbirth risk is higher in areas with low to intermediate endemicity compared to areas of high endemicity. 33 The risk of stillbirth can be modified with appropriate malaria intervention efforts. For example, the use of insecticide-treated bed nets (ITN) is associated with lower rates of placental malaria and stillbirth (risk ratio 0.67 [95% CI 0.45 to 1.00] for stillbirth). 34

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IUGR = Intrauterine growth retardation. Reprinted with permission ( 4 ).

MIP increases the risk of low birth weight (LBW), and approximately 20% of cases of LBW in malaria-endemic areas are attributed to placental infection with malaria ( Figure 1 ). 35 A mother with a malaria-infected placenta is twice as likely to have a baby with LBW. 36 LBW in turn is associated with higher infant mortality rates. In Africa, LBW has been associated with a three - to 20-fold increase in the probability of infant mortality. 36 , 37 Parity is an important factor in LBW. Primigravidae with MIP have two to seven higher odds of LBW and mortality than multigravidae. 38 The timing of infection also seems to play a role in infant size. Second-trimester infection is more likely to result in LBW than third-trimester infection; but data on first-trimester infection are limited. 39

MIP causes LBW due to both intrauterine growth restriction (IUGR) and prematurity. Up to 70% of IUGR in endemic areas is due to malaria, presumably as a result of impaired oxygen and nutrient delivery to the fetus. 35 , 36 The contribution of malaria to preterm birth is also substantial, with up to 36% of prematurity in malaria-endemic areas attributable to Plasmodium infection. Prematurity may result from the host’s immune response to malaria parasites triggering early labor. 33 These adverse fetal effects are species specific, as P. ovale and P. malariae species are not associated with adverse birth outcomes.

Congenital Malaria

Congenital malaria is defined as the identification of asexual P. falciparum parasites in the cord blood or peripheral blood of an infant during the first 7 days of life. 40 The true prevalence of congenital malaria is uncertain. While the prevalence was previously thought to be between <1% and 6%, 40 more recent studies have demonstrated a prevalence rate up to 33% in high-endemicity areas; but it is not clear how many of these congenital infections persist and cause clinical illness. 41 Most descriptive reports of congenital malaria are from infants who are born in non-endemic areas to mothers with a history of travel to endemic areas. Infant symptoms include fever associated with hepatosplenomegaly, hemolytic anemia, thrombocytopenia, and feeding intolerance. 41 These infants often become symptomatic between 10 and 30 days of life, although they can present later. Their symptoms may progress rapidly and can be fatal. 27 , 42 Because, much of the literature on congenital malaria is derived from case reports, more research is needed to better understand the epidemiology and pathophysiology of congenital malaria.

Effects in Early Childhood

Offspring are affected by placental malaria into childhood, ( Figure 1 ). Prenatal malaria exposure is associated with an increased risk of early malaria infection in children as young as four to six months of age. 40 Placental parasitemia may increase the risk of malaria infections in infancy and childhood through several mechanisms. For example, MIP might interfere with maternal antibody passage to offspring, compromising the immunity of the fetus and newborn, making the offspring vulnerable to early malaria infections. 40 In utero exposure to malaria induces the development of T reg cells that lead to fetal immune tolerance to malaria antigens that persists into childhood. 43 Placental malaria has been associated with subsequent susceptibility to non-malaria infections, including measles and tetanus, suggesting additional effects on infant immunity that may be due to the obstruction of antibody passage across the placenta. 44 Acute placental malaria infection has been associated with increased one-year mortality in infants 45 and decreased length and weight gain in the first year of life. 46 , 47 MIP is also associated with anemia during infancy and the infant’s risk for anemia with maternal peripheral parasitemia at delivery is 11.8% and 9.2% with placental malaria infection. 48

The diagnosis of MIP can be challenging due to placental sequestration of parasitized erythrocytes, low circulating levels of parasites and limited resources in malaria endemic areas for advanced diagnostic techniques. Microscopic identification of malaria from the blood by an experienced and well-equipped technician remains the gold standard for malaria diagnosis. 49 However, rapid diagnostic tests (RDTs) that test for malaria antigens, like histidine-rich protein-1 (PfHRP2), are another option for malaria diagnosis. 49 – 51 RDTs are easier than microscopy to perform in low-resource settings, because they are not dependent on highly trained technicians in well-equipped laboratories. Therefore, RDTs might be the most appropriate point of care testing among symptomatic mothers in low-resource settings. 31 , 50 However, the use of RDTs might be insufficient in diagnosing MIP among mothers with asymptomatic infection, because RDTs require a higher circulating parasite burden than microscopy for detection. 52 RDTs are also insufficient to detect low amounts of circulating parasites because of placental sequestration. In research studies, the gold standard for malaria diagnosis has been placental histopathology, but it is not practical in many field sites. 53 , 54 Using microscopy of placental blood as the referent, the sensitivity of RDTs is 81% (95% CI 55–93) and the specificity is 94% (95% CI 76–99). 31 Molecular techniques, such as polymerase chain reaction (PCR) diagnosis, have increased sensitivity of diagnosis when compared to microscopy of placental blood to 94% (95% CI 86–98), but specificity of 94% (95% CI 86–98). 31 A new generation of ultrasensitive RDT’s is now being developed and might mitigate these diagnostic problems. 55

Prevention and Treatment

Prevention strategies in africa.

In malaria-endemic areas in Africa, a combination of vector control (preventing exposure to mosquitos) and chemoprevention (preventive medication-based treatment) strategies are used to prevent MIP. The World Health Organization (WHO) recommends a combined approach using insecticide treated bed nets (ITNs) to reduce exposure to mosquitoes carrying malaria and chemoprevention. 56 ITNs work by providing a physical barrier from mosquitoes, and repelling or killing susceptible mosquitoes, which reduces mosquito density and maintains the nets’ effectiveness even after the integrity of the barrier is compromised. 57 The use of ITNs in Africa have been shown to reduce LBW by 23%, miscarriages and stillbirths by 33%, and placental parasitemia by 23%. 58 Despite the proven efficacy of ITNs, uptake was estimated at only 39% in Africa between 2009 and 2011. 59 Since that time, ITN use has steadily increased, and an estimated 61% of pregnant women at risk for malaria slept under an ITN in 2017 56 , ( Figure 2 ). Malarial resistance to pyrethroids, the most commonly used insecticide in ITNs has been reported across sub-Saharan Africa and might impair future efficacy. 57

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Percentage of the population in Sub-Saharan Africa at risk for malaria with access to ITN and using ITNs.

