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

• 1 Department of Medicine (Infectious Diseases), Albert Einstein College of Medicine, Bronx, New York
• 2 D. Samuel Gottesman Library, Albert Einstein College of Medicine, Bronx, New York
• Medical News & Perspectives Vaccine Development Is Charting a New Path in Malaria Control Bridget M. Kuehn, MSJ JAMA
• JAMA Patient Page Patient Information: Malaria Kristin Walter, MD, MS; Chandy C. John, MD, MS JAMA
• Global Health Updated Malaria Recommendations for Children and Pregnant People Howard D. Larkin JAMA
• Medical News in Brief First Ever Malaria Vaccine to Be Distributed in Africa Emily Harris JAMA

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: 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.

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 ).

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 ).

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 ).

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 .

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 .

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.

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.

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.

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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How to cite this article

Phillips, M. A. et al . Malaria. Nat. Rev. Dis. Primers 3 , 17050 (2017).

Miller, L. H., Ackerman, H. C., Su, X. Z. & Wellems, T. E. Malaria biology and disease pathogenesis: insights for new treatments. Nat. Med. 19 , 156–167 (2013).

CAS   PubMed   PubMed Central   Google Scholar  

White, N. J. et al . Malaria. Lancet 383 , 723–735 (2014).

PubMed   Google Scholar  

Cowman, A. F., Healer, J., Marapana, D. & Marsh, K. Malaria: biology and disease. Cell 167 , 610–624 (2016). References 1–3 comprehensively review malaria biology and the disease.

CAS   PubMed   Google Scholar  

Baker, D. A. Malaria gametocytogenesis. Mol. Biochem. Parasitol. 172 , 57–65 (2010).

Waters, A. P. Epigenetic roulette in blood stream Plasmodium : gambling on sex. PLoS Pathog. 12 , e1005353 (2016).

PubMed   PubMed Central   Google Scholar  

White, N. J. Determinants of relapse periodicity in Plasmodium vivax malaria. Malar. J. 10 , 297 (2011).

Wassmer, S. C. et al . Investigating the pathogenesis of severe malaria: a multidisciplinary and cross-geographical approach. Am. J. Trop. Med. Hyg. 93 , 42–56 (2015). Comprehensively reviews the causes of severe malaria and ongoing research efforts to understand malaria pathophysiology.

Wassmer, S. C. & Grau, G. E. Severe malaria: what's new on the pathogenesis front? Int. J. Parasitol. 47 , 145–152 (2017).

World Health Organization. Severe malaria. Trop. Med. Int. Health 19 (Suppl. 1), 7–131 (2014).

Google Scholar  

Dondorp, A. M. & Day, N. P. The treatment of severe malaria. Trans. R. Soc. Trop. Med. Hyg. 101 , 633–634 (2007).

Bernabeu, M. & Smith, J. D. EPCR and malaria severity: the center of a perfect storm. Trends Parasitol. 33 , 295–308 (2017). Reviews the molecular basis of parasite sequestration in the tissues, which leads to the obstruction of the microvasculature and severe disease, and discusses the key role of EPCR in these processes.

Bhatt, S. et al . The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015. Nature 526 , 207–211 (2015). Attempts to identify the relative contribution of different antimalaria measures in reducing the number of malaria cases over the 2000–2015 period.

Mitchell, S. N. et al . Mosquito biology. Evolution of sexual traits influencing vectorial capacity in anopheline mosquitoes. Science 347 , 985–988 (2015).

Sinka, M. E. et al . The dominant Anopheles vectors of human malaria in Africa, Europe and the Middle East: occurrence data, distribution maps and bionomic precis. Parasit. Vectors 3 , 117 (2010).

World Health Organization. Eliminating malaria: learning from the past, looking ahead. WHO http://www.path.org/publications/files/MCP_rbm_pi_rpt_8.pdf (2011).

World Health Organization. World malaria report 2015. WHO http://www.who.int/malaria/publications/world-malaria-report-2015/report/en/ (2015).

Florens, L. et al . A proteomic view of the Plasmodium falciparum life cycle. Nature 419 , 520–526 (2002).

Gardner, M. J. et al . Genome sequence of the human malaria parasite Plasmodium falciparum . Nature 419 , 498–511 (2002). Reports for the first time the P. falciparum genome, which has formed the basis for research into the molecular basis of pathogenesis and parasite biology; a modern-day understanding of the disease would not be possible without this groundbreaking work.

Winzeler, E. A. Advances in parasite genomics: from sequences to regulatory networks. PLoS Pathog. 5 , e1000649 (2009).

Gething, P. W. et al . Mapping Plasmodium falciparum mortality in Africa between 1990 and 2015. N. Engl. J. Med. 375 , 2435–2445 (2016).

Maitland, K. Severe malaria in African children — the need for continuing investment. N. Engl. J. Med. 375 , 2416–2417 (2016).

Miller, L. H., Mason, S. J., Clyde, D. F. & McGinniss, M. H. The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy . N. Engl. J. Med. 295 , 302–304 (1976). Describes the discovery that led to a molecular understanding of why most Africans are resistant to infection by P. vivax , thereby explaining the limited penetration of P. vivax in Africa.

Mercereau-Puijalon, O. & Menard, D. Plasmodium vivax and the Duffy antigen: a paradigm revisited. Transfus. Clin. Biol. 17 , 176–183 (2010).

Howes, R. E. et al . Plasmodium vivax transmission in Africa. PLoS Negl. Trop. Dis. 9 , e0004222 (2015).

Sutherland, C. J. et al . Two nonrecombining sympatric forms of the human malaria parasite Plasmodium ovale occur globally. J. Infect. Dis. 201 , 1544–1550 (2010).

Cox-Singh, J. et al . Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening. Clin. Infect. Dis. 46 , 165–171 (2008).

Singh, B. et al . A large focus of naturally acquired Plasmodium knowlesi infections in human beings. Lancet 363 , 1017–1024 (2004). Describes the discovery that P. knowlesi , which was previously thought to primarily infect macaques, accounted for over half of the cases of malaria in their study in the Kapit district (Malaysia). Demonstrates for the first time that P. knowlesi should be considered as an emerging infectious disease in humans. Whether transmission via mosquitoes was occurring from monkey to man or from man to man remained an open question.

Brock, P. M. et al . Plasmodium knowlesi transmission: integrating quantitative approaches from epidemiology and ecology to understand malaria as a zoonosis. Parasitology 143 , 389–400 (2016).

Imwong, M., Nakeesathit, S., Day, N. P. & White, N. J. A review of mixed malaria species infections in anopheline mosquitoes. Malar. J. 10 , 253 (2011).

Ginouves, M. et al . Frequency and distribution of mixed Plasmodium falciparum – vivax infections in French Guiana between 2000 and 2008. Malar. J. 14 , 446 (2015).

Srisutham, S. et al . Four human Plasmodium species quantification using droplet digital PCR. PLoS ONE 12 , e0175771 (2017).

Armed Forces Health Surveillance Branch. Update: malaria, U. S. Armed Forces, 2016. MSMR 24 , 2–7 (2017).

IISS: International Institute for Strategic Studies. Armed Conflict Survey 2016 (IISS, 2016).

Mueller, I. et al . Natural acquisition of immunity to Plasmodium vivax: epidemiological observations and potential targets. Adv. Parasitol. 81 , 77–131 (2013).

Ataide, R., Mayor, A. & Rogerson, S. J. Malaria, primigravidae, and antibodies: knowledge gained and future perspectives. Trends Parasitol. 30 , 85–94 (2014).

Desai, M. et al . Epidemiology and burden of malaria in pregnancy. Lancet Infect. Dis. 7 , 93–104 (2007).

McGready, R. et al . Adverse effects of falciparum and vivax malaria and the safety of antimalarial treatment in early pregnancy: a population-based study. Lancet Infect. Dis. 12 , 388–396 (2012).

Cohen, C. et al . Increased prevalence of severe malaria in HIV-infected adults in South Africa. Clin. Infect. Dis. 41 , 1631–1637 (2005).

Mulu, A. et al . Epidemiological and clinical correlates of malaria–helminth co-infections in southern Ethiopia. Malar. J. 12 , 227 (2013).

Gwamaka, M. et al . Iron deficiency protects against severe Plasmodium falciparum malaria and death in young children. Clin. Infect. Dis. 54 , 1137–1144 (2012).

Neuberger, A., Okebe, J., Yahav, D. & Paul, M. Oral iron supplements for children in malaria-endemic areas. Cochrane Database Syst. Rev. 2 , CD006589 (2016).

Tilley, L., Straimer, J., Gnadig, N. F., Ralph, S. A. & Fidock, D. A. Artemisinin action and resistance in Plasmodium falciparum . Trends Parasitol. 32 , 682–696 (2016). Comprehensively reviews the emerging threat of artemisinin resistance, covering what is known about the mechanism of action of the drug and the molecular basis of artemisinin resistance.

Woodrow, C. J. & White, N. J. The clinical impact of artemisinin resistance in Southeast Asia and the potential for future spread. FEMS Microbiol. Rev. 41 , 34–48 (2017).

Menard, D. et al . A worldwide map of Plasmodium falciparum K13-propeller polymorphisms. N. Engl. J. Med. 374 , 2453–2464 (2016).

Imwong, M. et al . The spread of artemisinin-resistant Plasmodium falciparum in the greater Mekong subregion: a molecular epidemiology observational study. Lancet Infect. Dis. 17 , 491–497 (2017).

Paul, A. S., Egan, E. S. & Duraisingh, M. T. Host–parasite interactions that guide red blood cell invasion by malaria parasites. Curr. Opin. Hematol. 22 , 220–226 (2015). Reviews the molecular basis of parasite invasion.

Lim, C. et al . Reticulocyte preference and stage development of Plasmodium vivax isolates. J. Infect. Dis. 214 , 1081–1084 (2016).

Boddey, J. A. & Cowman, A. F. Plasmodium nesting: remaking the erythrocyte from the inside out. Annu. Rev. Microbiol. 67 , 243–269 (2013).

Spillman, N. J., Beck, J. R. & Goldberg, D. E. Protein export into malaria parasite-infected erythrocytes: mechanisms and functional consequences. Annu. Rev. Biochem. 84 , 813–841 (2015). Reviews the biology associated with red blood cell remodelling upon parasite invasion.

Phillips, M. A. in Neglected Diseases and Drug Discovery (eds Palmer, M. & Wells, T. N. C. ) 65–87 (RCS Publishing, 2011).

Istvan, E. S. et al . Validation of isoleucine utilization targets in Plasmodium falciparum . Proc. Natl Acad. Sci. USA 108 , 1627–1632 (2011).

Wunderlich, J., Rohrbach, P. & Dalton, J. P. The malaria digestive vacuole. Front. Biosci. (Schol. Ed.) 4 , 1424–1448 (2012).

Chugh, M. et al . Protein complex directs hemoglobin-to-hemozoin formation in Plasmodium falciparum . Proc. Natl Acad. Sci. USA 110 , 5392–5397 (2013).

Sigala, P. A. & Goldberg, D. E. The peculiarities and paradoxes of Plasmodium heme metabolism. Annu. Rev. Microbiol. 68 , 259–278 (2014).

Spillman, N. J. et al . Na + regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials. Cell Host Microbe 13 , 227–237 (2013). Identifies the protein target of one of the key new antimalarials that is in clinical development.

Spillman, N. J. & Kirk, K. The malaria parasite cation ATPase PfATP4 and its role in the mechanism of action of a new arsenal of antimalarial drugs. Int. J. Parasitol. Drugs Drug Resist. 5 , 149–162 (2015).

Jimenez-Diaz, M. B. et al . (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium . Proc. Natl Acad. Sci. USA 111 , E5455–E5462 (2014).

McNamara, C. W. et al . Targeting Plasmodium PI(4)K to eliminate malaria. Nature 504 , 248–253 (2013). Identifies an important new target for drug discovery.

Rosenberg, R., Wirtz, R. A., Schneider, I. & Burge, R. An estimation of the number of malaria sporozoites ejected by a feeding mosquito. Trans. R. Soc. Trop. Med. Hyg. 84 , 209–212 (1990).

Sinnis, P. & Zavala, F. The skin: where malaria infection and the host immune response begin. Semin. Immunopathol. 34 , 787–792 (2012).

Frischknecht, F. et al . Imaging movement of malaria parasites during transmission by Anopheles mosquitoes. Cell. Microbiol. 6 , 687–694 (2004).

Zheng, H., Tan, Z. & Xu, W. Immune evasion strategies of pre-erythrocytic malaria parasites. Mediators Inflamm. 2014 , 362605 (2014).

Duraisingh, M. T. & Horn, D. Epigenetic regulation of virulence gene expression in parasitic protozoa. Cell Host Microbe 19 , 629–640 (2016).

Smith, J. D. The role of PfEMP1 adhesion domain classification in Plasmodium falciparum pathogenesis research. Mol. Biochem. Parasitol. 195 , 82–87 (2014).

Dobbs, K. R. & Dent, A. E. Plasmodium malaria and antimalarial antibodies in the first year of life. Parasitology 143 , 129–138 (2016).

Fowkes, F. J., Boeuf, P. & Beeson, J. G. Immunity to malaria in an era of declining malaria transmission. Parasitology 143 , 139–153 (2016).

Teo, A., Feng, G., Brown, G. V., Beeson, J. G. & Rogerson, S. J. Functional antibodies and protection against blood-stage malaria. Trends Parasitol. 32 , 887–898 (2016).

Marsh, K. & Kinyanjui, S. Immune effector mechanisms in malaria. Parasite Immunol. 28 , 51–60 (2006).

Parroche, P. et al . Malaria hemozoin is immunologically inert but radically enhances innate responses by presenting malaria DNA to Toll-like receptor 9. Proc. Natl Acad. Sci. USA 104 , 1919–1924 (2007).

Karunaweera, N. D., Grau, G. E., Gamage, P., Carter, R. & Mendis, K. N. Dynamics of fever and serum levels of tumor necrosis factor are closely associated during clinical paroxysms in Plasmodium vivax malaria. Proc. Natl Acad. Sci. USA 89 , 3200–3203 (1992).

Vijaykumar, M., Naik, R. S. & Gowda, D. C. Plasmodium falciparum glycosylphosphatidylinositol-induced TNF-α secretion by macrophages is mediated without membrane insertion or endocytosis. J. Biol. Chem. 276 , 6909–6912 (2001).

Wijesekera, S. K., Carter, R., Rathnayaka, L. & Mendis, K. N. A malaria parasite toxin associated with Plasmodium vivax paroxysms. Clin. Exp. Immunol. 104 , 221–227 (1996).

Hosseini, S. M. & Feng, J. J. How malaria parasites reduce the deformability of infected red blood cells. Biophys. J. 103 , 1–10 (2012).

Gillrie M. R. et al . Thrombin cleavage of Plasmodium falciparum erythrocyte membrane protein 1 inhibits cytoadherence. mBio 7 e01120-16 (2016).

Bernabeu, M. et al . Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass. Proc. Natl Acad. Sci. USA 113 , E3270–E3279 (2016).

Fox, L. L. et al . Histidine-rich protein 2 plasma levels predict progression to cerebral malaria in Malawian children with Plasmodium falciparum infection. J. Infect. Dis. 208 , 500–503 (2013).

Seydel, K. B. et al . Brain swelling and death in children with cerebral malaria. N. Engl. J. Med. 372 , 1126–1137 (2015).

Lopez, C., Saravia, C., Gomez, A., Hoebeke, J. & Patarroyo, M. A. Mechanisms of genetically-based resistance to malaria. Gene 467 , 1–12 (2010).

Piel, F. B. The present and future global burden of the inherited disorders of hemoglobin. Hematol. Oncol. Clin. North Am. 30 , 327–341 (2016).

Elguero, E. et al . Malaria continues to select for sickle cell trait in Central Africa. Proc. Natl Acad. Sci. USA 112 , 7051–7054 (2015).

Kwiatkowski, D. P. How malaria has affected the human genome and what human genetics can teach us about malaria. Am. J. Hum. Genet. 77 , 171–192 (2005).

Cheng, Y. et al . Plasmodium vivax GPI-anchored micronemal antigen (PvGAMA) binds human erythrocytes independent of Duffy antigen status. Sci. Rep. 6 , 35581 (2016).

Gunalan, K. et al . Role of Plasmodium vivax Duffy-binding protein 1 in invasion of Duffy-null Africans. Proc. Natl Acad. Sci. USA 113 , 6271–6276 (2016).

Guindo, A., Fairhurst, R. M., Doumbo, O. K., Wellems, T. E. & Diallo, D. A. X-Linked G6PD deficiency protects hemizygous males but not heterozygous females against severe malaria. PLoS Med. 4 , e66 (2007).

Cholera, R. et al . Impaired cytoadherence of Plasmodium falciparum -infected erythrocytes containing sickle hemoglobin. Proc. Natl Acad. Sci. USA 105 , 991–996 (2008).

Fairhurst, R. M. et al . Abnormal display of PfEMP-1 on erythrocytes carrying haemoglobin C may protect against malaria. Nature 435 , 1117–1121 (2005). References 84 and 86 identify key genetic traits that are associated with protection against P. falciparum malaria.

World Health Organization. Malaria: diagnostic testing. WHO http://www.who.int/malaria/areas/diagnosis/en/ (2016).