ITN: insecticide-treated bed nets Sources: World Health Organization and Malaria Atlas Project. Reprinted with permission ( 56 ).

Spraying the walls of households with insecticide to reduce human exposure to mosquitos, a procedure known as indoor residual spraying (IRS) is part of a comprehensive vector control program. Globally, IRS usage has declined and only 3% of the population at risk was protected by IRS in 2017, which might be related to a switch in insecticide from pyrethroids to more expensive chemicals. 56 IRS has been shown to improve outcomes of MIP, with women protected by IRS having lower incidence of MIP and lower risk of placental malaria. 60 , 61 When women were protected during greater than 90% of the time of their pregnancies, women had lower risk of preterm birth (risk ratio 0.35, 95% CI, 0.15–0.84). 60 IRS is an important part of a comprehensive vector control program and might contribute to improved birth outcomes in malaria-endemic regions.

Chemoprevention strategies have been successfully used to prevent adverse health outcomes associated with MIP. The most efficacious of these strategies uses a technique of intermittent preventive treatment in pregnancy (IPTp). IPTp consists of providing monthly doses of anti-malarial medication to all pregnant women starting in the second trimester. Women who receive at least 2 courses of IPTp have a relative risk reduction of 40% for moderate to severe anemia, 61% for antenatal parasitemia, 55% for placental parasitemia and 27% for low birthweight. 62 Since 2012, the WHO has recommended monthly IPTp to reduce the incidence of these complications of pregnancy. 63 However, despite WHO recommendations, in 2017, only 22% of pregnant women received three or more doses of IPTp in Sub-Saharan Africa ( Figure 3 ). 64

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Percentage of pregnant women receiving IPTp, by dose in Sub-Saharan Africa, 2010–2017.

ANC: antenatal care, IPTp: intermittent preventive treatment in pregnancy, listed by dose. Sources: National Malaria Programme, World Health Organization, US Centers for Disease Control and Prevention. Reprinted with permission ( 56 ).

Sulfadoxine-pyrimethamine (SP) has been the drug of choice for IPTp in women who are HIV-negative. 65 Plasmodium resistance to SP has emerged through multiple mutations in the P. falciparum dihydrofolate reductase (Pfdhfr) and dihydropteroate synthetase (Pfdhps), with penetrance of this haplotype in some areas of greater than 90%. 66 Due to increasingly more resistant organisms, IPTp with SP is less effective at inhibiting parasite growth and preventing fetal growth restriction. 66 In light of increasing resistance, alternative strategies for chemoprevention are being tested, including IPTp with alternative medications and strategies of intermittent screening and treatment in pregnancy (ISTp). ISTp strategies use RDTs to diagnosis MIP at multiple time points and treat only when RDTs are positive. However, these strategies depend on accurate diagnosis of MIP and have not been proven to be effective alternatives to IPTp-SP even in highly resistant areas. 66 IPTp with dihydroartemisinin-piperaquine (DP) might be a promising alternative to IPTp-SP, but more research is needed in this area. 66

Prevention Strategies Outside of Africa

In South America and Asia, where malaria transmission is typically lower than in Africa, data on traditional chemoprophylaxis is limited. Prophylaxis with mefloquine or chloroquine has been efficacious for preventing MIP in pregnant women in Thailand. 67 , 68 Other chemoprophylactic strategies employed outside of Africa have included monthly IPTp-SP with azithromycin and ISTp-SP and artesunate. These strategies show promise in the reduction of low birth weight or maternal parasitemia.

Treatment of uncomplicated malaria

All MIP infections should be treated promptly to avoid complications to the mother and fetus. 31 To ensure safety of treatment in pregnancy, the WHO recommends trimester-specific and species-specific treatment strategies for uncomplicated malaria ( Table 1 ). For first trimester treatment of P. falciparum , the WHO recommends a 7-day treatment course of quinine with clindamycin, and second line treatment includes artemisinin-based combination therapy (ACT) or oral artesunate with clindamycin. 65 First trimester treatment of uncomplicated non- falciparum malaria consists of chloroquine or quinine for chloroquine-resistant infections.

Second and third trimester treatment of uncomplicated malaria follows the same guidelines as treatment for malaria in non-pregnant adults. 31 Therefore, first line treatments with ACTs can be used in MIP. ACTs include a short-acting artemisinin component and a longer acting partner drug, such as SP. 69 The potent artemisinin reduces the number of parasites quickly and the longer acting partner drug acts on the remaining parasites and provides a post-treatment prophylactic effect, preventing new infections. 69 ACTs have achieved cure rates as high as 99.2% for uncomplicated MIP without demonstrating significant safety concerns. 70

Treatment of Severe Malaria

Severe malaria has historically been attributed to infections with P. falciparum , but more recent evidence has included P. vivax as a significant contributor to severe malaria. 30 For pregnant patients with severe malaria, the WHO recommends the same treatments for both P. falciparum and P. vivax infections. The WHO also recommends treatment with primaquine after delivery to achieve cure and prevent relapses by eradicating P. vivax sequestered in the liver, ( Table 1 ). 30

Artemisinins are the most efficacious drugs for severe MIP after the first trimester. Because they are embryotoxic and teratogenic in animal studies, the WHO does not recommend their use in the first trimester for uncomplicated malaria. However, their use is recommended even in the first trimester in cases of severe malaria because of the high risk of maternal mortality. 30 Data on the use of artemisinins in the first trimester in humans show no associated increased risk of adverse pregnancy outcomes. 30 Long-term neurodevelopmental studies are needed to evaluate the safety of different drug combinations on child development.

Quinine is an alternative to artemisinin that has been used for centuries for the treatment of malaria. Although it is not considered embryotoxic or teratogenic in animal studies, it is less well-tolerated in humans. 30 Quinine can prolong the cardiac QT interval and is associated with tinnitus, headache, blurred vision, altered auditory acuity, nausea, diarrhea, and, rarely, massive hemolysis. 65 These side effects reduce compliance with treatment regimens and lead to higher levels of treatment failure. 30

An efficacious vaccine against malaria could be of particular benefit for pregnant women. One vaccine, RTS,S, is now approved by the European Medicines Agency, but is only modestly effective. 71 Efforts are also underway to develop a vaccine targeting the VAR2CSA antigen to protect women against pregnancy-associated malaria. 72

Co-Infection with HIV

Co-infections with malaria and HIV worsen morbidity and mortality for each disease, possibly due to alterations in the balance between the immune response to malaria and stimulation of viral replication. 73 MIP is associated with a two-fold higher HIV viral load. Conversely, women living with HIV experience more placental and peripheral malaria, higher parasite densities, more frequent febrile illnesses, more severe anemia and worse birth outcomes compared to non-HIV infected mothers with MIP. 73 Chemoprevention for women living with HIV in malaria-endemic areas includes daily co-trimoxazole. SP is discouraged for chemoprevention due to potential adverse drug reactions between SP and co-trimoxazole. 74 Although pregnant women living with HIV have the greatest risk of severe MIP, treatment strategies for severe malaria in conjunction with HIV treatments have not been well studied. 30 , 73 The WHO recommends against the use of zidovidine or efavirenz and the use of artesunate amodiaquine due to neutropenia and hepatotoxicity respectively. 65 Pregnant women receiving highly active antiretroviral therapy regimens should receive quinine when cardiac monitoring is available.

Conclusions

Malaria is among the most common and easily preventable causes of poor birth outcomes in the world. IPTp and ITNs distribution programs have helped decrease malaria risk among pregnant women in many parts of the world. However, greater efforts are needed especially in light of increasing drug and insecticide resistance. A better understanding of the pathogenesis of malaria during pregnancy could lead to the development of new interventions to prevent its health consequences.

Gaps in Knowledge (sidebar)

  • What are the mechanisms by which malaria during pregnancy affects fetal growth?
  • What is the natural history of congenital malaria?
  • How can we increase uptake of IPTp and ITN’s by pregnant women?
  • When is the optimal gestational age to start IPTp?
  • How can we enable women to begin IPTp earlier during pregnancy?
  • When malaria prevalence drops, when is it appropriate to stop IPTp?
  • When high levels of resistance to SP develop, what should be done to protect pregnant women from malaria?
  • Will it be possible to vaccinate primigravidae against pregnancy-associated malaria?

DISCLOSURES

The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.

Reference List

literature review on malaria pdf

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Microfluidic systems for infectious disease diagnostics.

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a Laboratory of Microsystems, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland E-mail: [email protected]

Microorganisms, encompassing both uni- and multicellular entities, exhibit remarkable diversity as omnipresent life forms in nature. They play a pivotal role by supplying essential components for sustaining biological processes across diverse ecosystems, including higher host organisms. The complex interactions within the human gut microbiota are crucial for metabolic functions, immune responses, and biochemical signalling, particularly through the gut–brain axis. Viruses also play important roles in biological processes, for example by increasing genetic diversity through horizontal gene transfer when replicating inside living cells. On the other hand, infection of the human body by microbiological agents may lead to severe physiological disorders and diseases. Infectious diseases pose a significant burden on global healthcare systems, characterized by substantial variations in the epidemiological landscape. Fast spreading antibiotic resistance or uncontrolled outbreaks of communicable diseases are major challenges at present. Furthermore, delivering field-proven point-of-care diagnostic tools to the most severely affected populations in low-resource settings is particularly important and challenging. New paradigms and technological approaches enabling rapid and informed disease management need to be implemented. In this respect, infectious disease diagnostics taking advantage of microfluidic systems combined with integrated biosensor-based pathogen detection offers a host of innovative and promising solutions. In this review, we aim to outline recent activities and progress in the development of microfluidic diagnostic tools. Our literature research mainly covers the last 5 years. We will follow a classification scheme based on the human body systems primarily involved at the clinical level or on specific pathogen transmission modes. Important diseases, such as tuberculosis and malaria, will be addressed more extensively.

Graphical abstract: Microfluidic systems for infectious disease diagnostics

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T. Lehnert and M. A. M. Gijs, Lab Chip , 2024, Advance Article , DOI: 10.1039/D4LC00117F

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  • Open access
  • Published: 15 February 2024

Time series analysis of malaria cases to assess the impact of various interventions over the last three decades and forecasting malaria in India towards the 2030 elimination goals

  • Mrigendra P. Singh 1 ,
  • Harsh Rajvanshi 1 , 2 ,
  • Praveen K. Bharti 3 ,
  • Anup R. Anvikar 3 &
  • Altaf A. Lal 1 , 4 , 5  

Malaria Journal volume  23 , Article number:  50 ( 2024 ) Cite this article

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Despite the progress made in this decade towards malaria elimination, it remains a significant public health concern in India and many other countries in South Asia and Asia Pacific region. Understanding the historical trends of malaria incidence in relation to various commodity and policy interventions and identifying the factors associated with its occurrence can inform future intervention strategies for malaria elimination goals.

This study analysed historical malaria cases in India from 1990 to 2022 to assess the annual trends and the impact of key anti-malarial interventions on malaria incidence. Factors associated with malaria incidence were identified using univariate and multivariate linear regression analyses. Generalized linear, smoothing, autoregressive integrated moving averages (ARIMA) and Holt’s models were used to forecast malaria cases from 2023 to 2030.

The reported annual malaria cases in India during 1990–2000 were 2.38 million, which dropped to 0.73 million cases annually during 2011–2022. The overall reduction from 1990 (2,018,783) to 2022 (176,522) was 91%. The key interventions of the Enhanced Malaria Control Project (EMCP), Intensified Malaria Control Project (IMCP), use of bivalent rapid diagnostic tests (RDT-Pf/Pv), artemisinin-based combination therapy (ACT), and involvement of the Accredited Social Health Activists (ASHAs) as front-line workers were found to result in the decline of malaria significantly. The ARIMA and Holt’s models projected a continued decline in cases with the potential for reaching zero indigenous cases by 2027–2028. Important factors influencing malaria incidence included tribal population density, literacy rate, health infrastructure, and forested and hard-to-reach areas.