Worldwide Antimalarial Resistance Network (WWARN) AL Dose Impact Study Group. The effect of dose on the antimalarial efficacy of artemether–lumefantrine: a systematic review and pooled analysis of individual patient data. Lancet Infect. Dis. 15 , 692–702 (2015). Describes data from the Worldwide Antimalarial Resistance Network (WWARN), which has set up computational tools that measure parasite reduction from human data; the WWARN also collects information on emerging resistance.

Joanny, F., Lohr, S. J., Engleitner, T., Lell, B. & Mordmuller, B. Limit of blank and limit of detection of Plasmodium falciparum thick blood smear microscopy in a routine setting in Central Africa. Malar. J. 13 , 234 (2014).

Azikiwe, C. C. et al . A comparative laboratory diagnosis of malaria: microscopy versus rapid diagnostic test kits. Asian Pac. J. Trop. Biomed. 2 , 307–310 (2012).

McCarthy, J. S. et al . A pilot randomised trial of induced blood-stage Plasmodium falciparum infections in healthy volunteers for testing efficacy of new antimalarial drugs. PLoS ONE 6 , e21914 (2011). Describes the use of the human blood-stage challenge model for drug testing. This model has gone on to be an important tool for the early evaluation of the clinical efficacy of new antimalarial compounds.

Phiri, K. et al . Parasitological clearance rates and drug concentrations of a fixed dose combination of azithromycin–chloroquine in asymptomatic pregnant women with Plasmodium Falciparum parasitemia: an open-label, non-comparative study in sub-Saharan Africa. PLoS ONE 11 , e0165692 (2016).

Imwong, M. et al . Numerical distributions of parasite densities during asymptomatic malaria. J. Infect. Dis. 213 , 1322–1329 (2016).

Notomi, T. et al . Loop-mediated isothermal amplification of DNA. Nucleic Acids Res. 28 , E63 (2000).

Sema, M. et al . Evaluation of non-instrumented nucleic acid amplification by loop-mediated isothermal amplification (NINA-LAMP) for the diagnosis of malaria in northwest Ethiopia. Malar. J. 14 , 44 (2015).

Pholwat, S. et al . The malaria TaqMan array card includes 87 assays for Plasmodium falciparum drug resistance, identification of species, and genotyping in a single reaction. Antimicrob. Agents Chemother. 61 e00110-17 (2017).

Foundation for Innovative New Diagnostics. Acute febrile syndrome strategy. FiND http://r4d.dfid.gov.uk/PDF/Outputs/FIND/0031-FIND-NMFI-document-print-inhouse.pdf (2012).

Gamboa, D. et al . A large proportion of P. falciparum isolates in the Amazon region of Peru lack pfhrp2 and pfhrp3 : implications for malaria rapid diagnostic tests. PLoS ONE 5 , e8091 (2010).

Akinyi, S. et al . Multiple genetic origins of histidine-rich protein 2 gene deletion in Plasmodium falciparum parasites from Peru. Sci. Rep. 3 , 2797 (2013).

Cheng, Q. et al . Plasmodium falciparum parasites lacking histidine-rich protein 2 and 3: a review and recommendations for accurate reporting. Malar. J. 13 , 283 (2014).

Bharti, P. K. et al . Prevalence of pfhrp2 and/or pfhrp3 gene deletion in Plasmodium falciparum population in eight highly endemic states in India. PLoS ONE 11 , e0157949 (2016).

Deme, A. B. et al . Analysis of pfhrp2 genetic diversity in Senegal and implications for use of rapid diagnostic tests. Malar. J. 13 , 34 (2014).

Parr, J. B. et al . Estimation of Plasmodium falciparum transmission intensity in Lilongwe, Malawi, by microscopy, rapid diagnostic testing, and nucleic acid detection. Am. J. Trop. Med. Hyg. 95 , 373–377 (2016).

Mouatcho, J. C. & Goldring, J. P. Malaria rapid diagnostic tests: challenges and prospects. J. Med. Microbiol. 62 , 1491–1505 (2013).

Soti, D. O. et al . Feasibility of an innovative electronic mobile system to assist health workers to collect accurate, complete and timely data in a malaria control programme in a remote setting in Kenya. Malar. J. 14 , 430 (2015).

Scherr, T. F., Gupta, S., Wright, D. W. & Haselton, F. R. Mobile phone imaging and cloud-based analysis for standardized malaria detection and reporting. Sci. Rep. 6 , 28645 (2016).

Ouédraogo, A. L. et al . Efficacy and safety of the mosquitocidal drug ivermectin to prevent malaria transmission after treatment: a double-blind, randomized, clinical trial. Clin. Infect. Dis. 60 , 357–365 (2015).

World Health Organization. Guidelines for the treatment of malaria, 3rd edn. WHO http://apps.who.int/iris/bitstream/10665/162441/1/9789241549127_eng.pdf (2015).

Chanda, E., Remijo, C. D., Pasquale, H., Baba, S. P. & Lako, R. L. Scale-up of a programme for malaria vector control using long-lasting insecticide-treated nets: lessons from South Sudan. Bull. World Health Organ. 92 , 290–296 (2014).

Ojuka, P. et al . Early biting and insecticide resistance in the malaria vector Anopheles might compromise the effectiveness of vector control intervention in southwestern Uganda. Malar. J. 14 , 148 (2015).

Hemingway, J. et al . Averting a malaria disaster: will insecticide resistance derail malaria control? Lancet 387 , 1785–1788 (2016). Discusses key issues relating to the continued control of the mosquito that transmits malaria.

Knapp, J., Macdonald, M., Malone, D., Hamon, N. & Richardson, J. H. Disruptive technology for vector control: the Innovative Vector Control Consortium and the US Military join forces to explore transformative insecticide application technology for mosquito control programmes. Malar. J. 14 , 371 (2015).

Sibanda, M. & Focke, W. Development of an insecticide impregnated polymer wall lining for malaria vector control. Malar. J. 13 (Suppl. 1), 80 (2014).

Kruger, T., Sibanda, M. M., Focke, W. W., Bornman, M. S. & de Jager, C. Acceptability and effectiveness of a monofilament, polyethylene insecticide-treated wall lining for malaria control after six months in dwellings in Vhembe District, Limpopo Province, South Africa. Malar. J. 14 , 485 (2015).

Burt, A. Heritable strategies for controlling insect vectors of disease. Phil. Trans. R. Soc. B 369 , 20130432 (2014).

Committee on Gene Drive Research in Non-Human Organisms. Recommendations for Responsible Conduct. Gene Drives on the Horizon: Advancing Science, Navigating Uncertainty and Aligning Research with Public Values (National Academies Press, 2016).

Oliva, C. F. et al . Current status and future challenges for controlling malaria with the sterile insect technique: technical and social perspectives. Acta Trop. 132 , S130–S139 (2014).

Bourtzis, K., Lees, R. S., Hendrichs, J. & Vreysen, M. J. More than one rabbit out of the hat: radiation, transgenic and symbiont-based approaches for sustainable management of mosquito and tsetse fly populations. Acta Trop. 157 , 115–130 (2016).

Black, W. C. 4th, Alphey, L. & James, A. A. Why RIDL is not SIT. Trends Parasitol. 27 , 362–370 (2011).

Windbichler, N. et al . A synthetic homing endonuclease-based gene drive system in the human malaria mosquito. Nature 473 , 212–215 (2011).

Esvelt, K. M., Smidler, A. L., Catteruccia, F. & Church, G. M. Concerning RNA-guided gene drives for the alteration of wild populations. eLife 3 , e03401 (2014).

Hammond, A. et al . A CRISPR–Cas9 gene drive system targeting female reproduction in the malaria mosquito vector Anopheles gambiae . Nat. Biotechnol. 34 , 78–83 (2016).

Gantz, V. M. et al . Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi . Proc. Natl Acad. Sci. USA 112 , E6736–E6743 (2015).

Bull, J. J. & Turelli, M. Wolbachia versus dengue: evolutionary forecasts. Evol. Med. Public Health 2013 , 197–207 (2013).

Wilke, A. B. & Marrelli, M. T. Paratransgenesis: a promising new strategy for mosquito vector control. Parasit. Vectors 8 , 342 (2015).

Wang, S. et al . Fighting malaria with engineered symbiotic bacteria from vector mosquitoes. Proc. Natl Acad. Sci. USA 109 , 12734–12739 (2012).

Lee, S. J., Ter Kuile, F. O., Price, R. N., Luxemburger, C. & Nosten, F. Adverse effects of mefloquine for the treatment of uncomplicated malaria in Thailand: a pooled analysis of 19, 850 individual patients. PLoS ONE 12 , e0168780 (2017).

Spinner, C. D. et al . HIV pre-exposure prophylaxis (PrEP): a review of current knowledge of oral systemic HIV PrEP in humans. Infection 44 , 151–158 (2016).

Margolis, D. A. & Boffito, M. Long-acting antiviral agents for HIV treatment. Curr. Opin. HIV AIDS 10 , 246–252 (2015).

World Health Organization. WHO policy recommendation: seasonal malaria chemoprevention (SMC) for Plasmodium falciparum malaria control in highly seasonal transmission areas of the Sahel sub-region in Africa. WHO http://www.who.int/malaria/publications/atoz/who_smc_policy_recommendation/en/ (2012).

Cairns, M. et al . Estimating the potential public health impact of seasonal malaria chemoprevention in African children. Nat. Commun. 3 , 881 (2012).

Noor, A. M. et al . Sub-national targeting of seasonal malaria chemoprevention in the Sahelian countries of the Nouakchott initiative. PLoS ONE 10 , e0136919 (2015).

Tagbor, H. et al . Seasonal malaria chemoprevention in an area of extended seasonal transmission in Ashanti, Ghana: an individually randomised clinical trial. Trop. Med. Int. Health 21 , 224–235 (2016).

Tine, R. C. et al . Feasibility, safety and effectiveness of combining home based malaria management and seasonal malaria chemoprevention in children less than 10 years in Senegal: a cluster-randomised trial. Trans. R. Soc. Trop. Med. Hyg. 108 , 13–21 (2014).

Zongo, I. et al . Randomized noninferiority trial of dihydroartemisinin–piperaquine compared with sulfadoxine–pyrimethamine plus amodiaquine for seasonal malaria chemoprevention in Burkina Faso. Antimicrob. Agents Chemother. 59 , 4387–4396 (2015).

Wilson, A. L. & IPTc Taskforce. A systematic review and meta-analysis of the efficacy and safety of intermittent preventive treatment of malaria in children (IPTc). PLoS ONE 6 , e16976 (2011).

Matondo, S. I. et al . High levels of sulphadoxine–pyrimethamine resistance Pfdhfr – Pfdhps quintuple mutations: a cross sectional survey of six regions in Tanzania. Malar. J. 13 , 152 (2014).

Gutman, J., Kovacs, S., Dorsey, G., Stergachis, A. & Ter Kuile, F. O. Safety, tolerability, and efficacy of repeated doses of dihydroartemisinin–piperaquine for prevention and treatment of malaria: a systematic review and meta-analysis. Lancet Infect. Dis. 17 , 184–193 (2017).

Doolan, D. L., Dobano, C. & Baird, J. K. Acquired immunity to malaria. Clin. Microbiol. Rev. 22 , 13–36 (2009).

Hoffman, S. L., Vekemans, J., Richie, T. L. & Duffy, P. E. The march toward malaria vaccines. Am. J. Prev. Med. 49 , S319–S333 (2015).

Keegan, L. T. & Dushoff, J. Population-level effects of clinical immunity to malaria. BMC Infect. Dis. 13 , 428 (2013).

McCarthy, J. S. et al . Experimentally induced blood-stage Plasmodium vivax infection in healthy volunteers. J. Infect. Dis. 208 , 1688–1694 (2013).

Roestenberg, M. et al . Long-term protection against malaria after experimental sporozoite inoculation: an open-label follow-up study. Lancet 377 , 1770–1776 (2011).

Engwerda, C. R., Minigo, G., Amante, F. H. & McCarthy, J. S. Experimentally induced blood stage malaria infection as a tool for clinical research. Trends Parasitol. 28 , 515–521 (2012).

Wykes, M. N., Horne-Debets, J. M., Leow, C. Y. & Karunarathne, D. S. Malaria drives T cells to exhaustion. Front. Microbiol. 5 , 249 (2014).

RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet 386 , 31–45 (2015). Describes a key clinical study that evaluates the efficacy of the only malaria vaccine that is currently at an advanced stage of clinical development.

Penny, M. A. et al . Public health impact and cost-effectiveness of the RTS,S/AS01 malaria vaccine: a systematic comparison of predictions from four mathematical models. Lancet 387 , 367–375 (2015).

Gosling, R. & von Seidlein, L. The future of the RTS, S/AS01 malaria vaccine: an alternative development plan. PLoS Med. 13 , e1001994 (2016). Describes strategies for effectively integrating the RTS,S/AS01 vaccine into malaria control strategies.

Hoffman, S. L. et al . Protection of humans against malaria by immunization with radiation-attenuated Plasmodium falciparum sporozoites. J. Infect. Dis. 185 , 1155–1164 (2002).

Draper, S. J. et al . Recent advances in recombinant protein-based malaria vaccines. Vaccine 33 , 7433–7443 (2015).

World Health Organization. WHO Product Development for Vaccines Advisory Committee (PD-VAC) meeting — 2015. WHO http://www.who.int/immunization/research/meetings_workshops/pdvac/en/ (2015).

Nunes, J. K. et al . Development of a transmission-blocking malaria vaccine: progress, challenges, and the path forward. Vaccine 32 , 5531–5539 (2014).

Shimp, R. L. Jr et al . Development of a Pfs25–EPA malaria transmission blocking vaccine as a chemically conjugated nanoparticle. Vaccine 31 , 2954–2962 (2013).

Kelley, B. Industrialization of mAb production technology: the bioprocessing industry at a crossroads. mAbs 1 , 443–452 (2009).

Robbie, G. J. et al . A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob. Agents Chemother. 57 , 6147–6153 (2013).

US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01939899 (2017).

US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02647489 (2016).

Daily, J. P. Malaria 2017: update on the clinical literature and management. Curr. Infect. Dis. Rep. http://dx.doi.org/ 10.1007/s11908-017-0583-8 (2017).

Harrison, N. In celebration of the Jesuit's powder: a history of malaria treatment. Lancet Infect. Dis. 15 , 1143 (2015).

Kinfu, G., Gebre-Selassie, S. & Fikrie, N. Therapeutic efficacy of artemether–lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in northern Ethiopia. Malar. Res. Treat. 2012 , 548710 (2012).

Sinclair, D., Donegan, S., Isba, R. & Lalloo, D. G. Artesunate versus quinine for treating severe malaria. Cochrane Database Syst. Rev. 6 , CD005967 (2012).

Dondorp, A. et al . Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 366 , 717–725 (2005). Describes a key study that demonstrates the efficacy of artesunate for the treatment of malaria and, therefore, supports the clinical use of artesunate.

Dondorp, A. M. et al . Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet 376 , 1647–1657 (2010).

Okebe, J. & Eisenhut, M. Pre-referral rectal artesunate for severe malaria. Cochrane Database Syst. Rev. 5 , CD009964 (2014).

Verhave, J. P. Experimental, therapeutic and natural transmission of Plasmodium vivax tertian malaria: scientific and anecdotal data on the history of Dutch malaria studies. Parasit. Vectors 6 , 19 (2013).

Llanos-Cuentas, A. et al . Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study. Lancet 383 , 1049–1058 (2014). Describes a key clinical study that demonstrates the efficacy of the only new compound that can prevent P. vivax relapse; tafenoquine and primaquine are the only compounds that have such activity.

White, N. J. Does antimalarial mass drug administration increase or decrease the risk of resistance? Lancet Infect. Dis. 17 , e15–e20 (2017).

Amato, R. et al . Genetic markers associated with dihydroartemisinin–piperaquine failure in Plasmodium falciparum malaria in Cambodia: a genotype–phenotype association study. Lancet Infect. Dis. 17 , 164–173 (2017).

Ariey, F. et al . A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature 505 , 50–55 (2014).

World Health Organization. World malaria report 2016. WHO http://www.who.int/malaria/publications/world-malaria-report-2016/report/en/ (2016).

Lu, F. et al . Emergence of indigenous artemisinin-resistant Plasmodium falciparum in Africa. N. Engl. J. Med. 376 , 991–993 (2017).

Sutherland, C. J. et al . Pfk13 -independent treatment failure in four imported cases of Plasmodium falciparum malaria treated with artemether–lumefantrine in the United Kingdom. Antimicrob. Agents Chemother. 61 e02382-16 (2017).

Lukens, A. K. et al . Harnessing evolutionary fitness in Plasmodium falciparum for drug discovery and suppressing resistance. Proc. Natl Acad. Sci. USA 111 , 799–804 (2014).

Taylor, A. R. et al . Artemether–lumefantrine and dihydroartemisinin–piperaquine exert inverse selective pressure on Plasmodium falciparum drug sensitivity-associated haplotypes in Uganda. Open Forum Infect. Dis. 4 , ofw229 (2017).

Gamo, F. J. et al . Thousands of chemical starting points for antimalarial lead identification. Nature 465 , 305–310 (2010).