Conclusions

Studies aimed at assessing the impact of major commodity and policy interventions on the incidence of disease and studies of disease forecasting will inform programmes and policymakers of steps needed during the last mile phase to achieve malaria elimination. It is proposed that these time series and disease forecasting studies should be performed periodically using granular (monthly) and meteorological data to validate predictions of prior studies and suggest any changes needed for elimination efforts at national and sub-national levels.

Malaria, a global public health issue, has been successfully eliminated from 41 countries through time-tested case management and vector control strategies. Despite these promising strides, in the year 2021, the World Health Organization (WHO) estimated an alarming 247 million malaria cases and 619,000 deaths worldwide. Of these cases, the WHO South East Asia (SEA) region accounted for about 2% of the global malaria burden. Amongst the SEA countries, India contributed approximately 79% of the malaria cases and 83% of the malaria-attributed deaths in the region [ 1 ].

Several countries in the WHO SEA region have eliminated malaria or are close to eliminating malaria. Maldives and Sri Lanka are malaria-free. Thailand, Timor-Leste, Bhutan and Nepal are referred to as “E2025” countries as they aim to achieve elimination by 2025. Countries of the Asia Pacific region have also committed to the malaria elimination goal of 2030, with the majority of cases concentrated in the island nations of Papua New Guinea and the Solomon Islands, with an Annual Parasitic Incidence of 65 and 119, respectively [ 1 ]. There is a common concern of emergence and spread of drug resistance from the Greater Mekong Sub region, which combined with the insecticide resistance poses a threat to realizing the goals of malaria elimination in the region.

The WHO Global Technical Strategy has set the objective to achieve at least 90% case reduction in the global malaria burden and zero indigenous malaria cases by 2030 [ 2 ]. Despite the commitment, not all countries are on track to meet the 2030 global target of reducing malaria case incidence and death rates by at least 90%. Certain countries in the region grapple with a complex interplay of socio-economic, ecological, and health system-related factors, which have proven formidable obstacles in their malaria elimination endeavours.

India’s malaria epidemiology is complex across diverse demography, topography, and socio-cultural landscapes, which presents a risk to sustain the reduction in malaria cases and achievements of the elimination goals in a timely manner [ 3 ]. The country has implemented the National Strategic Plan for Malaria Elimination 2017–22 [ 4 ] and the National Framework for Malaria Elimination (NFME) in 2016–2030 [ 3 ], describing the strategies of early diagnosis and prompt treatment, vector control, community engagement, and inter-sectorial cooperation, to achieve the national malaria elimination goal of 2030. The national programme has emphasized special focus on 27 high-priority districts with moderate to high malaria transmission.

Information obtained through disease forecasting and time series analysis of historical data presents an opportunity for the policymakers and programme managers to use curated intervention efforts in a context-specific manner for the high-burden areas that are posing problems for disease elimination. Several malaria forecasting studies have been conducted in India, China, Burundi, Mali, Afghanistan, Bhutan and Ethiopia [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. However, the studies conducted in India either used hospital based passive malaria cases [ 12 ] or data from selected Indian states [ 13 , 14 , 15 ], which did not allow for the time series analysis and predictive malaria forecasting of the entire country.

The three inter-related objectives of this study were: (1) identification of the trends of malaria cases in India over the period 1990 to 2022 using time series analysis in order to forecast future malaria case burden for 2023 and 2030; (2) perform segmented regression on interrupted time series data to assess the impact of major interventions adapted in the national malaria programme over the period 1990 to 2022; and (3) conduct analysis to determine the association of extraneous independent factors with malaria incidence for the period of 2011 to 2021.

For forecasting analysis and assessment of the impact of commodity and policy interventions, country-wide malaria data over 3 decades was used. For analysis of predictors of malaria, the state-wise annual malaria data was used.

Study design

This ecologic study employed an explanatory time-trend design to study the annual trend of malaria cases during 1990–2022 and forecast future malaria cases, assessing the impact of major anti-malarial interventions during the study period and assessing the extraneous factors associated with malaria incidence in India.

Data sources

Retrospectively reported annual malaria cases for the period of 1990 to 2022 was obtained from the World Malaria Reports (WMRs) 2012 and 2023. State-wise annual malaria incidence data for the period of 2011 to 2021 and the timelines of different interventions for malaria control in the country was obtained from the public domain of NCVBDC New Delhi [ 16 ]. The extraneous variables associated with malaria incidence were collected from Census of India, 2011; India State of Forest Report 2021, Forest Survey of India; Rural Health Statistics, National Health Mission, Government of India; Monthly rainfall data series for districts, states, and sub-divisions and all India, Additional Director General of Meteorology, Ministry of Earth and Science, India Meteorological Department [ 17 , 18 , 19 , 20 ].

Estimation of trend and impact analysis of interventions

The annual trends of the time series data of malaria cases during 1990–2022 were plotted using centred moving averages, exponential, linear, and locally weighted regression lines. Over the last 3 decades, at different timepoints, several commodities and policy interventions have been introduced in India. Some of these interventions were novel, and some helped in strengthening and scaling up the existing strategies. The major interventions used in the present study were: (1) In 1997, the Enhanced Malaria Control Programme (EMCP) was operational in 181 selected tribal dominant districts of the country with the assistance of the World Bank. Under EMCP, case detection was improved with robust surveillance particularly in high endemic, hard to reach tribal dominated areas; (2) Further, in the year 2006, the World Bank-assisted Intensified Malaria Control Project (IMCP) was launched in inaccessible, high endemic and Plasmodium falciparum dominant areas of the country [ 21 ]. Emphasis was given to early diagnosis and prompt treatment; (3) On-spot diagnosis using monovalent rapid diagnostic test for P. falciparum (RDT-Pf) and artemisinin-based combination therapy (Artesunate + Sulfadoxine-Pyrimethamine (ACT-SP) as first-line treatment of P. falciparum introduced in 2005; (4) Accredited Social Health Activists (ASHAs) engaged to provide diagnosis and treatment of malaria cases at village level in 2009; (5) Bivalent RDTs for diagnosis of P. falciparum and Plasmodium vivax (RDT-Pf/Pv) infections and long lasting insecticidal nets (LLINs) for vector control in 2009 [ 22 ]; (6) Revised national drug policy with introduction of artemether-lumefantrine combination (ACT-AL) as first-line drug to treat confirmed P. falciparum cases in North Eastern states of the country in 2013; (7) Scaling up of LLINs coverage in malaria-endemic areas from 2015; and (8) Launch of NFME in 2016 [ 3 , 4 , 23 ].

The major change points have been identified in the years 1997, 2006, 2013, and 2016, to determine the impact of respective interventions using the Generalized Least Square (GLS) model along with autocorrelation via a corARMA function in R 4.3.2 (The R Project for Statistical Computing) to an Interrupted Time Series (ITS) malaria data by dividing into pre-intervention and post-intervention segment periods (equation below) [ 24 ]. Two dummy variables such as a binary indication of whether the intervention has taken place at the time (x) and time elapsed since the intervention were created. The slopes of the interrupted time trends of malaria cases between these two segments were compared to the estimated quantum of change and their statistical significance. The immediate effect showed a decline in malaria cases during the year following the introduction of interventions along with the sustained effect showing a declining rate over the following years.

Prediction of malaria cases from 2023 to 2030

The data from WMR used in this study was from the years 1990 to 2022, which allowed for a robust non-seasonal disease forecasting analysis to predict future cases of malaria. The dataset was divided into two subsets: a training set and a testing set. The training set had been used to train the forecasting model, while the testing set was reserved to assess the model's performance on new and unseen data. The linear trend, quadratic, cubic, centred Moving Average (MA), LOWESS, Simple Exponential Smoothing (SES), Double Exponential Smoothing (ETS), Auto-correlation Integrated Moving Average (ARIMA), Holt’s additive and Holt’s multiplicative regression models were used for forecasting analysis.

Evaluating the accuracy of time series forecasting models is essential to ensure that the predictions are reliable and trustworthy. Measuring performance of time series prediction model provides capability of the forecast to the real values. The most common performance statistics used are: Mean Forecast Error (or Forecast Bias) indicates the tendency of a model to overestimate or underestimate where positive bias means the model tends to overestimate, while negative bias means it tends to underestimate; Mean Absolute Error (MAE) measures absolute average magnitude of error (difference between actual value and predicted value) in prediction without considering the direction; Mean Squared Error (MSE) measures the average of the squares of the errors, which gives more weight to the large errors; Root Mean Squared Error (RMSE) is the square root of the MSE which is easier to interpret. It provides an estimate of the standard deviation of the forecast errors; Mean Absolute Percentage Error (MAPE) measures the relative accuracy of a forecast by calculating the percentage difference between predicted and actual values; Mean Absolute Standard Error (MASE), Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC). The model accuracy was measured with the lowest Root Mean Square Error (RMSE), Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC), Mean Absolute Percent Error (MAPE), Mean Absolute Standard Error (MASE) in the time series data for the test period. Accurate forecasting using ARIMA requires normally distributed stationary data with constant mean and variance over time. The present study used annual time series data points due to the non-availability of seasonal malaria data. Therefore, a seasonality test was not performed. Augmented Dickey-Fuller test (ADF Test) was used to test whether a given time series is stationary or not. The regular differencing method was used to make stationary time series observations over the time period. In the differencing method, each observation was replaced by a difference between the current and previous observation [ 25 ]. The present study follows the EPIFORGE 2020 checklist for reporting forecasting and prediction research [ 26 ].

Association of extraneous factors with malaria incidence

The univariate and multivariate generalized linear regression model was used to determine the extraneous independent factors associated with state-wise annual parasite incidence (API) data from 2011 to 2021 as the trend of malaria over the study period was roughly linear. Homoscedasticity test with residual plot, normality test with Q-Q plot and multi-collinearity test were also performed. The multi-collinearity effect between the independent variables included in the model was tested using a pairwise correlation matrix. The analysis did not reveal any strongly correlated variables. Hence, all the independent variables were included in the multivariate model, such as the proportion of the tribal population and literacy rate as per the 2011 Census (in the demography domain), vacant positions of ASHAs and peripheral health workers, number of health facilities (in the health infrastructure domain), and geographical areas under forest, hilly terrain and annual average rainfall (in geo-climatic domain).

The API is the number of malaria-positive cases per thousand population. Since API is highly dependent on the annual blood examination rate (ABER), it was standardized with the 10% constant ABER in the analysis. The multicollinearity between the independent variables was resolved before applying the multivariate linear regression model. All the statistical analyses were performed in R 4.3.2 (The R Project for Statistical Computing).

Annual trends of malaria during 1990–2022

During 1990–2000, 2001–2010 and 2011–2022, 2.38 (95% CI 2.14, 2.63), 1.75 (95% CI 1.61, 1.89), and 0.73 (95% CI 0.45, 1.01) million malaria cases were reported annually, respectively. The annual percent decline was 0.64 (95% CI − 7.42, 8.69), − 2.15 (95% CI − 6.84, 2.54), and − 14.31 (95% CI − 27.67, − 0.95), respectively, during these 3 decades (Table  1 ). The per cent decline in malaria cases during the 3rd decade (2011–2022) was significantly higher than in 1990–2000 (coefficient = − 14.94; 95% CI − 27.95, − 1.94; p = 0.026); and 2001–2010 (coefficient = − 12.15; 95% CI − 25.16, − 0.99; p = 0.05).

During the 3 decades i.e. 1990–2000, 2001–2010 and 2011–2022, the annual mean P. falciparum and P. vivax cases were 1.00, 0.85, 0.42 and 1.38, 0.90, 0.30 million, respectively. The annual percent decline during 3 decades was 4.02, − 2.05, and − 12.51 in P. falciparum and − 1.57, − 2.11 and − 14.75 in P. vivax, respectively (Table  1 ). The mean percent change during 3 decades in P. falciparum and P. vivax did not differ significantly (p > 0.05). Similarly, the difference in mean percent change between total malaria cases and two species ( P. falciparum and P. vivax ) was also not found significant statistically (p > 0.05).