Möhrle, J. J. et al . First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials. Br. J. Clin. Pharmacol. 75 , 524–537 (2013).

Phyo, A. P. et al . Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial. Lancet Infect. Dis. 16 , 61–69 (2016). Describes the key phase II clinical study of one of only two new clinical candidates that have reached phase IIb clinical development.

McCarthy, J. S. et al . A phase II pilot trial to evaluate safety and efficacy of ferroquine against early Plasmodium falciparum in an induced blood-stage malaria infection study. Malar. J. 15 469 (2016).

Held, J. et al . Ferroquine and artesunate in African adults and children with Plasmodium falciparum malaria: a phase 2, multicentre, randomised, double-blind, dose-ranging, non-inferiority study. Lancet Infect. Dis. 15 , 1409–1419 (2015).

Leong, F. J. et al . A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel imidazolopiperazine KAF156 to assess its safety, tolerability, and pharmacokinetics in healthy adult volunteers. Antimicrob. Agents Chemother. 58 , 6437–6443 (2014).

White, N. J. et al . Antimalarial activity of KAF156 in falciparum and vivax malaria. N. Engl. J. Med. 375 , 1152–1160 (2016).

Kuhen, K. L. et al . KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment and prevention of disease transmission. Antimicrob. Agents Chemother. 58 , 5060–5067 (2014).

Huskey, S. E. et al . KAE609 (Cipargamin), a new spiroindolone agent for the treatment of malaria: evaluation of the absorption, distribution, metabolism, and excretion of a single oral 300- mg dose of [ 14 C]KAE609 in healthy male subjects. Drug Metab. Dispos. 44 , 672–682 (2016).

White, N. J. et al . Spiroindolone KAE609 for falciparum and vivax malaria. N. Engl. J. Med. 371 , 403–410 (2014).

McCarthy, J. S. et al . Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study. Lancet Infect. Dis. 17 , 626–635 (2017). References 184 and 185 describe key clinical studies that support the efficacy of new antimalarials in the clinical development portfolio.

Phillips, M. A. et al . A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Sci. Transl Med . 7 , 296ra111 (2015). Describes the biological activity and product profile of the first inhibitor of PfDHODH to reach clinical development.

Rüeckle, T. et al . A phase IIa proof-of-concept study to assess the efficacy, safety, tolerability and pharmacokinetics of single doses of DSM265 in adult patients with acute, uncomplicated Plasmodium falciparum or vivax malaria mono-infection over a 28-day-extended observation period in Iquitos, Peru. ASTMH http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=2e5199c4-aceb-4d61-8769-342586917c5a&cKey=d7fda50e-36c6-4a28-a76b-96bad2ec308b&mKey=%7bAB652FDF-0111-45C7-A5E5-0BA9D4AF5E12%7d (2015).

Sulyok, M. et al . DSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infection. Lancet Infect. Dis. 17 , 636–644 (2017). Describes the first use of a sporozoite human challenge study to demonstrate the chemopreventive activity of a compound that is under clinical development.

Das, S. et al . Na + influx induced by new antimalarials causes rapid alterations in the cholesterol content and morphology of Plasmodium falciparum . PLoS Pathog. 12 , e1005647 (2016).

Coteron, J. M. et al . Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential. J. Med. Chem. 54 , 5540–5561 (2011).

Ghidelli-Disse, S. et al . Identification of Plasmodium PI4 kinase as target of MMV390048 by chemoproteomics. Malar. J. 13 , S21 (2014).

Paquet, T. et al . Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase. Sci. Transl Med. 9 eaad9735 (2017).

Ge, J. F. et al . Discovery of novel benzo[ a ]phenoxazine SSJ-183 as a drug candidate for malaria. ACS Med. Chem. Lett. 1 , 360–364 (2010).

Abbat, S., Jain, V. & Bharatam, P. V. Origins of the specificity of inhibitor P218 toward wild-type and mutant PfDHFR: a molecular dynamics analysis. J. Biomol. Struct. Dyn. 33 , 1913–1928 (2015).

Wells, T. N. C., Hooft van Huijsduijnen, R. & Van Voorhis, W. C. Malaria medicines: a glass half full? Nat. Rev. Drug Discov. 14 , 424–442 (2015). Comprehensively reviews the malaria drug discovery pipeline.

Das, S. et al . Rapid reorganization of the parasite plasma membrane in response to a new class of antimalarial drugs. ISMMID http://immid-is.drexelmed.edu/2014_ISMMID_Abstract.pdf (2014).

Phillips, M. A. et al . A triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with improved drug-like properties for treatment and prevention of malaria. ACS Infect. Dis. 2 , 945–957 (2016).

Le Manach, C. et al . Identification of a potential antimalarial drug candidate from a series of 2-aminopyrazines by optimization of aqueous solubility and potency across the parasite life cycle. J. Med. Chem. 59 , 9890–9905 (2016).

Baragaña, B. et al . A novel multiple-stage antimalarial agent that inhibits protein synthesis. Nature 522 , 315–320 (2015).

Hameed, P. S. et al . Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate. Nat. Commun. 6 , 6715 (2015).

Zhang, Y. K. et al . Synthesis and structure–activity relationships of novel benzoxaboroles as a new class of antimalarial agents. Bioorg. Med. Chem. Lett. 21 , 644–651 (2011).

Chavchich, M. et al . Lead selection of the new aminomethylphenol, JPC-3210 for malaria treatment and prevention. Antimicrob. Agents Chemother. 60 , 3115–3118 (2016).

Basch, P. Textbook of International Health 2nd edn (Oxford Univ. Press, 1999).

Ouattara, A. F. et al . Malaria knowledge and long-lasting insecticidal net use in rural communities of central Cote d’Ivoire. Malar. J. 10 , 288 (2011).

Adetokunbo, O. & Gilles, H. Short Textbook of Public Health, Medicine for the Tropics (BookPower, 2006).

Carter, J. A. et al . Persistent neurocognitive impairments associated with severe falciparum malaria in Kenyan children. J. Neurol. Neurosurg. Psychiatry 76 , 476–481 (2005).

Fernando, S. D., Rodrigo, C. & Rajapakse, S. The ‘hidden’ burden of malaria: cognitive impairment following infection. Malar. J. 9 , 366 (2010).

Kihara, M., Carter, J. A. & Newton, C. R. The effect of Plasmodium falciparum on cognition: a systematic review. Trop. Med. Int. Health 11 , 386–397 (2006).

Holding, P. A. & Snow, R. W. Impact of Plasmodium falciparum malaria on performance and learning: review of the evidence. Am. J. Trop. Med. Hyg. 64 , 68–75 (2001).

World Health Organization. Global technical strategy for Malaria 2016–2030. WHO http://who.int/malaria/areas/global_technical_strategy/en/ (2016).

Noedl, H. et al . Evidence of artemisinin-resistant malaria in western Cambodia. N. Engl. J. Med. 359 , 2619–2620 (2008).

Singh, R. et al . Comparison of three PCR-based assays for the non-invasive diagnosis of malaria: detection of Plasmodium parasites in blood and saliva. Eur. J. Clin. Microbiol. Infect. Dis. 33 , 1631–1639 (2014).

Oguonu, T. et al . The performance evaluation of a urine malaria test (UMT) kit for the diagnosis of malaria in individuals with fever in South-east Nigeria: cross-sectional analytical study. Malar. J. 13 , 403 (2014).

Berna, A. Z. et al . Analysis of breath specimens for biomarkers of Plasmodium falciparum infection. J. Infect. Dis. 212 , 1120–1128 (2015).

Lukianova-Hleb, E. et al . Transdermal diagnosis of malaria using vapor nanobubbles. Emerg. Infect. Dis. 21 , 1122–1127 (2015).

World Health Organization. Emergency response to artemisinin resistance in the greater Mekong subregion. Regional framework for action 2013–2015. WHO http://www.who.int/malaria/publications/atoz/9789241505321/en/ (2013).

Rao, P. N. et al . A method for amplicon deep sequencing of drug resistance genes in Plasmodium falciparum clinical isolates from India. J. Clin. Microbiol. 54 , 1500–1511 (2016).

Wells, T. N., Burrows, J. N. & Baird, J. K. Targeting the hypnozoite reservoir of Plasmodium vivax : the hidden obstacle to malaria elimination. Trends Parasitol. 26 , 145–151 (2010). Discusses issues related to targeting the latent stages of P. vivax to address the lack of drug options that are safe in all patients to treat these stages of the parasite.

Chattopadhyay, R. et al . Establishment of an in vitro assay for assessing the effects of drugs on the liver stages of Plasmodium vivax malaria. PLoS ONE 5 , e14275 (2010).

Burrows, J. N., Hooft van Huijsduijnen, R., Möhrle, J. J., Oeuvray, C. & Wells, T. N. C. Designing the next generation of medicines for malaria control and eradication. Malar. J. 12 , 187 (2013). Defines TCPs and Target Product Profiles for malaria.

Burrows, J. N. et al . New developments in anti-malarial target candidate and product profiles. Malar. J. 16 , 26 (2017). Comprehensively analyses the compound properties that are required for the development of effective antimalarials that will cover all species and stages of the disease.

Tate, E. W., Bell, A. S., Rackham, M. D. & Wright, M. H. N -Myristoyltransferase as a potential drug target in malaria and leishmaniasis. Parasitology 141 , 37–49 (2014).

Pett, H. E. et al . Novel pantothenate derivatives for anti-malarial chemotherapy. Malar. J. 14 , 169 (2015).

Kato, N. et al . Diversity-oriented synthesis yields novel multistage antimalarial inhibitors. Nature 538 , 344–349 (2016).

Herman, J. D. et al . The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs. Sci. Transl Med. 7 , 288ra277 (2015).

Russo, I. et al . Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte. Nature 463 , 632–636 (2010).

Nilsen, A. et al . Quinolone-3-diarylethers: a new class of antimalarial drug. Sci. Transl Med. 5 , 177ra137 (2013).

Newton, C. R., Taylor, T. E. & Whitten, R. O. Pathophysiology of fatal falciparum malaria in African children. Am. J. Trop. Med. Hyg. 58 , 673–683 (1998).

Kalanon, M. & McFadden, G. I. Malaria. Plasmodium falciparum and its apicoplast. Biochem. Soc. Trans. 38 , 775–782 (2010). Describes the importance of the apicoplast genome to the malaria parasite and opportunities to target this unique organelle for drug discovery.

Bozdech, Z. et al . The transcriptome of the intraerythrocytic developmental cycle of Plasmodium falciparum . PLoS Biol. 1 , E5 (2003).

Hughes, K. R., Philip, N., Starnes, G. L., Taylor, S. & Waters, A. P. From cradle to grave: RNA biology in malaria parasites. Wiley Interdiscip. Rev. RNA 1 , 287–303 (2010).

Llinas, M., Bozdech, Z., Wong, E. D., Adai, A. T. & DeRisi, J. L. Comparative whole genome transcriptome analysis of three Plasmodium falciparum strains. Nucleic Acids Res. 34 , 1166–1173 (2006).

Ganesan, K. et al . A genetically hard-wired metabolic transcriptome in Plasmodium falciparum fails to mount protective responses to lethal antifolates. PLoS Pathog. 4 , e1000214 (2008).

Hu, G. et al . Transcriptional profiling of growth perturbations of the human malaria parasite Plasmodium falciparum . Nat. Biotechnol. 28 , 91–98 (2010).

Hoo, R. et al . Integrated analysis of the Plasmodium species transcriptome. EBioMedicine 7 , 255–266 (2016).

Caro, F., Ahyong, V., Betegon, M. & DeRisi, J. L. Genome-wide regulatory dynamics of translation in the Plasmodium falciparum asexual blood stages. eLife 3 , e04106 (2014). Describes a comprehensive analysis of the P. falciparum transcriptome over the red blood cell cycle.

PubMed Central   Google Scholar  

Kirchner, S., Power, B. J. & Waters, A. P. Recent advances in malaria genomics and epigenomics. Genome Med. 8 , 92 (2016). Comprehensively reviews of the role of epigenomics in gene expression in Plasmodium spp.

Lee, M. C. & Fidock, D. A. CRISPR-mediated genome editing of Plasmodium falciparum malaria parasites. Genome Med. 6 , 63 (2014). Reviews genetic approaches to manipulating the P. falciparum genome.

de Koning-Ward, T. F., Gilson, P. R. & Crabb, B. S. Advances in molecular genetic systems in malaria. Nat. Rev. Microbiol. 13 , 373–387 (2015). Reviews genetic approaches to manipulating the Plasmodium spp. genome.

Gomes, A. R. et al . A genome-scale vector resource enables high-throughput reverse genetic screening in a malaria parasite. Cell Host Microbe 17 , 404–413 (2015).

Corey, V. C. et al . A broad analysis of resistance development in the malaria parasite. Nat. Commun. 7 , 11901 (2016).

Allman, E. L., Painter, H. J., Samra, J., Carrasquilla, M. & Llinas, M. Metabolomic profiling of the malaria box reveals antimalarial target pathways. Antimicrob. Agents Chemother. 60 , 6635–6649 (2016).

Manyando, C. et al . Safety of artemether–lumefantrine in pregnant women with malaria: results of a prospective cohort study in Zambia. Malar. J. 9 , 249 (2010).

Yanow, S. K., Gavina, K., Gnidehou, S. & Maestre, A. Impact of malaria in pregnancy as Latin America approaches elimination. Trends Parasitol. 32 , 416–427 (2016).

Harrington, W. E., Morrison, R., Fried, M. & Duffy, P. E. Intermittent preventive treatment in pregnant women is associated with increased risk of severe malaria in their offspring. PLoS ONE 8 , e56183 (2013).

Dellicour, S. et al . First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: a meta-analysis of observational studies. PLoS Med. 14 , e1002290 (2017).

Van Voorhis, W. C., Hooft van Huijsduijnen, R. & Wells, T. N. C. Profile of William C. Campbell, Satoshi O®mura, and Youyou Tu, 2015 Nobel Laureates in Physiology or Medicine. Proc. Natl Acad. Sci. USA 112 , 15773–15776 (2015).

White, N. J., Hien, T. T. & Nosten, F. H. A. Brief history of qinghaosu. Trends Parasitol. 31 , 607–610 (2015). Reviews the history of the discovery of artemisinin derivatives.

White, N. J. et al . Averting a malaria disaster. Lancet 353 , 1965–1967 (1999).

White, N. J. & Olliaro, P. L. Strategies for the prevention of antimalarial drug resistance: rationale for combination chemotherapy for malaria. Parasitol. Today 12 , 399–401 (1996).

Hien, T. T. & White, N. J. Qinghaosu. Lancet 341 , 603–608 (1993).

Vaid, A., Ranjan, R., Smythe, W. A., Hoppe, H. C. & Sharma, P. PfPI3K, a phosphatidylinositol-3 kinase from Plasmodium falciparum , is exported to the host erythrocyte and is involved in hemoglobin trafficking. Blood 115 , 2500–2507 (2010).

Mbengue, A. et al . A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria. Nature 520 , 683–687 (2015).

Annan, Z. et al . Population genetic structure of Plasmodium falciparum in the two main African vectors. Anopheles gambiae and Anopheles funestus . Proc. Natl Acad. Sci. USA 104 , 7987–7992 (2007).

Josling, G. A. & Llinas, M. Sexual development in Plasmodium parasites: knowing when it's time to commit. Nat. Rev. Microbiol. 13 , 573–587 (2015).

Aly, A. S., Vaughan, A. M. & Kappe, S. H. Malaria parasite development in the mosquito and infection of the mammalian host. Annu. Rev. Microbiol. 63 , 195–221 (2009).

World Health Organization. Climate change and human health. WHO http://www.who.int/globalchange/summary/en/index5.html (2017).

Gething, P. W. et al . Modelling the global constraints of temperature on transmission of Plasmodium falciparum and P. vivax . Parasit. Vectors 4 , 92 (2011).

Weiss, G. E. et al . Revealing the sequence and resulting cellular morphology of receptor–ligand interactions during Plasmodium falciparum invasion of erythrocytes. PLoS Pathog. 11 , e1004670 (2015).

Egan, E. S. et al . Malaria. A forward genetic screen identifies erythrocyte CD55 as essential for Plasmodium falciparum invasion. Science 348 , 711–714 (2015).

Crosnier, C. et al . Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum . Nature 480 , 534–537 (2011). References 260 and 261 identify key receptors involved in P. falciparum invasion.

Volz, J. C. et al . Essential role of the PfRh5/PfRipr/CyRPA complex during Plasmodium falciparum invasion of erythrocytes. Cell Host Microbe 20 , 60–71 (2016). Provides a comprehensive molecular understanding of the role of the receptor basigin in P. falciparum invasion and provides a comprehensive molecular model for the invasion process that highlights the three key steps.

Zenonos, Z. A. et al . Basigin is a druggable target for host-oriented antimalarial interventions. J. Exp. Med. 212 , 1145–1151 (2015).

Srinivasan, P. et al . Binding of Plasmodium merozoite proteins RON2 and AMA1 triggers commitment to invasion. Proc. Natl Acad. Sci. USA 108 , 13275–13280 (2011).

Remarque, E. J., Faber, B. W., Kocken, C. H. & Thomas, A. W. Apical membrane antigen 1: a malaria vaccine candidate in review. Trends Parasitol. 24 , 74–84 (2008).