The temporal trend in malaria over the period of 1990 to 2022 revealed a 91.26% (95% CI − 91.29, − 91.22) reduction in the reported malaria cases. Overall, the average annual declining rate in the reported malaria cases was − 5.84% (95% CI − 11.56, − 0.12). Most of the annual decline was observed in 2017–2018 by 49%, which could be attributed to robust implementation of monitoring and evaluation frameworks of case management and vector control strategies that were part of the NFME 2016–30 (Fig.  1 ).

figure 1

Trend of malaria cases in India from 1990 to 2022 showing time series (red line) and smoothing curves: (1) Centred moving average (black line); (2) Exponential curve (green line); (3) Linear curve (grey line); and (4) Lowess curve (blue line)

Impact of major anti-malarial intervention from 1990–2022

The analysis of ITS has revealed that EMCP, which focused on tribal-dominated hilly forests and P. falciparum -prone areas, had the most significant impact and effects sustained during the post-intervention period (p < 0.0001). IMCP provided early case detection and prompt treatment using RDT-Pf and ACT-SP, which contributed to a significant yearly cases reduction of malaria (p = 0.002). ASHAs (since 2009) and diagnosis using RDT-Pf/Pv (since 2013), and treatment with ACT-AL (since 2013) in the North Eastern region states led to an additional reduction in malaria cases, which was significant (p = 0.048). The NFME and scaling-up of LLINs distribution in hard-to-reach high malaria endemic areas had the highest impact in the reduction of malaria cases. However, in the GLS regression model, the coefficient was not found statistically significant (p = 0.101), possibly due to the fewer follow-up years after the change point (Table  2 ; Fig.  2 ).

figure 2

Segmented regression analysis in interrupted time series to assess the impact of major anti-malarial Interventions change point from 1990 to 2022. The four major change points are depicted in the graph. EMCP: enhance malaria control programme; IMCP: intensified malaria control programme; RDT: rapid diagnostic test; Pf: Plasmodium falciparum ; Pv: Plasmodium vivax ; ACT: artemisinin combination therapy; SP: sulfadoxine pyrimethamine; ASHA: accredited social health activist; AL: artemether lumefantrine; NFME: national framework of malaria elimination; LLIN: long lasting insecticidal nets

Prediction of malaria from 2023 to 2030

The statistical accuracy was found highest in ARIMA (1,2,2) model, with the lowest RMSE (64,631), AIC (774.15), BIC (779.48), MAPE (32.57), and MASE (0.34) indicator scores. The next lowest values of these parameters were in Holt’s additive and followed by Holt’s multiplicative models (Table  3 ). The MASE in Holt’s multiplicative model is more than 50% (0.51) which showed it to be an inappropriate model of forecasting for the present time series data. However, the 95% confidence interval in the predicted malaria cases was wider in ARIMA (1,2,2), as compared to both Holt’s models. The forecasting of the malaria cases for the next eight years (2023–2030) showed that the rapid decline from 2017–2022 was likely to continue, assuming the extraneous factors would be constant and there are no outbreaks. These observations imply that the target level of zero indigenous malaria cases would be achieved by 2027–2028 (Fig.  3 ).

figure 3

Forecast analysis using time series data from 1990 to 2022 and prediction of malaria cases from 2023 to 2030 using ( A ) ARIMA and B Holt’s additive models. The various interventions from 1990 to 2022 are depicted in both models

Factors associated with malaria incidence

Univariate and multivariate linear regression analysis revealed that populations classified under Scheduled Tribes (indigenous people in India) were positively associated, and literacy rate was inversely associated with the API, both of which were statistically significant (p ≤ 0.001). Health infrastructure, which included the vacant position of ASHA workers (community-level health provider) per 1000 population and the vacant position of health workers at peripheral health facilities such as sub-centres, primary health centres, community health centres, and district hospitals (facility-level health provider) per 1000 population was positively associated with API (p ≤ 0.001). Whereas the number of health facilities per square km of geographical area was inversely associated with API (p = 0.04). Further analysis revealed that geographical areas under forest cover, hilly terrain, and annual average rainfall (mm) were positively associated with API (p < 0.0001). In the multivariate model, 37% of the variance in the API was attributed to the above independent factors included in the analysis (Table  4 ).

The use of longitudinal historical data for assessing the impact of intervention and forecasting studies is crucial for identifying interventions that have the most impact on achieving malaria elimination goals at national and sub-national levels. For conducting malaria forecasting analysis, the data quantity, quality, timelines, and consistency in reporting are key requirements. Generalized linear, ARIMA, and Holt–Winter’s models are the most commonly used statistical models in malaria forecasting studies. The selection of the appropriate forecasting model depends on the predictive accuracy, which is largely determined by RMSE, MAPE, MASE, MAE, MAD, 95% confidence intervals, and visual observation. In addition, AIC and BIC are also used as model-fitting criteria [ 12 , 27 , 28 ].

This study has used reported malaria cases data from the WMRs instead of the controversial estimated cases data. In India, efforts are being made to bridge the gap between reported and estimated cases with the increased community level awareness about the significant value of accessing public health systems. The mandatory reporting of malaria cases data by the private sector in almost all states of the country in the last 18 months and the introduction of newer data reporting tools such as the Integrated Health Information Platform are expected to shrink this gap.

The experiences from the Malaria Elimination Demonstration Project (MEDP) conducted for four years in Mandla, Madhya Pradesh have confirmed that treatments that are home-based or use alternate systems of medicine do not add significantly to the case data of state national programs. Through active surveillance and RDT-based diagnostics, it was found that malaria-attributable fever never went beyond 1%, so the individuals who receive treatment at home or receive treatment through alternative systems will not add significantly to the malaria case burden [ 29 ].

The present study has revealed a linear declining trend of malaria cases in India, with about a 91% reduction from 1990 to 2022. Between 1990 and 2000, there was an approximately 0.64% yearly increase in malaria cases. From 2001 to 2010, there was an annual malaria case reduction of about 2%, which could be attributed to the combination of several policy and commodities interventions such as the introduction of monovalent RDTs, replacement of chloroquine with ACT-SP for P. falciparum infections, enhanced surveillance under the IMCP, introduction of LLINs, and ASHAs. Complimenting the interventions done during the above period, in 2011–2022, the addition of NFME, bivalent RDTs, AL, and scaling-up of LLINs further contributed to about 14% yearly decline in malaria cases.