Yuthavong, Y. et al . Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target. Proc. Natl Acad. Sci. USA 109 , 16823–16828 (2012).

Sidhu, A. B., Verdier-Pinard, D. & Fidock, D. A. Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 298 , 210–213 (2002). Describes the identification of the molecular basis for chloroquine resistance.

Lek-Uthai, U. et al . Stronger activity of human immunodeficiency virus type 1 protease inhibitors against clinical isolates of Plasmodium vivax than against those of P. falciparum . Antimicrob. Agents Chemother. 52 , 2435–2441 (2008).

World Health Organization. Rainbow tables. WHO http://www.who.int/immunization/research/development/Rainbow_tables/en/ (2017).

Mishra, N. et al . Emerging polymorphisms in falciparum Kelch 13 gene in northeastern region of India. Malar. J. 15 , 583 (2016).

Spring, M. D. et al . Dihydroartemisinin–piperaquine failure associated with a triple mutant including kelch13 C580Y in Cambodia: an observational cohort study. Lancet Infect. Dis. 15 , 683–691 (2015).

Thuy-Nhien, N. et al . K13-propeller mutations in Plasmodium falciparum populations in malaria endemic regions of Vietnam from 2009 to 2016. Antimicrob. Agents Chemother. 61 , e01578-16 (2017).

Thanh, N. V. et al . Rapid decline in the susceptibility of Plasmodium falciparum to dihydroartemisinin–piperaquine in the south of Vietnam. Malar. J. 16 , 27 (2017).

Sanchez, C. P. et al . Evidence for a pfcrt -associated chloroquine efflux system in the human malarial parasite Plasmodium falciparum . Biochemistry 44 , 9862–9870 (2005).

Valderramos, S. G. & Fidock, D. A. Transporters involved in resistance to antimalarial drugs. Trends Pharmacol. Sci. 27 , 594–601 (2006). Comprehensively reviews transporter mutants that are involved in resistance to the aminoquinoline series of antimalarial drugs (for example, chloroquine).

Borges, S. et al . Genomewide scan reveals amplification of mdr1 as a common denominator of resistance to mefloquine, lumefantrine, and artemisinin in Plasmodium chabaudi malaria parasites. Antimicrob. Agents Chemother. 55 , 4858–4865 (2011).

Humphreys, G. S. et al . Amodiaquine and artemether–lumefantrine select distinct alleles of the Plasmodium falciparum mdr1 gene in Tanzanian children treated for uncomplicated malaria. Antimicrob. Agents Chemother. 51 , 991–997 (2007).

Baliraine, F. N. & Rosenthal, P. J. Prolonged selection of pfmdr1 polymorphisms after treatment of falciparum malaria with artemether–lumefantrine in Uganda. J. Infect. Dis. 204 , 1120–1124 (2011).

Martin, R. E. & Kirk, K. The malaria parasite's chloroquine resistance transporter is a member of the drug/metabolite transporter superfamily. Mol. Biol. Evol. 21 , 1938–1949 (2004).

Ehrhardt, S. et al . Large-scale surveillance of Plasmodium falciparum crt(K76T) in northern Ghana. Antimicrob. Agents Chemother. 51 , 3407–3409 (2007).

Figueiredo, P. et al . Prevalence of pfmdr1 , pfcrt , pfdhfr and pfdhps mutations associated with drug resistance, in Luanda, Angola. Malar. J. 7 , 236 (2008).

Mens, P. F. Ambiguous role of pfcrt K76 in Plasmodium falciparum : a marker of resistance or increased susceptibility. Expert Rev. Anti Infect. Ther. 7 , 409–412 (2009).

Restrepo-Pineda, E., Arango, E., Maestre, A., Rosário, V. E. D. & Cravo, P. Studies on antimalarial drug susceptibility in Colombia, in relation to Pfmdr1 and Pfcrt . Parasitology 135 , 547–553 (2008).

Drew, M. E. et al . Plasmodium food vacuole plasmepsins are activated by falcipains. J. Biol. Chem. 283 , 12870–12876 (2008).

Witkowski, B. et al . A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype–genotype association study. Lancet Infect. Dis. 17 , 174–183 (2017).

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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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Malaria 2017: Update on the Clinical Literature and Management

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• 1 Department of Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY, 10461, USA. [email protected].
• PMID: 28634831
• DOI: 10.1007/s11908-017-0583-8

Purpose of review: Malaria is a prevalent disease in travelers to and residents of malaria-endemic regions. Health care workers in both endemic and non-endemic settings should be familiar with the latest evidence for the diagnosis, management and prevention of malaria. This article will discuss the recent malaria epidemiologic and medical literature to review the progress, challenges, and optimal management of malaria.

Recent findings: There has been a marked decrease in malaria-related global morbidity and mortality secondary to malaria control programs over the last few decades. This exciting progress is tempered by continued levels of high transmission in some regions, the emergence of artemisinin-resistant Plasmodium falciparum malaria in Southeast Asia, and the lack of a highly protective malaria vaccine. In the United States (US), the number of travelers returning with malaria infection has increased over the past few decades. Thus, US health care workers need to maintain expertise in the diagnosis and treatment of this infection. The best practices for treatment and prevention of malaria need to be continually updated based on emerging data. Here, we present an update on the recent literature on malaria epidemiology, drug resistance, severe disease, and prevention strategies.

Keywords: Drug resistance in malaria; Malaria control; Malaria epidemiology; Malaria treatment; Post-artemisinin delayed hemolysis; Severe malaria.

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• INTRODUCTION
• Protocol and registration.
• Search strategy and selection criteria.
• Study selection.
• Data collection and management.
• Synthesis of results.
• Meta-analysis.
• Risk of bias in individual studies.
• Summary of selected literatures.
• Evidence of effectiveness in improving malaria outcomes.
• Evidence of cost-effectiveness.
• Effect of the intervention on specific vulnerable populations.
• Risk of bias assessment.
• ACKNOWLEDGMENTS

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of the search strategy.

Pooled estimates of epidemiological outcomes from the 14 included studies using random-effect meta-analysis methods.

Risk of bias assessment for the 14 studies included in the systematic literature review. This figure appears in color at www.ajtmh.org .

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World Health Organization , 2019 . World Malaria Report 2019 . Geneva, Switzerland : WHO .

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Feachem RGA et al. , 2019 . Malaria eradication within a generation: ambitious, achievable, and necessary . Lancet 394 : 1056 – 1112 .

Alonso PL , 2020 . The role of mass drug administration of antimalarials . Am J Trop Med Hyg 103 : 1 – 2 .

Cheaveau J , Mogollon DC , Mohon MAN , Golassa L , Yewhalaw D , Pillai DR , 2019 . Asymptomatic malaria in the clinical and public health context . Expert Rev Anti Infect Ther 17 : 997 – 1010 .

World Health Organization , 2015 . The Role of Mass Drug Administration, Mass Screening and Treatment, and Focal Screening and Treatment for Malaria . Geneva, Switzerland : WHO .

White NJ , 2004 . Antimalarial drug resistance . J Clin Invest 113 : 1084 – 1092 .

Sooyoung Kim, Henrik S, Joacim R, Yesim T, 2020. A systematic review of the effectiveness and cost-effectiveness of intermittent mass test-and-treat (MTAT) interventions for malaria. PROSPERO: International prospective register of systematic reviews. CRD42020214610. Available at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020214610 .

Cunningham J et al. , 2019 . A review of the WHO malaria rapid diagnostic test product testing programme (2008–2018): performance, procurement and policy . Malar J 18 : 387 .

World Health Organization , Roll Back Malaria & United States , Agency for International D , 2000 . New Perspectives: Malaria Diagnosis: Report of a Joint WHO/USAID Informal Consultation, 25–27 October 1999 . Geneva, Switzerland : WHO .

Harrer M , Cuijpers P , Furukawa TA , Ebert DD , 2019 . Doing Meta-Analysis in R: A Hands-on Guide . Boca Raton, FL: Chapman & Hall/CRC Press.

Higgins JP et al. , 2011 . The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials . BMJ 343 : d5928 .

Schwarzer G , Carpenter J , Rücker G , 2015 . Meta-Analysis with R . New York, NY: Springer-Verlag.

Sutanto I et al. , 2018 . Negligible impact of mass screening and treatment on mesoendemic malaria transmission at West Timor in eastern Indonesia: a cluster-randomized trial . Clin Infect Dis 67 : 1364 – 1372 .

Conner RO et al. , 2020 . Mass testing and treatment for malaria followed by weekly fever screening, testing and treatment in northern Senegal: feasibility, cost and impact . Malar J 19 : 252 .

Ahmed R et al. , 2019 . Efficacy and safety of intermittent preventive treatment and intermittent screening and treatment versus single screening and treatment with dihydroartemisinin–piperaquine for the control of malaria in pregnancy in Indonesia: a cluster-randomised, open-label, superiority trial . Lancet Infect Dis 19 : 973 – 987 .

Halliday KE , Okello G , Turner EL , Njagi K , McHaro C , Kengo J , Allen E , Dubeck MM , Jukes MC , Brooker SJ , 2014 . Impact of intermittent screening and treatment for malaria among school children in Kenya: a cluster randomised trial . PLOS Med 11 : e1001594 .

Larsen DA , Bennett A , Silumbe K , Hamainza B , Yukich JO , Keating J , Littrell M , Miller JM , Steketee RW , Eisele TP , 2015 . Population-wide malaria testing and treatment with rapid diagnostic tests and artemether-lumefantrine in southern Zambia: a community randomized step-wedge control trial design . Am J Trop Med Hyg 92 : 913 – 921 .

Silumbe K , Yukich JO , Hamainza B , Bennett A , Earle D , Kamuliwo M , Steketee RW , Eisele TP , Miller JM , 2015 . Costs and cost-effectiveness of a large-scale mass testing and treatment intervention for malaria in Southern Province, Zambia . Malar J 14 : 211 .

Consortium C , 2019 . Community-based malaria screening and treatment for pregnant women receiving standard intermittent preventive treatment with sulfadoxine-pyrimethamine: a multicenter (The Gambia, Burkina Faso, and Benin) cluster-randomized controlled trial . Clin Infect Dis 68 : 586 – 596 .

Desai MR et al. , 2020 . Impact of intermittent mass testing and treatment on incidence of malaria infection in a high transmission area of western Kenya . Am J Trop Med Hyg 103 : 369 – 377 .

Samuels AM et al. , 2020 . Impact of community-based mass testing and treatment on malaria infection prevalence in a high transmission area of western Kenya: a cluster randomized controlled trial . Clin Infect Dis 72 : 1927 – 1935 .

Natama HM et al. , 2018 . Additional screening and treatment of malaria during pregnancy provides further protection against malaria and nonmalarial fevers during the first year of life . J Infect Dis 217 : 1967 – 1976 .

Tagbor H , Bruce J , Agbo M , Greenwood B , Chandramohan D , 2010 . Intermittent screening and treatment versus intermittent preventive treatment of malaria in pregnancy: a randomised controlled non-inferiority trial . PLoS One 5 : e14425 .

Tiono AB , Guelbeogo MW , Sagnon NF , Nebie I , Sirima SB , Mukhopadhyay A , Hamed K , 2013 . Dynamics of malaria transmission and susceptibility to clinical malaria episodes following treatment of Plasmodium falciparum asymptomatic carriers: results of a cluster-randomized study of community-wide screening and treatment, and a parallel entomology study . BMC Infect Dis 13 : 535 .

Tiono AB , Ouedraogo A , Ogutu B , Diarra A , Coulibaly S , Gansane A , Sirima SB , O’Neil G , Mukhopadhyay A , Hamed K , 2013 . A controlled, parallel, cluster-randomized trial of community-wide screening and treatment of asymptomatic carriers of Plasmodium falciparum in Burkina Faso . Malar J 12 : 79 .

Kuepfer I et al. , 2019 . Effectiveness of intermittent screening and treatment for the control of malaria in pregnancy: a cluster randomised trial in India . BMJ Glob Health 4 : e001399 .

World Health Organization , Baltussen R et al. 2003 . Making Choices in Health: WHO Guide to Cost-Effectiveness Analysis . Geneva, Switzerland : WHO .

van Eijk AM et al. , 2019 . The burden of submicroscopic and asymptomatic malaria in India revealed from epidemiology studies at three varied transmission sites in India . Sci Rep 9 : 17095 .

World Health Organization , 2015 . Mass Drug Administration, Mass Screening and Treatment and Focal Screening and Treatment for Malaria . Geneva, Switzerland : WHO .

Cook J et al. , 2015 . Mass screening and treatment on the basis of results of a Plasmodium falciparum -specific rapid diagnostic test did not reduce malaria incidence in Zanzibar . J Infect Dis 211 : 1476 – 1483 .

Stresman GH et al. , 2015 . Focal screening to identify the subpatent parasite reservoir in an area of low and heterogeneous transmission in the Kenya highlands . J Infect Dis 212 : 1768 – 1777 .

Mfuh KO , Achonduh-Atijegbe OA , Bekindaka ON , Esemu LF , Mbakop CD , Gandhi K , Leke RGF , Taylor DW , Nerurkar VR , 2019 . A comparison of thick-film microscopy, rapid diagnostic test, and polymerase chain reaction for accurate diagnosis of Plasmodium falciparum malaria . Malar J 18 : 73 .

Wardhani P , Butarbutar TV , Adiatmaja CO , Betaubun AM , Hamidah N , Aryati , 2020 . Performance comparison of two malaria rapid diagnostic test with real time polymerase chain reaction and gold standard of microscopy detection method . Infect Dis Rep 12 : 8731 .

Griffin JT et al. , 2010 . Reducing Plasmodium falciparum malaria transmission in Africa: a model-based evaluation of intervention strategies . PLoS Med 7 : e1000324 .

Rosas-Aguirre A et al. , 2015 . Modelling the potential of focal screening and treatment as elimination strategy for Plasmodium falciparum malaria in the Peruvian Amazon Region . Parasit Vectors 8 : 261 .

Yukich JO et al. , 2020 . Cost-effectiveness of focal mass drug administration and mass drug administration with dihydroartemisinin-piperaquine for malaria prevention in Southern Province, Zambia: results of a community-randomized controlled trial . Am J Trop Med Hyg 103 : 46 – 53 .

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A Systematic Review of the Evidence on the Effectiveness and Cost-Effectiveness of Mass Screen-and-Treat Interventions for Malaria Control

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Malaria elimination and eradication efforts have stalled globally. Further, asymptomatic infections as silent transmission reservoirs are considered a major challenge to malaria elimination efforts. There is increased interest in a mass screen-and-treat (MSAT) strategy as an alternative to mass drug administration to reduce malaria burden and transmission in endemic settings. This study systematically synthesized the existing evidence on MSAT, from both epidemiological and economic perspectives. Searches were conducted on six databases (PubMed, EMBASE, CINALH, Web of Science, Global Health, and Google Scholar) between October and December 2020. Only experimental and quasi-experimental studies assessing the effectiveness and/or cost-effectiveness of MSAT in reducing malaria prevalence or incidence were included. Of the 2,424 citation hits, 14 studies based on 11 intervention trials were eligible. Eight trials were conducted in sub-Saharan Africa and three trials in Asia. While five trials targeted the community as a whole, pregnant women were targeted in five trials, and school children in one trial. Transmission setting, frequency, and timing of MSAT rounds, and measured outcomes varied across studies. The pooled effect size of MSAT in reducing malaria incidence and prevalence was marginal and statistically nonsignificant. Only one study conducted an economic evaluation of the intervention and found it to be cost-effective when compared with the standard of care of no MSAT. We concluded that the evidence for implementing MSAT as part of a routine malaria control program is growing but limited. More research is necessary on its short- and longer-term impacts on clinical malaria and malaria transmission and its economic value.

Malaria is a vector-borne disease that affected over 200 million people in 2019, 1 and imposes a significant economic burden on endemic countries. According to the 2019 WHO malaria report, 19 countries collectively account for 85% of global malaria burden. 1 All of these high-burden countries are also resource poor, and (except for India) are located in sub-Saharan Africa (SSA). In these countries, Plasmodium falciparum and P. vivax infections account for the majority of malaria cases. 1 In the past two decades, great strides have been made in malaria control, and this has increased enthusiasm toward malaria elimination with the ultimate goal of its eradication. 2 Worryingly, progress on malaria elimination and eradication has stalled globally in the last few years, 1 and it has been argued that we have reached the limits of what we can achieve with the imperfect tools and limited resources we have. 3 Currently, a serious obstacle to malaria control and elimination efforts is asymptomatic infections that provide Anopheles mosquitoes with a silent parasite reservoir that sustain transmission in endemic areas. 4

Mass drug administration (MDA) is being reexamined by the malaria community as an intervention strategy as it remains one of the few strategies whose full potential has yet to be realized in endemic areas. 3 In MDA, irrespective of the presence of symptoms or infection, every member of a population living in a defined geographic area receives a full therapeutic course of an effective antimalarial drug. 5 Typically, MDA is repeated at intervals, and each round is conducted over a short time span. MDA not only clears symptomatic infections, but also has the potential to reduce the prevalence of asymptomatic parasitemia that is chronic and often goes undetected and untreated in clinical settings.