EMCP had the highest impact, possibly because in the year 1996, the number of malaria cases was higher. The impact of EMCP was due to a number of interventions introduced through EMCP, particularly in tribal-dominated high-burden areas of the country. RDTs for P. falciparum in the national programme. While the terms EMCP or IMCP are not mentioned now, but the components of the intervention have been continued with the addition of various new tools and methodologies.

ARIMA and Holt’s time series regression models are the most common tools for disease forecasting [ 30 ]. In the present study, the ARIMA (1,2,2) was the most fitted model to predict malaria cases compared to nine other models. The ARIMA (1,2,2) model predicted that zero malaria cases might be achieved in the year 2028. However, there was a wide range of 95% Confidence Interval (CI). Further, Holt’s additive model predicted the achievement of zero malaria cases by the year 2026 to 2028. In a state-wide study done in Odisha, the authors found that Holt’s Winter was the most fitted model across varying endemicities, which predicted a slowing down of the decline in 2014–2016, hence, missing the state elimination goal [ 13 ].

The present study has found that the vacant positions of health providers at the community and facility levels were associated with an increased risk of malaria incidence. It has also revealed that if the health care facilities per square kilometre were to be increased, particularly in hard-to-reach malaria high-endemic areas, the incidence of malaria could decrease. However, while assessing the relationship between healthcare facilities and malaria incidence in remote areas, studies have found that increased travel time and distance to healthcare facilities significantly affect the likelihood of seeking care. For instance, a study in Uganda indicated that as travel time to a health facility increased, the probability of seeking care for malaria symptoms decreased [ 31 ]. Circular associations may arise if, for example, high malaria incidence deters healthcare professionals from working in these areas, further exacerbating staff shortages and weakening the healthcare infrastructure. Consequently, this can lead to a vicious cycle where increasing malaria incidence and decreasing healthcare provision could reinforce each other.

The present study has also found that tribal-dominated, hilly and forested areas have a greater risk of malaria infection. This finding is complemented by a study done in the state of Madhya Pradesh, where it was found that communities with high literacy had a lower burden of malaria, possibly because of better health-seeking behaviour [ 32 ]. The phenomenon of high literacy and low malaria burden is supported by the national trends where most malaria burden is found in inaccessible hilly forested terrains and tribal-dominated areas with poor healthcare infrastructure and low levels of literacy [ 33 ].

The Goalkeepers Report 2021 by the Bill and Melinda Gates Foundation (BMGF) has predicted that the global malaria cases would be 32 new cases per 1000 people in 2030, which is almost the same as the reported malaria burden of 31 new cases per 1000 people in 2020. The report gives a range of 21–42 cases per 1000 population as the best and the worst situations in 2030, respectively. A similar trend has been predicted for South East Asia + East Asia + Oceania, predicting zero to one case per 1000 population as the best and the worst situations in 2030, respectively. In comparison, in sub-Saharan Africa, 68 to 195 malaria cases per 1000 population are predicted as the best and worst-case scenarios in 2030. For India, the prediction showed one to four cases per 1000 population in 2030, indicating a potential miss of the national malaria elimination goal [ 34 ]. However, the present study has suggested that India might be able to achieve the national malaria elimination goal, subject to the absence of disease outbreaks, climatic changes, emergence of anti-malarial drug resistance, and other independent factors. It is also critical to use context specific and curated elimination protocols for each of the 27 high burden districts in India to eliminate indigenous transmission. If this is accomplished in three to four years, as was demonstrated in Mandla through MEDP, and there are no disease outbreaks and issue related to climate change and drug resistance a malaria free India in 2030 is possible.

A study conducted in Odisha state reported about three times higher annual declining rates in malaria incidence during the intensified post-intervention period (2009–2013) compared to the pre-intervention period (2003–2008). This study attributed the drop to integrated vector control measures, rapid diagnosis and prompt treatment, service decentralisation, inter-sectoral convergence, and behaviour change communication (13). LLINs, RDTs with ACT and biological vector control interventions helped in a significant reduction in malaria cases during 2011–2021 in the Karnataka state [ 35 ]. The present study has also found that optimal coverage of ITNs/LLINs effectively decreased the malaria caseload. Similarly, ITNs/LLINs were found to be a cost-effective intervention tool in Bangladesh [ 36 ] and Sri Lanka, which have been malaria-free since 2016 [ 37 ].

This study used reported annual malaria cases in the absence of granular and monthly malaria data of the country in public domain. Therefore, seasonality and geographical variability in malaria cases could not be analysed in the time series modelling. Further, in the present forecasting model, the effect of climatic variables such as rainfall, humidity, and temperature have not been quantitated, although these are significant covariates of malaria as reported by other studies [ 38 ]. The data in the context of roads and telecommunications infrastructure were also not analysed in the present study.

The significant decrease in malaria incidence in India from 1990 to 2022 highlights the successful implementation of various anti-malarial strategies and interventions. This study reveals a significant negative trend in malaria cases over the past 3 decades, with a remarkable reduction of 91%. Factors contributing to this substantial decrease include focused interventions such as EMCP, IMCP, ASHAs’ contribution, RDT-Pf/Pv and ACT deployment, the NFME, and scaling-up of LLINs distribution.

Out of these predictive models, the ARIMA and Holt’s additive have shown reliable predictive capabilities, indicating that the decreasing malaria cases are likely to continue, forecasting zero indigenous malaria cases by 2027–2028. The study also identified the most impactful combination of intervention packages. Disease modelling studies will have the most impact during the last mile of disease elimination, provided the information is used in real-time by the programmes and policymakers. It is proposed that such time series and disease modelling efforts should be repeated periodically to validate prior predictions of recent years and suggest any changes needed in the interventions required for a malaria-free India.

Availability of data and materials

Data analysed in the present study was obtained from public domain and the references have been cited. The analysed data is available with corresponding author.

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This study was conducted with the financial support from the Foundation for Disease Elimination and Control of India (FDEC-India), which is a non-profit organization under Corporate Social Responsibility (CSR) of Sun Pharmaceutical Industries, Mumbai, India. The funding agency did not have any role in the study design, data collection and analysis.

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MPS, HR, and AAL conceptualized the study. MPS and AAL performed data analysis and interpretation of the data. MPS, HR and AAL wrote the manuscript. PKB and ARA participated in review of data and writing of the manuscript. All authors reviewed the final draft of the manuscript for submission.