Currently, MDA is not recommended as a core malaria intervention. 3 This is because long-term use of MDA in areas with stable malaria transmission has raised a number of concerns, including that frequent administration of antimalarial drugs in a population may present safety issues. 6 – 10 Perhaps a greater concern is the possibility of inducing drug resistance as a result of repeated use of in the context of MDA. 6 Hence, the WHO limits the use of MDA as part of a multipronged approach to reduce transmission for achieving malaria elimination in low-to-moderate transmission settings where there is access to case management and other malaria control interventions, or in complex emergency and epidemic settings where healthcare systems are overwhelmed and incapable of providing routine malaria services. 5

A mass screen-and-treat (MSAT) strategy has been proposed as an alternative to MDA to achieve malaria elimination in endemic settings. The principle undergirding MSAT is active detection of infections, both symptomatic and asymptomatic, in a given population, using malaria diagnostic tools such as rapid diagnostic tests (RDTs), light microscopy (LM), and molecular methods such as polymerase chain reaction (PCR), prior to treatment with antimalarials. MSAT may hold comparative advantage to MDA in minimizing the excess use of antimalarial drugs on those who do not need them, thus reducing the risk of antimalarial drug resistance and enabling better use of resources. The 2015 WHO recommendation on MSAT was stricter compared with MDA, limiting its use to only complex emergencies and epidemics, and was informed by the findings of only a handful of existing studies. This systematic review built on this initial assessment and reviewed all experimental and quasi-experimental studies that assessed the effectiveness of MSAT in reducing malaria prevalence or incidence since then. In particular, we synthesized the existing evidence on MSAT, from both epidemiological and economic perspectives, to identify knowledge gaps and provide guidance on future research and implementation of MSAT in the context of malaria control and elimination programs.

MATERIALS AND METHODS

This systematic literature review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol (Supplemental Appendix 1). The protocol of the systematic review was registered in International Prospective Register of Systematic Reviews (PROSPERO; CRD42020214610). 7

Searches were conducted on six different databases, namely, PubMed, EMBASE, CINALH, Web of Science, Global Health, and Google Scholar, between October and December 2020. The search strategy is built using the MeSH terms for malaria and other search terms. All databases, expect EMBASE, were searched using these MeSH terms, with all the subheadings, as well as other key words. For EMBASE, similarly, Emtree terms associated with malaria and other search terms were used, with all the subcategories. The search strategy details for each database are given in Supplemental Appendix 1 . The intervention of interest for this review was defined as detecting and treating human malaria infections using a mass testing and treatment approach. Given the heterogeneity of the terminology used in the malaria literature, we included both “screen-and-treat” and “test-and-treat” as search terms, as well as their variants. We limited our inclusion criteria to intervention trials that were conducted one-time or at regular intervals but over a short period of time, using RDTs, LM, or PCR. Only studies reporting epidemiological and/or cost-effectiveness outcomes were included. The outcomes of interest included effect size estimates of the intervention in reducing malaria prevalence or incidence, expressed as risk difference (RD), risk ratio (RR), incidence rate ratio (IRR), hazard ratio (HR), or odds ratio (OR), as well as cost-effectiveness estimates, expressed as incremental cost-effectiveness ratio (ICER). To ensure the quality of evidence on intervention effectiveness, studies only with experimental or quasi-experimental designs were considered. The review focused on published peer-reviewed literature between January 1, 2000 and November 1, 2020, given the wide expansion in use of RDTs in the field in early 2000s, following the WHO’s consultation on the topic in 1999, which was published in 2000. 8 , 9 Searches were performed without any language restrictions.

We excluded studies with observational designs with no control group and model-based studies of intervention effectiveness, as well as study protocols, literature reviews, and conference abstracts. We also excluded any study that did not include all components of the intervention strategy. For example, any mass treatment intervention without a testing component, a focal test-and-treat (FTAT) intervention targeting only a narrow group of people around index cases, or any community-based treatment intervention based on passive surveillance of cases in clinical settings were excluded from the review.

After removing duplicates, two reviewers (SK and VL) independently screened all studies by title and abstract based on the inclusion and exclusion criteria. Any disagreements between the two reviewers were resolved by consensus. Full texts of selected studies were then reviewed by the same two reviewers to confirm inclusion. We further reviewed the references of all included studies to identify other potentially eligible studies. Any disagreements were resolved by a third reviewer (YT), who reviewed and validated the final list of included studies. Excluded studies were recorded with reasons for exclusion.

To minimize errors and bias, two reviewers (SK and VL) independently extracted data from included studies using a data extraction form that was developed and tested for reliability. Information extracted included country of study, year of publication, study period, study setting regarding malaria transmission (i.e., seasonality, transmission intensity, and predominant parasite species), study design, sample characteristics (i.e., sample size, age, gender), statistical and economic outcome measures reported, and intervention characteristics (target population, duration and frequency of MSAT rounds, malaria diagnostic test, and antimalarial drug used). The supplemental materials of included studies were also reviewed to identify any relevant information. The data extracted by the two reviewers were first compared and then merged into one database after resolving any disagreements. The data extraction form and all extracted data are available in Supplemental Appendix 1 and 2 .

Extracted data was cleaned by the principal reviewer (SK) for further analysis. Extracted data on intervention effects were categorized by effect size calculation method and yielded five mutually exclusive categories: RD, RR, HR, IRR, and OR. Economic outcomes included ICER and other reported cost estimates associated with the intervention, such as cost per tested or treated. Outcome data were also broadly grouped into four categories for the purposes of narrative synthesis and meta-analysis: incidence, prevalence, costs, and cost-effectiveness.

The selection of outcomes and the statistical methods for meta-analysis were guided by Harrer et al. 10 Based on the data we extracted, outcome measures that were reported consistently across multiple individual studies were selected for meta-analysis—namely, IRR and HR for incidence, and OR and RR for prevalence. We combined estimates of IRR and HR to calculate a pooled estimate of the incidence of malaria, whereas for malaria prevalence, two separate meta-analyses were conducted using ORs and RRs. 11 When multiple measures were reported for an outcome in a study, the reviewers established a set of criteria for the prioritization and selection of outcomes. Specifically, in efficacy trials, we prioritized the results of per-protocol (PP) analysis over intent-to-treat (ITT) analysis when both analyses were conducted. For prevalence and incidence, we prioritized outcomes by malaria diagnostic tool in descending order from PCR, LM, RDT to clinical diagnosis to best capture the effectiveness of the intervention on asymptomatic/subclinical malaria cases. Lastly, we considered results over all cases of malaria rather than species-specific results.

When multiple (≥ 2) individual studies targeting the same population reported on the same outcome measures, the results were pooled in R software (version 3.6.3) using the package “meta” for random-effect meta-analysis. 12 Forest plots reporting individual study outcomes and pooled effect sizes were generated together with I 2 values and 95% confidence intervals to assess heterogeneity in the included studies. Furthermore, outcomes reported for specific vulnerable populations (e.g., school children, pregnant women) were assessed separately in a sub-analysis, and a pooled effect size was derived, when data are appropriate for meta-analysis.

Two individual reviewers (SK, VL) conducted independent risk of bias assessment on all included studies using the Cochrane Collaboration’s tool. 11 The assessed domains using this tool included random sequence generation, allocation concealment, masking of participants and personnel, masking of outcome assessment, incomplete outcome data, selective reporting, and other biases. Since many studies followed cluster-randomized design where masking of individual participants was not possible because of ethical reasons, the assessment on this criterion not only considered the existence of participant masking in the study design, but also the extent to which masking or the lack of masking of participants are likely to affect the results to be biased. The assessment was done at the study level and any disagreements between the reviewers were reconciled by consensus. The summarized risk of bias was used to inform our synthesis of findings and discussion.

The database search identified a total of 2,424 studies. After removing duplicates, 2,387 studies were screened by title and abstract. Of these, 2,355 did not meet the inclusion criteria. We reviewed 32 full-text studies, of which 14 were deemed eligible for inclusion ( Figure 1 ). These 14 studies presented data from 11 different intervention trials (hereafter referred to as “trials”). Table 1 provides a summary of the key features of each study.

Citation: The American Journal of Tropical Medicine and Hygiene 105, 6; 10.4269/ajtmh.21-0325

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Summary characteristics of the 14 included studies in the systematic literature review

PF = P. falciparum ; PV = P. vivax ; U = Unspecified.

Of the 11 trials, three took place in Asian countries while the rest were conducted in SSA. All trials, except one, had a cluster-randomized design ( N  = 10), and none was masked to participants due to feasibility and ethical considerations. The intervention was targeted at pregnant women in five trials, and at school children in one trial. The target population in the remaining five trials was the community as a whole.

Malaria transmission intensity ranged from low to high across study sites. Five trials explicitly mentioned perennial transmission, while all study sites reported seasonal variability in transmission, with either one peak ( N  = 9) or two peaks ( N  = 2). Some trials involved multiple study sites with differing malaria transmission intensities. Overall, three trials included study sites in low transmission settings; 13 – 15 five trials had at least one study site with moderate transmission; 15 – 19 and two trials included study sites in high transmission settings. 19 – 22 Three trials did not specify transmission intensity. 23 – 26

In studies targeting the community as a whole, the number of MSAT rounds ranged between one and six over a period of 3–12 months. In all studies, control arms received standard care for malaria, while two studies had an additional study arm to assess the effectiveness of: 1) different rounds of MSAT, 13 or 2) weekly fever screen, test, and treat. 14 Post-intervention assessment of epidemiological outcomes was carried out either immediately after the final round of MSAT or up to 6 months.

In studies targeting pregnant women, MSAT was initiated in the first trimester of pregnancy and continued up until time of delivery. While some studies aimed to test and treat pregnant women for malaria monthly, three to four MSAT rounds were typically conducted. In only one study, women and their babies were followed up to 12 months after birth for longer-term outcome assessment. The single study targeting school children conducted five MSAT rounds over 20 months, and children were followed up to 6 months post-intervention.

The incidence of malaria was reported as IRR in three studies, 14 , 17 , 20 as HR in two studies, 13 , 20 and as RR in one study. 13 The pooled effect size for the incidence of malaria, combining IRRs and HRs, was 0.81 (95% CI: 0.64–1.03, I 2  = 79% [95% CI: 44%; 92%]), suggesting a marginal and statistically nonsignificant decrease in incidence ( Figure 2A ). The prevalence of malaria was reported as OR in two studies 13 , 17 and as RR in three studies. 16 , 21 , 24 The pooled effect size for the prevalence of malaria was significant for OR (0.35, 95% CI: 0.16–0.75, I 2  = 81% [95% CI: 18%; 96%]), but not for RR (1.02, 95% CI: 0.77–1.35, I 2  = 35% [95% CI: 0%; 75%]) ( Figure 2B and C). However, two out of three meta-analyses showed high inter-study heterogeneity, as expressed in I 2 value close to 100%, posing challenges in interpreting the pooled effects. All data used in these meta-analyses are provided in Supplemental Appendix 1 .

Two studies reported the costs of MSAT intervention, 14 , 18 whereas only one of these studies assessed its cost-effectiveness. 18 The cost-effectiveness analysis was conducted from a provider perspective, and estimated an ICER of US$894 per DALY averted for a three-round MSAT intervention in Zambia. Conducted between June and November 2012, the intervention was estimated to prevent over 16,000 cases and 30 deaths from malaria in a target population of 135,649 across 18 catchment areas and to avert over 1,300 DALYs. As the mean estimated ICER was lower than Zambia’s gross domestic product per capita of US$1,414, the intervention was found to be cost-effective compared with no MSAT. 27

In Zambia, the cost per test administered was estimated at US$4.39 and ranged between US$3.45–US$5.94 depending on catchment area size and number of MSAT rounds. 18 A study conducted in Senegal estimated the cost per person tested at US$14.3 for one round of MSAT covering 22,170 people over 6 months, 14 which was found to be significantly higher than the cost of other malaria control interventions in this setting. In both studies, cost estimates were most sensitive to training and transportation costs. These findings suggest that once MSAT becomes part of a routine malaria program, there may be economies of scale with significant reductions in implementation costs.

Interventions targeting pregnant women were not effective in reducing the prevalence of maternal malaria infection measured at both placental (pooled OR: 1.05, 95% CI: 0.85–1.31) and peripheral (pooled OR: 0.94, 95% CI: 0.76–1.15) levels. The pooled estimates for each outcome are summarized in Supplemental Appendix 1 .

The risk of bias was found to be generally low across all assessed domains but one (i.e., other sources of bias), and the quality of information provided in studies to assess risk was, overall, high ( Figure 3 ). None of the studies was masked to participants, and most measured outcomes were not likely to be affected by this lack of masking. Three studies 24 – 26 were, however, assessed to have high risk of bias due to non-masked study design; two studies 24 , 25 reporting on the same trial relied on self-reported number of healthcare visits to measure incidence post-intervention; and one study 26 reported significantly lower adherence rate among participants in the intervention arm compared with the control arm. Another study among pregnant women 19 was evaluated to have a high risk of bias because women in the intervention arm were more frequently tested, and this potentially resulted in a higher estimate of malaria incidence in the intervention arm compared with the control arm. Another potential source of bias in outcome measurements was mitigated in 13 of the 14 studies by masking laboratory staff to the allocated study arm. Only one study did not provide sufficient information to assess this bias.

Regarding the measurement of epidemiological outcomes, a high risk of bias was observed in 11 of the 14 studies. The prevalence of malaria was most commonly assessed by RDTs. Only five studies 13 , 15 , 24 – 26 used PCR. In four of the five studies, the target population was pregnant women, and placental malaria was the principal outcome of interest. As a result, the evaluation of MSAT’s impact in reducing malaria prevalence was limited by the detection of cases by conventional RDTs or LM. Hence, the potential impact of MSAT on the prevalence of asymptomatic parasitemia remains poorly quantified.

Similar biases affected the measurement of malaria incidence in the trials. Out of the nine studies that included incidence as an outcome measure, six used patient records from health facilities to retrospectively measure this outcome post-intervention. This led to an exclusion of symptomatic cases that did not seek care, asymptomatic cases that could have been detected by RDT or LM, and sub-patent cases that could only be detected by PCR. Given that in most malaria endemic areas, the majority of cases are asymptomatic, 4 , 28 this could have influenced the results of these trials.

To the best of our knowledge, this is the first systematic literature review on the effectiveness and the cost-effectiveness of MSAT, and the second attempt to revisit this intervention since the WHO Malaria Policy Advisory Committee (MPAC) issued a recommendation on its use in 2015. 5 In the absence of sufficient evidence, the WHO MPAC discouraged the use of MSAT in situations other than complex emergencies and epidemics. 29 This recommendation was informed by a review of only four studies that evaluated MSAT-like interventions, including focal screening-and-test (FSAT)—which is similar to, but different from MSAT, for instance, in terms of geographic scope. Two of these four studies were included in this systematic review 17 , 25 while the other two did not meet our eligibility criteria and hence were excluded. 30 , 31 Cook et al. 30 conducted the MSAT intervention in Zanzibar, Tanzania, but only reported a before–after comparison of the malaria prevalence in the target population. Stresman et al. 31 conducted and reported the results of sentinel-based focal screening to explore an alternative strategy to MDA or MSAT, but did not report any outcome related to the effectiveness of treatment of individuals identified through screening. However, both studies raised the potential advantage of introducing screening before treatment in comparison to mass treatment approach, such as MDA. 30 , 31

Our review includes a total of 12 additional studies with an experimental design that were not reviewed by the MPAC 16 , 18 , 23 , 24 and also published after 2015. 13 – 15 , 19 – 22 , 26 The results of our meta-analysis reaffirm that the effects of MSAT on malaria incidence and prevalence are marginal and statistically nonsignificant, and there are currently few studies available for evidence synthesis. It is important to note that a total of 11 trials were eligible to be included in the final synthesis, and meta-analyses were conducted with as few as two to three studies using average intervention effects given the limited number of trials. Further, the trials included study sites with varied transmission intensities, and also reported on a variety of outcome measures. Hence, we were unable to conduct a meta-analysis by transmission setting. In addition, most of the studies reported a mix of significant and nonsignificant intervention effects, with the majority being nonsignificant, which made interpretation of the results difficult. However, a handful of trials conducted in low 13 , 14 and moderate 17 malaria transmission settings suggested the potential impact of mass test-and-treat (MTAT) in reducing malaria incidence and prevalence, when measured by microscopy or PCR. On the other hand, the trials that were set in high malaria transmission settings 20 , 21 showed mixed effects in reducing clinical cases.

This systematic review demonstrates that the existing epidemiological evidence on the effectiveness of MSAT is still limited and highlights deficiencies in trial design and reporting that warrant further attention. First, incidence and prevalence estimates were largely based on symptomatic and patent infections due to the low sensitivity of the diagnostic methods used. Almost all studies used RDTs and/or microscopy to detect malaria cases pre-, during, and post-intervention; however, it is well-established that the sensitivity of these technologies is suboptimal compared with PCR. 32 Even the most sensitive RDTs are estimated to have less than 80% sensitivity compared with PCR. 33 The reliability of RDTs is even lower for non- falciparum species when coinfections with other pathogens precede or exist due to the antigen–antibody cross-reactions. 4 The choice of diagnostic technology also presents a major challenge in real-life implementation settings, and this highlights the importance of improving the insufficient sensitivity of existing field diagnostics to detect asymptomatic infections. Only four studies assessed the effectiveness of MSAT in reducing the incidence of asymptomatic or sub-patent infections, 15 , 22 , 24 , 25 Two of which targeted pregnant women and their newborns. 15 , 22 Tiono et al. 24 , 25 showed a temporary reduction in the prevalence of asymptomatic carriers during the second and third round of MSAT; however, the reduction became nonsignificant after the implementation of all four rounds. There was no significant reduction in the incidence of asymptomatic infection among newborns during the 12-month follow-up period after birth. 22 Ahmed et al. 15 compared sub-patent–level malaria infections across different malaria transmission settings, but was not able to deduce the effectiveness of MSAT in reducing the incidence or prevalence sub-patent malaria infections.

Second, while most studies included in this review provided a detailed description of the intervention protocol, we failed to systematically extract information on intervention coverage and level of adherence to treatment across all included studies and were not able to assess the role of these factors on intervention efficacy. Thus, the observed differences in intervention effectiveness across included studies can potentially stem from higher adherence to intervention protocols. The WHO recommendation emphasized the importance of high intervention coverage for MDA, MSAT, and FTAT strategies. 5 Even if the majority of included studies reported relatively high coverage, ranging between 74% and 96%, the studies did not provide information on adherence levels to antimalarial treatment. Some studies conducted both ITT and PP analyses, 15 , 17 , 23 while most of the studies provided results based on only one method and did not justify their choice of method.

Third, intervention duration and follow-up periods were relatively short, which did not allow for an assessment of the longer-term effects of MSAT. With the exception of 2 studies, where the intervention was delivered over 20 months and the follow-up period was 4–6 months, 16 , 21 all studies were conducted within a 12-month period. In sum, the limited evidence makes it challenging to understand whether these unsatisfactory results are due to poor sensitivity of the diagnostic methods used, insufficient coverage of the target populations, inadequate adherence to antimalarial treatment, treatment failure due to antimalarial resistance, insufficient duration of intervention, or a combination of these factors.

Existing mathematical modeling studies sheds light on some of the pending questions. Griffin et al. 34 studied the effectiveness of MSAT in six different hypothetical African settings where long-lasting insecticidal nets (LLINs) were widely distributed (> 80%), and assumed that RDTs had a high diagnostic sensitivity similar to microscopy along with full treatment adherence among those who tested positive, as well as an intervention duration of 25 years. This model-based study showed that the combination of MSAT with scaled-up LLIN usage was effective to reduce parasite prevalence to less than 1% in low-to-moderate transmission settings. 34 Another modeling study using the findings of a cohort study conducted in the Peruvian Amazon where the prevalence of asymptomatic malaria, mostly sub-patent, was estimated at 5–14%, showed that three consecutive rounds of MSAT with the start of the dry season would result in significant reductions in malaria incidence and prevalence, but at least 5 consecutive years of intervention would be required to eliminate the disease in the area. 35 Based on the findings of these model-based studies, it is plausible that the trials included in this review failed to address the dynamics asymptomatic and sub-patent malaria infections, an area that is yet to be better understood. 28

We also reviewed the existing evidence on the cost-effectiveness of MSAT, an important consideration for policymakers and program managers to assess the feasibility and sustainability of this intervention in resource-constrained settings. Cost per test administered was higher than other nontreatment interventions, but the one study that calculated ICER concluded that the intervention was cost-effective compared with no MSAT. 18 The potential for further reduction in intervention costs was also suggested if implementation continued over years at scale since the initial training of staff would require a large investment. When compared with the ICER of MDA from a study conducted in the same country, 36 it seemed even plausible that MSAT would be more cost-effective than MDA.

This review has a number of limitations. First, despite our best efforts to finetune the search strategy by including all relevant search terms related to MSAT, it is important to note the heterogeneity of nomenclature, which might have led to the exclusion of potentially eligible studies. Of the 14 studies included in this review, only two shared the same nomenclature for the intervention (community-wide screening and treatment) 24 , 25 since these studies were based on the same trial. In the abbreviated form, there was more consistency: MTAT was used by five studies; 14 , 17 , 18 , 20 , 21 community-based scheduled screening and treatment was used by two; 19 , 22 and two studies used Intermittent Screen and Treat. 15 , 16 None of the studies used MSAT, which is the terminology used by WHO. 5 , 29 In addition, two studies that we encountered during the literature search but did not meet our eligibility criteria, described the intervention as an example of FSAT, 31 , 35 although the description of the intervention strategy was closer to MSAT than FSAT. We believe that this review serves as a good starting point for streamlining the nomenclature in order for the intervention to be more systematically documented and reviewed in the future. Toward this end, we consider that both MSAT and MTAT explicate the key characteristics of the intervention around mass screening and treating well.

Second, as mentioned previously, the various outcome measures reported across studies made it challenging to obtain pooled estimates of intervention effects. This heterogeneity across studies also precluded an investigation of intervention effects by malaria transmission setting. Moving forward, to undertake a more robust assessment of the effectiveness of MSAT, there is a need for guidelines on the key outcomes to be measured in intervention trials.

In conclusion, the evidence for implementing MSAT as part of a routine malaria control program has grown since the WHO MPAC in 2015, but is limited. The time-limited nature of implementation and the simplicity of MSAT hold certain advantages to implement this intervention in hard-to-reach and resource-poor settings, and humanitarian crises and emergencies, where healthcare systems are disrupted. Compared with MDA, MSAT is likely to have more significant longer-term benefits in terms of reducing the development of antimalarial resistance and operational costs. However, due to the complex dynamics of malaria transmission and the myriad of factors that may affect program implementation, further research is needed to bolster current evidence on the effectiveness and cost-effectiveness of MSAT across different malaria transmission settings.

This publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number U19AI089676. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Author Notes

Authors’ addresses: addresses: Sooyoung Kim and Yesim Tozan, NYU School of Global Public Health, New York, NY, E-mails: [email protected] and [email protected] . Verah Nafula Luande and Joacim Rocklöv, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden, E-mails: [email protected] and [email protected] . Jane M. Carlton, Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY, E-mail: [email protected] .

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Peer-reviewed

Research Article

Knowledge, attitudes and practices regarding malaria prevention and control in communities in the Eastern Region, Ghana, 2020

Roles Data curation, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review & editing

Affiliation Tetteh Quarshie Memorial Hospital, Mampong, Ghana

Roles Conceptualization, Formal analysis, Methodology, Project administration, Supervision, Validation, Writing – review & editing

* E-mail: [email protected]

Affiliation Department of Medical Laboratory Sciences, School of Biomedical and Allied Health Sciences, College of Health Sciences, University of Ghana, Korle Bu, Accra, Ghana

• Aquel Rene Lopez, 
• Charles Addoquaye Brown

• Published: August 30, 2023
• https://doi.org/10.1371/journal.pone.0290822
• Reader Comments

In sub-Saharan Africa countries including Ghana, the malaria burden remains unacceptably high and still a serious health challenge. Evaluating a community’s level of knowledge, attitude, and practice (KAP) regarding malaria is essential to enabling appropriate preventive and control measures. This study aimed to evaluate knowledge of malaria, attitudes toward the disease, and adoption of control and prevention practices in some communities across the Eastern Region of Ghana.

A cross‑sectional based study was carried out in 13 communities across 8 districts from January -June, 2020. Complete data on socio-demographic characteristics and KAP were obtained from 316 randomly selected household respondents by a structured pre-tested questionnaire. Associations between KAP scores and socio-demographic profiles were tested by Chi-square and binary logistic regression. Data analysis was done with SPSS version 26.0.

Most respondents (85.4%) had good knowledge score about malaria. Preferred choice of treatment seeking place (50.6%) was the health center/clinic. All respondents indicated they would seek treatment within 24 hours. Mosquito coils were the preferred choice (58.9%) against mosquito bites. Majority of households (58.5%) had no bed nets and bed net usage was poor (10.1%). Nearly half of the respondents (49.4%) had a positive attitude toward malaria and 40.5% showed good practices. Chi-square analysis showed significant associations for gender and attitude scores (p = 0.033), and educational status and practice scores (p = 0.023). Binary logistic regression analysis showed that 51–60 year-olds were less likely to have good knowledge (OR = 0.20, p = 0.04) than 15–20 year-olds. Respondents with complete basic schooling were less likely to have good knowledge (OR = 0.33, p = 0.04) than those with no formal schooling. A positive attitude was less likely in men (OR = 0.61, p = 0.04). Good malaria prevention practice was lower (OR = 0.30, p = 0.01) in participants with incomplete basic school education compared to those with no formal schooling.

Overall scores for respondents’ knowledge, though good, was not reflected in attitudes and levels of practice regarding malaria control and prevention. Behavioral change communication, preferably on radio, should be aimed at attitudes and practice toward the disease.

Citation: Lopez AR, Brown CA (2023) Knowledge, attitudes and practices regarding malaria prevention and control in communities in the Eastern Region, Ghana, 2020. PLoS ONE 18(8): e0290822. https://doi.org/10.1371/journal.pone.0290822

Editor: Enoch Aninagyei, University of Health and Allied Sciences, GHANA

Received: February 11, 2023; Accepted: August 16, 2023; Published: August 30, 2023

Copyright: © 2023 Lopez, Brown. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting information files.

Funding: The author(s) received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

In sub-Saharan Africa, the malaria burden remains unacceptably high and still a serious health challenge [ 1 ]. The West African sub-region, due to its current high rates of malaria infections and fatalities, is a hotspot for the disease’s transmission. The sub-region accounts for about half of the malaria global burden [ 1 , 2 ].

Ghana is among the countries in West Africa with the highest burden of malaria [ 3 ]. Ghana has a hyperendemic malaria problem, thus every region is susceptible to infection [ 4 , 5 ]. The most vulnerable populations are children under 5 years and pregnant women, with malaria accounting for 40.0% of all outpatient attendance [ 6 ].

One of the seven work packages created by the WHO Strategic Advisory Group on Malaria Eradication (SAGme) is community engagement for the elimination and eradication of malaria [ 7 ]. Thus, the necessity of inclusive and cooperative efforts to eradicate malaria and the significance of maintaining the target community at the forefront of the fight against the disease cannot be overstated. The willingness of each community member to participate and act is greatly influenced by their attitudes toward the disease and the use of any existing control measures if a malaria control program is to succeed in reducing both morbidity and mortality in that community [ 8 ]. These attitudes are influenced by their level of knowledge, understanding, and perception [ 9 , 10 ]. For example, decisions likely to be taken when putative malaria symptoms set in such as, whether to just stay at home, use herbal treatment, buy over-the-counter drugs for self -medication, or go to a health facility [ 9 , 10 ] may affect treatment outcomes. “Fever”, which is synonymous with malaria in many settings, unfortunately is present in other tropical diseases common in malaria-endemic areas [ 11 ]. It thus is important that individuals experiencing a fever seek medical attention as soon as possible to rule out malaria or other possible causes of their illness [ 11 ]. Any choice that ultimately results in delayed diagnosis and treatment, particularly in children, may have fatal consequences [ 12 , 13 ].

Knowledge, attitudes, and practices (KAP) surveys are frequently used tools that can gather crucial data to inform the design of malaria control and prevention activities and interventions, ensuring community participation, acceptance, and adherence [ 14 , 15 ]. Malaria KAP surveys have been conducted in many African countries including Cape Verde [ 16 ], Cameroon [ 17 , 18 ], Ethiopia [ 19 – 22 ], Nigeria [ 23 , 24 ] and Senegal [ 25 ]. Similar studies have also been conducted in some regions in Ghana [ 26 – 29 ]. However, to our knowledge, there is a scarcity of data on malaria KAP in the Eastern Region of Ghana. The current study therefore aimed to evaluate knowledge of malaria, attitudes toward the disease, adoption of control and prevention practices, and care-seeking behaviors in communities across the Eastern Region of Ghana. The study also investigated variables linked to KAP regarding malaria.

Study area and population

The Eastern Region ( Fig 1 ) has a land area of 19,323 square kilometers (which is 8.1% of the total land area of Ghana) [ 30 ]. Koforidua is the administrative capital. The Region can be described as urbanized (over 50% of the population live in urban areas). Based on the 2021 population census it has a population 2,917,039 which makes up 9.5% of the total population of the country [ 31 ]. There are 49.2% men and 50.8% women in the population, with an urban-rural divide of 43.3% to 56.6%, respectively. About 41.3% of the population is < 5 years. About 53% of the population are engaged in agriculture which is the region’s primary economic activity; 10.7% and about 22% of the population are in industry and in the services sub-sector, respectively.

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Ghana and Eastern Region maps adapted from USGS National Map Viewer.

https://doi.org/10.1371/journal.pone.0290822.g001

Study design and sampling strategy

This household-based cross-sectional descriptive and analytical survey was conducted in 13 communities across 8 districts in the Eastern Region of Ghana. The study was conducted between January -June, 2020.

For this KAP study, 8 districts accessible by the N6 and N4 highways were chosen for logistical feasibility. All districts also had ≤5 km intra-regional proximity to a healthcare facility. Communities in each district were chosen through systematic random sampling. The community was sampled for participants using a two-stage cluster sampling method. Six geographic divisions of the community were made, and four of them were chosen. Households were located within chosen clusters using proportional systematic random sampling to guarantee that every household had an equal chance of being included. Every third household was surveyed after a randomly chosen starting point (a household) was made. When a home was empty or the residents were away when the visit was made, the nearest household that had an eligible participant was contacted.

In the presence of the household head or the spouse, or an adult (over 18 years old) inhabitant, the goal of the study was explained and the willingness to participate in the study sort. Thus, the study’s participants were households/ household respondents that provided informed verbal consent. Only one individual per household was interviewed; either only the household head or the spouse, or adult inhabitant. The spouse or another family member who was an adult was questioned only when the household head was not available.

Sample size

Sample size was calculated using the StatCalc Sample Size and Power function in Epi Info 7.2.5.0. Using a population size of 2,917,039, [ 31 ] an expected frequency of 70%, acceptable margin of error of 5%, design effect 1.0% and leaving both design effect and cluster equal to 1, a sample size of 323 was estimated at 95% confidence level.

Ethical considerations

This study was approved by the Ethics and Protocol Review Committee of the School of Biomedical and Allied Health Sciences, College of Health Sciences, University of Ghana, Korle-bu, Accra. Verbal consent was also obtained from the household respondents before interview.

Data collection (KAP surveys)

House-to-house surveys were conducted by adequately trained field staff. After gaining free and informed consent, the interviewee was given a structured, standardized, and pre-tested questionnaire translated into the Akan local language. The questionnaire comprised 58 questions, and was divided into six main sections. The first section collected information on socio-demographic characteristics. The second section addressed basic knowledge of malaria with a sub-section on bed net use and the third section, sources of information about malaria. The fourth and fifth sections addressed treatment seeking behaviors and attitudes toward malaria, respectively. The last section addressed practices toward malaria prevention. The questionnaire was adapted from the 2019 Malaria Indicator Survey in Ghana [ 32 ] and different peer reviewed KAP papers [ 20 , 33 , 34 ].

Data analysis

Data collected was entered and analyzed using SPSS version 26.0 (IBM Corp, NY, USA). Relevant tables and figures were created from the data to allow for easy analysis and interpretation. Continuous variables such as age were presented in ranges. Categorical variables were reported using descriptive statistics such as frequencies and percentages. Variables analyzed included socio-demographic factors and malaria-related KAP.

These criteria were used to determine the participants’ knowledge scores regarding malaria. The responses to five different questions—including the mode of transmission, malaria signs and symptoms, and preventive measures—were combined to determine the respondents’ knowledge of malaria. Each correct knowledge response received a score of 1, while an incorrect or uncertain response received a score of 0. A modified Bloom’s cut-off was adapted using a score of above 60% of correct answers to indicate good knowledge and a score of below 60% to indicate poor knowledge [ 35 , 36 ].

Attitude was measured using Likert scaling technique. According to the Likert scale, responses to the affirmative and negative statements ranged from strongly agree (score of 4), agree (score of 3), disagree (score of 2), and to strongly disagree (score of 1). Each respondent received a total score after the responses were added up. When the mean score was calculated, respondents with scores greater than or equal to 40.4 were considered to have a positive attitude toward malaria, while those with scores below 40.4 were considered to have a negative attitude.

Using the Likert scale, the respondents’ practices were also identified. The Likert scale scoring system was applied to the respondents’ responses, with scores ranging from never (score of 0), sometimes (score of 1), and always (score of 2). Each respondent’s total score was calculated after the responses were added up, and the study participants’ mean practice scores were calculated as well. When a respondent’s overall practice score was greater than the mean practice score (6.3), he/she was considered to have good practice. However, when an overall practice score fell below the mean practice score (6.3), that respondents was considered to have poor practice.

To examine the relationships between knowledge, attitude and practice scores and socio-demographic profile, Chi-square tests were carried out. Age, gender, and education were the independent variables. To determine how the independent variables associated with the dependent variable, binary logistic regression analyses were carried out. Statistical significance was defined at p < 0.05.