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Singh, M.P., Rajvanshi, H., Bharti, P.K. et al. Time series analysis of malaria cases to assess the impact of various interventions over the last three decades and forecasting malaria in India towards the 2030 elimination goals. Malar J 23 , 50 (2024). https://doi.org/10.1186/s12936-024-04872-8

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  8. Malaria 2017: Update on the Clinical Literature and Management

    Malaria 2017: Update on the Clinical Literature and Management 2017 Aug;19 (8):28. doi: 10.1007/s11908-017-0583-8. Department of Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY, 10461, USA. [email protected]. 28634831 10.1007/s11908-017-0583-8 Purpose of review:

  9. PDF Org. Review research on malaria*

    T. LEPES1 This review ofprogress in malaria research over the periods 1951-1970 and 1970-1973 indicates the results so far achieved in research on the parasite, on the immune response of the host, and on the vector; refers to the means of controlling or eradicating malaria that have been developed in recent years; and outlines the present status...

  10. Systematic literature review and meta-analysis of the ...

    Published: 13 December 2017 Systematic literature review and meta-analysis of the efficacy of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: methodological challenges Makoto Saito, Mary Ellen Gilder, François Nosten, Rose McGready & Philippe J. Guérin

  11. Malaria resurgence: a systematic review and assessment of its causes

    The review identified 75 resurgence events in 61 countries, occurring from the 1930s through the 2000s. Almost all resurgence events (68/75 = 91%) were attributed at least in part to the weakening of malaria control programmes for a variety of reasons, of which resource constraints were the most common (39/68 = 57%).

  12. Plasmodium falciparum Malaria

    HHS Vulnerability Disclosure Malaria is a mosquito-borne disease caused by five protozoa: Plasmodium falciparum, P. vivax, P. malariae, P. ovale, and most recently implicated P.knowlesi.

  13. Malaria

    1 Citing Article In this documentary video from the New England Journal of Medicine, physicians and scientists from across the world discuss the epidemiology of malaria and outline key strategies...

  14. Malaria

    Introduction Malaria is a vector-borne parasitic tropical disease found in 91 countries worldwide. 1 Of more than 120 Plasmodium species infecting mammals, birds, and reptiles, only six are known to infect human beings regularly.

  15. Complex interactions between malaria and malnutrition: a systematic

    This systematic review aimed to assess the evidence of the interplay between malaria and malnutrition. Methods Database searches were conducted in PubMed, Global Health and Cochrane Libraries and articles published in English, French or Spanish between Jan 1980 and Feb 2018 were accessed and screened.

  16. PDF CDC's Malaria Research.

    CDC's strategic research helped develop and evaluate each of the effective tools now used throughout the world to prevent and control malaria: Massive scale-up of these proven interventions in the last decade has led to unprecedented gains in the fight against malaria. From 2000 to 2012, 3.3 million lives were saved globally, and malaria ...

  17. A systematic review of factors influencing ...

    Published: 20 April 2021 A systematic review of factors influencing participation in two types of malaria prevention intervention in Southeast Asia Breagh Cheng, Saw Nay Htoo, Naw Pue Pue Mhote & Colleen M. Davison Malaria Journal 20, Article number: 195 ( 2021 ) Cite this article 3860 Accesses 7 Citations 20 Altmetric Metrics Abstract Background

  18. PDF Knowledge Attitudes and Practices About Malaria Treatment and

    At the conclusion of this literature review is a summary of challenges to 1 Comm erc i a lme thod sof mp vnu od ate d ce rg y il b e on the market such as: nets, IRS, mosquito repellants/coils and mosquito sprays. Non commercial methods of malaria prevention refer to the use of traditional methods such as slashing the compound, burning of

  19. A systematic review of changing malaria disease burden in sub-Saharan

    PMID: 32345315 A systematic review of changing malaria disease burden in sub-Saharan Africa since 2000: comparing model predictions and empirical observations Alice Kamau, 1,2 Polycarp Mogeni, 1 Emelda A. Okiro, 1 Robert W. Snow, 1,2 and Philip Bejon 1,2 Author information Article notes Copyright and License information PMC Disclaimer

  20. [PDF] A Literature Review of Malaria Intervention in Zanzibar

    This review examines malaria control and treatment interventions in Zanzibar to better understand cultural barriers to intervention, and to make recommendations on how malaria prevention and treatment activities might be adapted to address underlying cultural barriers. Objectives: This review examines malaria control and treatment interventions in Zanzibar. This review seeks to identify ...

  21. Investigating the upsurge of malaria prevalence in Zambia between 2010

    Malaria is among the top causes of mortality and morbidity in Zambia. Efforts to control, prevent, and eliminate it have been intensified in the past two decades which has contributed to reductions in malaria prevalence and under-five mortality. However, there was a 21% upsurge in malaria prevalence between 2010 and 2015. Zambia is one of the only 13 countries to record an increase in malaria ...

  22. Malaria in pregnancy: a literature review

    10.1016/j.jmwh.2008.02.012 Pregnant women are more likely than nonpregnant women to become infected with malaria and to have severe infection. The effects of malaria during pregnancy include spontaneous abortion, preterm delivery, low birth weight, stillbirth, congenital infection, and maternal death.

  23. An Overview of Malaria in Pregnancy

    We review the challenges to diagnosing malaria in pregnancy, as well as strategies to prevent and treat malaria in pregnancy. Finally, we discuss the current gaps in knowledge and potential areas for continued research. Go to: Introduction

  24. Microfluidic systems for infectious disease diagnostics

    We will follow a classification scheme based on the human body systems primarily involved at the clinical level or on specific pathogen transmission modes. Important diseases, such as tuberculosis and malaria, will be addressed more extensively. This article is part of the themed collection: Lab on a Chip Review Articles 2024.

  25. Time series analysis of malaria cases to assess the impact of various

    Despite the progress made in this decade towards malaria elimination, it remains a significant public health concern in India and many other countries in South Asia and Asia Pacific region. Understanding the historical trends of malaria incidence in relation to various commodity and policy interventions and identifying the factors associated with its occurrence can inform future intervention ...