Socio-demographic data

A total of 316 completed questionnaires of household respondents from 13 communities in 8 districts ( Table 1 ) were used in the analysis of the survey data. The highest number of respondents (14.2%) were sampled in Apedwa, with the least (1.3%) from Somanya. Majority of the respondents were males (60.4%) ( Table 2 ). Household heads (32.3%) and adult inhabitants not related to the household heads (21.2%) were the highest respondents. The age category of 41–50 years had the largest number of respondents (37.7%). Majority of the respondents had gone to school with 25.0% having completed primary school and 20.9% with post-secondary school qualifications. However, about a fifth (19.6%) of the respondents had no formal schooling. Household sizes of six or more (38.6%) and four or five (38.0%) were the highest. Only four (1.3%) respondents stayed alone. Majority of the houses in the communities had unburnt bricks, mud and poles, thatch/straw, timber, etc. as the major construction material of the house external wall (54.7%), and iron sheets or tiles for the major construction material for the house roof (88.0%). The main sources of income were agriculture based (38.3%) and craft/creative work (35.4%). All the respondents had a form of trading as a second source of income ( Table 2 ).

https://doi.org/10.1371/journal.pone.0290822.t001

https://doi.org/10.1371/journal.pone.0290822.t002

Basic knowledge about malaria

Basic knowledge about malaria can be found under Table 3 . All the respondents had heard about malaria and 76.9% knew the mosquito as the malaria vector. Majority of respondents (69.9%) also knew that mosquito bites can transmit malaria. However, other routes of disease transmission chosen included drinking contaminated water (3.5%), and eating contaminated food (3.5%). Majority of the respondents (60.1%) knew untreated malaria could be fatal.

https://doi.org/10.1371/journal.pone.0290822.t003

Headache (42.4%), high temperature/ fever (29.7%), and vomiting (13.6%), were the most common signs and symptoms indicated for malaria infection. The least signs and symptoms indicated for malaria infection were loss of energy (0.9%) and sweating (0.3%). Use of insecticide spray (52.5%) was indicated as the most common way to control and prevent malaria. Majority of the respondents (58.3%) were aware mosquitoes feed at night. The most common personal protection measure to guard against malaria (58.9%) was the use of mosquito coils. Majority of the households (58.5%) did not have bed nets and where they were available the ownership was by others (55.1%) but not the father or mother. Only a few bed nets (22.8%) were in use because of heat (77.2%).

Sources of information about malaria

All the respondents had heard or received malaria-related information. The main information sources were radio (32.0%), a community health worker (20.3%) or a health center/clinic (16.5%) ( Fig 2 ). Malaria-related information from newspapers (0.3%), a neighbor in the village (0.9%) and family member at home (1.65%) were the least.

https://doi.org/10.1371/journal.pone.0290822.g002

Treatment seeking behaviors

Most respondents (65.8%) reported a case of malaria in the household in the last six months ( Table 4 ). The preferred choice of treatment seeking place (50.6%) was the health center/clinic, followed by a traditional healer (26.9%). Seeking treatment from a community health worker was the least (3.5%) option. All respondents indicated they would seek treatment within 24 hours. Most respondents (97.8%) indicated they did not have adequate information about malaria and wanted mainly information about prevention (42.7%), preferring the radio (40.5%) and the church (34.2%) as the primary sources ( Table 4 ).

https://doi.org/10.1371/journal.pone.0290822.t004

Attitudes toward malaria

Majority of the respondents (60.1%) strongly agreed that malaria is a serious and life-threatening disease and all also strongly agreed to seek for advice or treatment when they get malaria ( Table 5 ). Majority (88.9%) strongly disagreed that malaria can be transmitted like the common cold and almost half (49.4%) strongly disagreed that only pregnant women and children were at risk of getting malaria. Majority (50.6%) disagreed that recovery from malaria occurs spontaneously with no treatment and 55.1% also disagreed to avoiding people with malaria. Most respondents (50.3%) agreed anyone can get malaria, most (52.5%) also agreed that they can self-treat by anti-malaria drugs purchased from a pharmacy/drug store and most (81.6%) strongly agreed to take the drugs only after checking they had not expired. However, 37.0% (strongly disagree) and 33.5% (disagree) saw no danger with incomplete medication.

https://doi.org/10.1371/journal.pone.0290822.t005

Almost half (49.4%) agreed on having a blood test done at the health center on suspicion of having malaria and 28.2% strongly disagreed they can give themselves self- treatment. On prevention from getting malaria, most (56.3%) strongly agreed sleeping under a mosquito net at night can prevent them from getting malaria and 38.0% strongly agreed on avoiding mosquito bites. There was agreement (37.7%) and strong agreement (29.1%) of greater risk of malaria infection from working or sleeping overnight on the farm or in the forest.

Practices toward malaria prevention

All respondents reported that they never slept in mosquito nets and never checked or repaired holes in the nets ( Fig 3 ). Also, only 10.1% of the households sometimes used mosquito nets. For prevention of mosquito bites, use of mosquito repellent coils was always used 52.8% of the time as compared with anti-mosquito sprays (24.7%). Draining stagnant water (29.1%) and clearing/cutting bushes (54.1%) made up the two main parts of the environmental management activities used to control the malaria vectors around the household.

https://doi.org/10.1371/journal.pone.0290822.g003

Overall KAP scores of the respondents and its association with of malaria control and prevention

According to the results of the knowledge score assessment, 85.4% of the respondents had good knowledge about malaria and nearly half (49.4%) had a positive attitude toward malaria in terms of its seriousness or threat, prevention, and control. Also, the overall practice score for malaria prevention and control among the respondents showed 40.5% had good practices.

Associations of KAP scores of the respondents with their socio-demographic status

From the Chi-square tests (Tables A to C in S1 Table ), none of the selected socio-demographic factors was associated with the knowledge score of malaria (all ps > 0.05). Chi-square analysis only showed significant associations for gender and attitude scores (p = 0.033), and educational status and practice scores (p = 0.023).

Tables D-F in S1 Table show the results of the binary logistic regression analyses. Respondents aged 51–60 years were 80% less likely to have good knowledge score [OR = 0.20 (95%CI: 0.04–0.95)] compared those aged 15–20 years. Respondents with complete basic school education were 67% less likely to have good knowledge score [OR = 0.33 (95%CI: 0.12–0.94)] compared to those with no formal schooling. The odds of positive attitude regarding malaria were 39% [OR = 0.61 (95%CI: 0.38–0.98)] lower among males compared to females (Table E in S1 Table ). Compared to respondents with no formal schooling, those with incomplete basic school education level [OR = 0.30 (95%CI:0.12–0.77)] were 70% less likely to practice good malaria prevention (Table F in S1 Table ).

Complex personal and societal factors that affect people’s behavior are linked to initiatives that seek to prevent and control malaria and lessen the burden that comes with it. These factors do, however, vary between nations and within communities. These highlight the importance of understanding local malaria risk factors. The current study therefore aimed to evaluate knowledge of malaria, attitudes toward the disease, adoption of control and prevention practices, and care-seeking behaviors in 13 communities across the Eastern Region of Ghana.

The majority of respondents were in the 41–50 years age range, which does not correspond to the Eastern Region’s current population proportion [ 31 ]. Due to the mainly rural nature of the communities used in the Eastern Region, about one-fifth of the respondents had no formal education. Our findings (38.3%) support agriculture as the primary source of income (32.0%) in the nation [ 31 ].

Results of the knowledge score assessment showed that 85.4% of the respondents had good knowledge about malaria. Thus, there was a high level of community awareness of malaria transmission, signs and symptoms, and treatment. This observation is comparable with the other studies in Swaziland [ 37 ], Northwest Ethiopia [ 22 ], Cameroon [ 17 , 38 ], and North-western Tanzania [ 39 ]. However, the findings of this study are higher than the ones reported in Nigeria [ 23 ] and Southern Ethiopia [ 21 , 40 ]. Although comparable to what other studies have found, the high level of knowledge may in part be due to health education campaigns [ 26 ]. A few respondents in this study, however, had knowledge gaps and included drinking contaminated water (3.5%), and eating contaminated food (3.5%) as ways that malaria is spread. It is very surprising that some respondents in this study and others conducted in malaria-endemic nations linked malaria to drinking contaminated water or other incorrect causes. In similar studies conducted in Zimbabwe [ 41 ] and Uganda [ 42 ], higher percentage of respondents provided the same answers. Studies in rural West African communities also reported comparable responses [ 43 , 44 ].

How individual community members seek malaria treatment is crucial to the success of mortality prevention of the disease [ 45 , 46 ]. Just over half (50.6%) of respondents indicated that health facilities were the best place to seek treatment for malaria although all respondents indicated they would seek treatment within 24 hours after suspecting malaria. Seeking treatment within 24 hours is extremely important especially in children under 5 years because they have little or no immunity and thus more likely to develop severe malaria [ 47 ]. Moreover, since malaria symptoms are generally non-specific and uncomplicated falciparum malaria can quickly progress to severe forms of the illness which can almost always lead to fatal outcomes without treatment, early diagnosis and prompt, effective treatment within 24–48 hours of the onset of malaria symptoms should be ensured [ 48 ]. In addition, since individual immunity can vary greatly, even in areas with moderate to high transmission intensity, the early treatment seeking behavior as indicated by all respondents is highly encouraging. It is also important to note that almost all the respondents (97.8%) wanted more information about prevention. This information was to come preferably from radio, which most respondent have access to on their phones, or from church, as majority of the respondents are Christians [ 31 ] and within the Ghanaian context, religion strongly influences how people live their daily lives [ 49 ]. Radio can be used to effectively spread malaria education because it is frequently stated that people access health information on radio [ 50 , 51 ] as also revealed in this study.

In the present study, majority of the respondents (60.1%) strongly agreed that malaria is a serious and life-threatening disease which is lower compared with a study carried out in Ethiopia [ 19 ]. Despite this, all the respondents strongly agreed to seek for advice or treatment when they contract malaria, and almost half agreed on having a blood test done at the health center on suspicion of having malaria although majority (52.5%) also agreed to self-medication. Studies in Ghana [ 29 , 52 ] and countries where malaria is endemic, Uganda [ 53 ], Southern Sudan [ 54 ], Tanzania [ 55 ] and Kenya [ 56 ], have noted the use of drugs purchased from drug stores and general stores for self-treatment. Even more intriguingly, studies conducted in Nigeria [ 57 ] and Ghana [ 52 ] revealed that self-medication with herbal preparations is regarded as the primary method of treating malaria. Therefore, it is clear that taking self-medication causes patients to put off getting the proper medical attention, which could worsen malaria outcomes. Self-medication may also be the cause of the observed noncompliance with national malaria treatment recommendations, which affects treatment outcomes and aids in the emergence of drug resistance. What was also a concern was the fact that 37.0% (strongly disagree) and 33.5% (disagree) saw no danger with incomplete medication which can result in treatment failure when complete doses are admitted later [ 58 , 59 ].

On prevention from getting malaria, although most (56.3%) strongly agreed sleeping under a mosquito net at night can prevent them from getting malaria and 38.0% strongly agreed on avoiding mosquito bites, in practice mosquito net usage was largely absent. Only 10.1% of households sometimes used nets and all the respondents never used them. Low net usage (15%) was also reported in a study in Ghana [ 29 ]. This practice starkly disagrees with net usage in studies done in Ghana [ 27 ], and in other countries such as Cameroon [ 17 , 18 ], Tanzania [ 39 ], Ethiopia [ 19 , 21 ], Guinea [ 50 ], and Nigeria [ 24 ]. The main reason given by majority of respondents (77.2%) for the non-usage of the nets in this study was heat. This agrees with results of the other studies in Ghana [ 27 , 29 ] and a study in Cameroon [ 17 ]. To increase the use of bed nets, continuous behavior change communication should be carried out in the districts [ 60 ]. In this current study, respondents preferred use of mosquito coils (52.8%) for prevention of mosquito bites in agreement with other studies in Ghana [ 27 , 28 ]. Clearing of bushes against mosquito bites was also high (54.1%) among the households. Use of multiple mosquito control and preventive methods have been observed in other studies [ 18 , 27 , 28 ].

In this study, despite the high good knowledge score (85.4%) among the respondents, this was not reflected in their attitude (50.6% negative attitude) and practice (59.5% poor practice) scores toward malaria control and prevention. The negative attitude scores are higher than those reported from studies in Ethiopia [ 19 ]. The practice scores in this study are also lower than those of studies in Ethiopia [ 19 , 40 ] and Sri Lanka [ 61 ] but higher than that of the study in Lao PDR [ 62 ]. Studies on bed net use and malaria prevention have found instances where participants’ increased knowledge did not result in better use of bed nets thus raising doubt on behavioral theories that presuppose a linear relationship between comprehension and application of malaria prevention strategies. Knowledge scores may be affected by differences in communities’ demographic, socioeconomic, educational, and cultural characteristics and by the lack of, access to, or accuracy of information about malaria [ 26 – 28 , 52 ]. This present study revealed that female gender was the explanatory variable which influenced positive attitude to malaria control and prevention although the majority of respondents were males. This disagrees with studies carried out in rural Ghana [ 26 ] and Bangladesh [ 51 ]. Given the patriarchal nature in the Ghanaian society [ 49 ] this is surprising. This study’s findings indicated that respondents’ education status in general did not significantly influence good practice of malaria prevention and control efforts. This might be due to the fact that about a third of the respondents had incomplete educational status. The degree of education, however, has shown a significant influence on populations’ malaria-related KAP in many parts of the world [ 8 , 17 , 19 , 20 , 51 ].

Conclusions

Overall score for respondents’ knowledge of malaria was good. However, attitudes and levels of practice regarding malaria did not match the knowledge score. Bednet use was almost non-existent. Health education, preferably on radio and at churches, aimed at prevention and control of the disease through changes in attitude and practice is urgently required.

Supporting information

S1 file. study questionnaire..

https://doi.org/10.1371/journal.pone.0290822.s001

S2 File. Malaria KAP dataset.

https://doi.org/10.1371/journal.pone.0290822.s002

S1 Table. Tables presenting the results of Chi-square tests and binary logistic regression analyses for the associations of KAP scores of the respondents with their socio-demographic status.

https://doi.org/10.1371/journal.pone.0290822.s003

Acknowledgments

We are grateful to all household respondents.

• 1. WHO. World malaria report 2022. Geneva: World Health Organisation, 2022.
• 2. The Global Fund. Regional impact report: malaria in West Africa. 2016
• 3. WHO. World malaria report 2021. Geneva: World Health Organisation, 2021.
• 4. Ghana Health Service. 2015 annual report. Accra: National Malaria Control Programme 2016.
• 5. The DHS Program. Ghana MIS 2016 malaria fact sheet. 2017.
• View Article
• Google Scholar
• 7. WHO. Malaria eradication: benefits, future scenarios and feasibility. A report of the strategic advisory group on malaria eradication. Geneva: World Health Organization, 2020.
• PubMed/NCBI
• 30. GhanaDistricts. Districts Eastern Region undated [23/10/2020]. http://ghanadistricts.com/Home/District/96 .
• 32. Ghana Statistical Service-GSS, National Malaria Control Programme-NMCP, National Public Health Reference Laboratory-NPHRL, ICF. Ghana malaria indicator survey 2019. Accra, Ghana, and Rockville, Maryland, USA: GSS/ICF, 2020.
• 35. Bloom BS, Engelhart MD, Furst EJ, Hill WH, Krathwohl DR. Taxonomy of educational objectives: the classification of educational goals; Handbook I: Cognitive domain. New York: David McKay; 1956.
• 48. WHO. WHO guidelines for malaria. World Health Organisation, 2022.

• Open access
• Published: 27 March 2018

Comparative effectiveness of malaria prevention measures: a systematic review and network meta-analysis

• Kinley Wangdi 1 ,
• Luis Furuya-Kanamori 1 , 2 ,
• Justin Clark 3 ,
• Jan J. Barendregt 4 , 5   an1 ,
• Michelle L. Gatton 6 ,
• Cathy Banwell 1 ,
• Gerard C. Kelly 1 ,
• Suhail A. R. Doi 1 , 2 &
• Archie C. A. Clements 1  

Parasites & Vectors volume  11 , Article number:  210 ( 2018 ) Cite this article

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Malaria causes significant morbidity and mortality worldwide. There are several preventive measures that are currently employed, including insecticide-treated nets (ITNs, including long-lasting insecticidal nets and insecticidal-treated bed nets), indoor residual spraying (IRS), prophylactic drugs (PD), and untreated nets (UN). However, it is unclear which measure is the most effective for malaria prevention. We therefore undertook a network meta-analysis to compare the efficacy of different preventive measures on incidence of malaria infection.

A systematic literature review was undertaken across four medical and life sciences databases (PubMed, Cochrane Central, Embase, and Web of Science) from their inception to July 2016 to compare the effectiveness of different preventive measures on malaria incidence. Data from the included studies were analysed for the effectiveness of several measures against no intervention (NI). This was carried out using an automated generalized pairwise modeling (GPM) framework for network meta-analysis to generate mixed treatment effects against a common comparator of no intervention (NI).

There were 30 studies that met the inclusion criteria from 1998–2016. The GPM framework led to a final ranking of effectiveness of measures in the following order from best to worst: PD, ITN, IRS and UN, in comparison with NI. However, only ITN (RR: 0.49, 95% CI: 0.32–0.74) showed precision while other methods [PD (RR: 0.24, 95% CI: 0.004–15.43), IRS (RR: 0.55, 95% CI: 0.20–1.56) and UN (RR: 0.73, 95% CI: 0.28–1.90)] demonstrating considerable uncertainty associated with their point estimates.

Current evidence is strong for the protective effect of ITN interventions in malaria prevention. Even though ITNs were found to be the only preventive measure with statistical support for their effectiveness, the role of other malaria control measures may be important adjuncts in the global drive to eliminate malaria.

Malaria imposes a great health and socio-economic burden on humanity, with an estimated 3.2 billion people at risk of being infected with malaria [ 1 ]. In 2016, there were approximately 216 million cases with 445,000 deaths, most of which were in children aged under 5 years in Africa [ 1 ]. Between 2000 and 2015, it has been estimated that there was a 37% global reduction in malaria incidence [ 2 ]. This improvement was likely made possible by economic development and urbanization in many endemic countries [ 3 ] as well as a substantial increase in investment in tackling malaria [ 4 ], leading to an increase in preventative activities, and improved diagnostics and treatment. The Global Technical Strategy for Malaria 2016–2030 (GTS) has a target to eliminate malaria in at least ten countries by 2020, 20 countries by 2025, and 30 countries by 2030 [ 2 , 5 ].

Vector control remains an essential component of malaria control and elimination. The capacity of vectors to transmit parasites and their vulnerability to vector control measures vary by mosquito species and are influenced by local environmental factors. Personal preventive measures that prevent contact between the adult mosquitoes and human beings are the main methods of prevention currently in practice. These include insecticide-treated nets (ITNs), and indoor residual spraying (IRS) [ 6 ]. ITNs are of two types: long-lasting insecticidal nets (LLINs) that have the insecticide incorporated into fibers during the manufacturing process, which leads to a longer duration of effectiveness and insecticide-treated nets (ITNs) which are impregnated with insecticides every six months. Indoor residual spraying (IRS) involves spraying insecticides on the walls of the houses. Additionally, antimalarial chemoprophylaxis is used for prevention of malaria in children and pregnant women. The commonly used prophylactic drugs (PD) are sulphadoxine-pyrimethamine (SP), mefloquine (MQ), amodiaquine (AQ), dihydroartemisinin-peperaquine (DP) and artesunate (AS). The main advantage of using PD is that they only require a single dose to achieve a full prophylactic effect [ 7 , 8 ]. However, the most common PD is SP and it is becoming less effective due to resistance [ 9 , 10 , 11 , 12 , 13 ]. As a result, other drugs such as MQ and AQ are increasingly being used as a substitute for or in combination with SP [ 12 , 14 ]. MQ provides a longer period of prophylaxis but side effects (agranulocytosis in 1 per 2000 patients) [ 15 ] are the main problem [ 16 , 17 ]. Similarly, AQ has been used in combination with SP but AQ is not well tolerated [ 14 ]. Many other less commonly utilized measures include insecticide-treated curtains (ITC), mosquito coils, insecticide-treated hammocks, and insecticide-treated tarpaulins.

There has been a decrease in malaria incidence worldwide, but what remains unclear is which of the common preventive interventions is the most effective for prevention of malaria infection. This knowledge may help prioritise resourcing of these interventions. There has been one comparative study of preventive efficacy that compares mortality across ITN, IRS and PD and this study demonstrated that the impact of IRS is equal to that of ITN on reducing malaria-attributable mortality in children [ 18 ]. There have also been several systematic reviews and meta-analyses focusing on single preventive measures. These reviews of existing data suggest that PD [ 19 , 20 , 21 , 22 ], is effective in preventing malaria infection in children when treated on a monthly basis with no protection when given three-monthly. The reviews of both ITN [ 23 , 24 , 25 ] and IRS [ 26 , 27 ] provide support for their effectiveness as malaria preventive measures, but there is no data on the effectiveness of one measure over another.

Therefore, this study aims to present an up-to-date comparison of the effectiveness of the four common malaria preventive measures (ITNs, UNs, IRS and PDs) for which data are readily available and compare these against no intervention [NI, defined as no intervention or placebo or a study group with standard care (any intervention given to all participants)]. A network meta-analysis methodology was chosen to pool the data as it allows comparisons of multiple preventive measures simultaneously and allows comparisons across preventive measures not directly tested in the included trials (indirect comparisons across a pair of studies that share a common comparator). In addition, this method allows ranking of the effectiveness of these measures for decision making.

Search strategy and eligibility criteria

A systematic literature review was undertaken using four medical and life sciences databases (PubMed, Cochrane Central, Embase and Web of Science). They were searched from their inception to March 2016 for trials that compared the effectiveness of malaria preventive measures. Search terms included were “ malaria ”, “ Plasmodium falciparum ”, “ Plasmodium vivax ”, “ bed net ”, “ mosquito control ”, “ antimalarial ”, and “insecticides” ; the specific keywords and connectors for each database are listed in the Additional file 1 : Table S1.

The inclusion of studies were restricted to (i) interventional studies; (ii) conducted in humans (with no restriction of age or sex); (iii) that compared two or more of the following malaria preventive measures: ITN, UN, IRS, PD or NI; and (iv) reported the number of new malaria cases diagnosed through microscopy or rapid diagnostic tests (RDT) after each intervention compared amongst a population at risk over time. Exclusion criteria included: (i) non-intervention studies; (ii) conference abstracts; and (iii) other less commonly utilized malaria preventive measures including ITC, mosquito coils, insecticide-treated hammocks and insecticide-treated tarpaulins. No language restrictions were imposed. Since we used a generalized pairwise modeling approach (see below), odd numbers of treatments (e.g. three treatment arms) required selection of a pair for inclusion in this study and we therefore excluded the arm that had the most available data in this synthesis [(i) arms that we excluded do not make a difference, (ii) concurrent interventions and no effect modification].

Study selection and data extraction

The citation search was developed and executed by JC, followed by selection of citations by title and abstract independently by two researchers (KW and LFK). The selected studies underwent a full-text review for all potentially relevant studies. Data from the included studies were then independently extracted in a spreadsheet by the same two researchers. The extracted data included: (i) the country of study; (ii) year(s) when the study was conducted; (iii) study design; (iv) study population characteristics; (v) preventive measures employed in the trial; and (vi) the number of new cases of malaria and person-months at risk. The extracted data were then cross-checked by the two researchers and any discrepancies during the selection of studies or data extraction were resolved through discussion and consensus following independent evaluation by another author (SARD).

Statistical analysis

The outcome of interest was the rate ratio (RR) of new malaria cases in intervention-A vs intervention-B following the implementation of different preventative measures. An automated generalized pairwise modeling (GPM) framework [ 28 ] was used to generate mixed treatment effects against a common comparator (NI). This framework is an extension of the Bucher method [ 29 ] that automates the single three-treatment loop method. This analysis starts by pooling effect sizes based on direct comparisons between any two interventions using meta-analytic methods. The indirect comparison was then performed by automated generation of all possible closed loops of three-treatments such that one of them was common to the two studies and formed the node where the loop began and ended but where the common node was never NI, while one of the other nodes was always NI. Finally, the mixed effects (multiple direct/indirect effects) were pooled using the same meta-analysis model as used for pooling direct effects. The analysis therefore led to a final mixed treatment effect estimate for different interventions versus NI. Estimates of preventive effectiveness were then ranked by their point estimates. It should be pointed out that it is common for network plots based on Bayesian methods to rank treatments by the surface under the cumulative ranking curve (SUCRA). From our frequentist perspective, treatment effects are thought of as fixed parameters and thus, strictly speaking SUCRA does not apply. A frequentist alternative called the P-score has been proposed but SUCRA or P-scores have no major advantage compared to what we have done, i.e. ranking treatments by their point estimates [ 30 ].

All direct estimates were pooled using the inverse variance heterogeneity (IVhet) model [ 31 ] as were all mixed estimates, but this synthesis process was also repeated using the random effects model for comparison (the random effects analysis was undertaken under the GPM framework as well as under the frequentist multivariate meta-analysis framework for comparison (see Additional file 1 : Tables S2 and S3 for details).

Cluster randomized controlled trials (RCT) were combined with other study types after accounting for clustering using the design effect (DEFF). The DEFF was calculated as follows:

where ρ is the intra-class correlation for the statistic in question and c is the average size of the cluster. We then divided the numbers in each 2 × 2 table of the study by the DEFF to calculate a corrected sample size, which was then utilized in the meta-analysis. Different units of clusters such as villages and households were used in different studies. The intra-class correlation coefficient ( ρ ) was provided only in one study [ 32 ], and this ( ρ = 0.048) was used for calculation of the DEFF for other cluster RCT studies.

Statistical heterogeneity across direct effects pooled in the meta-analysis were assessed by the Cochran’s Q and the H index which is the square root of H 2 , the estimated residual variance from the regression of the standardized treatment effect estimates against the inverse standard error in each direct meta-analysis. H was computed as follows:

where n is the number of study estimates pooled and Q represents the Chi squared from Cochran’s Q .

Transitivity was assessed statistically by looking at inconsistency across the network as a whole using the weighted pooled H index ( \( \overline{H} \) ) which was computed as follows from the Cochran’s Q statistic for the k final comparisons:

where n is the number of estimates pooled across each comparison and s is the number comparisons (out of k ) were n = 1. The minimum value H or \( \overline{H} \) can take is 1, it is not influenced by n , and \( \overline{H}<3 \) was taken to be minimal inconsistency based on our simulations of H in homogenous direct meta-analyses [ 28 ].

Sensitivity analyses were undertaken through limiting the network to (i) studies conducted in children or (ii) studies including only Plasmodium falciparum infection and then re-running the GPM analysis.

Publication bias was assessed using a ‘comparison adjusted’ funnel plot where on the horizontal axis the difference of each study’s observed ln(RR) from the comparison’s mean ln(RR) obtained from the pairwise fixed effect meta-analysis was plotted. In the absence of small-study effects, we expect the studies to form an inverted funnel centred at zero [ 33 ]. All the analyses involved in the generalised pairwise modelling (GPM) framework for multiple indirect and mixed effects were conducted using MetaXL v5.2 (EpiGear International, Sunrise Beach, Australia) [ 28 ]. Funnel and network plots were produced using Stata version 13 (Stata Corporation, College Station, TX, USA).

Quality assessment

The quality of the included studies was assessed using a modification of a quality checklist used in another study by one of the authors [ 34 ]. The studies were assessed on inclusion of safeguards relating to study design, selection, information, blinding of study assessors, and analytical biases. There were 12 questions with a possible maximum count of 17 safe-guards (Additional file 1 : Table S4).

Data extraction

The search strategy identified 7940 citations (Cochrane Central = 353, PubMed = 2698, Web of Science = 1534 and Embase = 3355). After deleting duplicate citations, a total of 4941 citations were retrieved for the initial screening. Of these, 4692 citations were excluded based on title only. Records of 249 citations were screened and 161 citations were excluded based on the title and abstract. Eighty eight articles were assessed for eligibility, of which 58 articles were excluded (Additional file 1 : Table S5). Thirty citations fulfilled eligibility criteria and were included in the meta-analysis (Fig. 1 ). Data from the included studies were extracted and summarized in a spreadsheet (Table 1 ).

Search flowchart. Note : details of excluded studies in Additional file 1 : Table S5

Characteristics of included studies

The literature search on malaria control and preventive measures led to the identification of the five treatment groups across the studies (ITN, UN, PD, IRS and NI). A total of 30 studies were included in the current meta-analysis. These studies were conducted from 1988 to 2015. Eighteen studies were conducted in Africa [ 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ], 11 studies were from Asia [ 32 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ] and one study from South America [ 63 ]. Ten studies did not restrict study participants to any age [ 36 , 41 , 51 , 55 , 57 , 58 , 60 , 61 , 62 , 63 ], four studies only included adults as study participants [ 40 , 53 , 56 , 59 ], and the rest of the studies (16) were conducted in children and adolescents (0–19 years) [ 32 , 35 , 37 , 38 , 39 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 52 , 54 ]. There were 21 studies that reported P. falciparum infection rates separately [ 32 , 35 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 45 , 46 , 47 , 48 , 50 , 51 , 52 , 54 , 55 , 58 , 60 , 62 ]. The latter two groups were used in a sensitivity analysis (see below). The most common study design was the RCT with 16 studies [ 37 , 38 , 39 , 40 , 42 , 43 , 46 , 47 , 48 , 50 , 51 , 53 , 54 , 56 , 59 , 62 ], eight studies were cluster RCT [ 32 , 36 , 44 , 49 , 52 , 57 , 58 , 60 ], and the rest (6) were quasi-experimental studies with a control group [ 35 , 41 , 45 , 55 , 61 , 63 ]. Twenty one studies had two arms [ 32 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 44 , 49 , 50 , 52 , 53 , 54 , 55 , 57 , 59 , 60 , 61 , 62 , 63 ], eight studies had three arms, [ 35 , 45 , 46 , 47 , 48 , 51 , 56 , 58 ] and one had four arms [ 43 ]. Of those with three arms we dropped the curtain arm in two studies [ 31 , 51 ] (not part of this review) and one of the PD arms in four other studies [ 43 , 46 , 48 , 56 ] that reported PD comparisons at different dosages or intervals. Microscopy was used for detection of Plasmodium parasites in 25 studies [ 32 , 35 , 37 , 38 , 39 , 40 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ], three studies used both microscopy and RDTs [ 49 , 62 , 63 ], and one study each used RDT [ 41 ] and polymerase chain reaction (PCR) and microscopy [ 36 ] for diagnosis (Table 1 ).

Interventions utilized across studies

Twenty five studies had a NI arm [ 32 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 48 , 49 , 50 , 51 , 52 , 55 , 56 , 57 , 59 , 61 , 62 , 63 ], and seven studies had a UN arm [ 45 , 47 , 52 , 53 , 54 , 58 , 60 ]. Of the eleven studies that used a PD arms [ 37 , 38 , 40 , 42 , 43 , 46 , 47 , 48 , 50 , 56 , 59 ], the regimens were all different (Additional file 1 : Table S6). Fourteen studies reported the use of ITN in one arm [ 32 , 35 , 39 , 44 , 51 , 53 , 54 , 55 , 57 , 58 , 60 , 61 , 62 , 63 ]. In these studies, different types of nets and insecticides for treating such nets were used (Additional file 1 : Table S7). The insecticides used for IRS in the three studies of this intervention were also different and are listed in (Additional file 1 : Table S8) [ 36 , 41 , 49 ].

The quality of the studies including types of study, randomization and other characteristics was assessed through 17 safeguards against bias as outlined in the supplementary material. They were combined into a univariate overall quality score consisting of counts of safeguards ranging between 7 and 17 out of a maximum possible of 17. The ranges of the scores were 10–17, 7–14, 9–16, 10–16, and 8–11 in PD vs NI, ITN vs NI, IRS vs NI, ITN vs UN, and UN vs NI studies, respectively. The most common safeguards missing were consideration of confounders such as socio-economic status, owning LLINs, malaria prevalence and blinding of assessors in between 46.7–93.3% of studies (Additional file 1 : Table S9).

Quantitative synthesis

Seven direct estimates based on head-to-head comparison within 30 studies, which included 60 treatment groups, were available (Table 2 and Fig. 2 ). In these direct comparisons, PD (RR: 0.21, 95% confidence interval [CI] 0.13–0.33), ITN (RR: 0.57, 95% CI: 0.41–0.81), and UN (RR: 0.67, 95% CI: 0.49–0.92) were significantly better than NI. Similarly, UN (0.12, 95% CI: 0.01–0.94) was better as compared to PD, and IRS (RR: 0.55, 95% CI: 0.20–1.56) was not significantly different from NI.

Network plot showing the comparison groups. The circle size is proportional to the number of studies including that intervention while line width is proportional to the number of comparisons. Abbreviations : ITN, insecticide-treated nets; UN, untreated net; IRS, indoor residual spraying; NI, no intervention; PD, prophylactic drug

The indirect estimate for ITN (RR: 0.37, 95% CI: 0.24–0.58) was consistent with the direct estimate, while that for PD (RR: 5.70, 95% CI: 0.70–46.58) demonstrated an inconsistent and very uncertain effect as opposed to the direct estimate. UN had two indirect estimates possible and both were inconsistent with the direct effect but in opposite directions with either a grossly positive effect (RR: 0.02, 95% CI: 0.003–0.21) or a negative effect (RR: 1.03, 95% CI: 0.64–1.66) (Table 2 ).

The final estimates were based on all evidence for these interventions in comparison with NI and results showed that, PD (RR: 0.24, 95% CI: 0.004–15.43), ITN (RR: 0.49, 95% CI: 0.32–0.74), IRS (RR: 0.55, 95% CI: 0.20–1.56), and UN (RR: 0.73, 95% CI: 0.28–1.90) were all less likely to be associated with incident infection as compared to participants using no preventive measure (NI). However, only ITN demonstrated a statistically significant effect (Table 2 and Fig. 3 ).

Results of network meta-analysis of 30 studies comparing listed interventions against NI. Only the PD-NI mixed effects showed modest inconsistency and this is reflected in the marked uncertainty (wide 95% confidence intervals) of the effect estimate

There was overall minimal statistical network inconsistency ( \( \overline{H}=2.21\Big) \) over comparisons despite the inconsistent direct and indirect effects, because of the huge uncertainty associated with indirect effects possibly reflecting heterogeneity in terms of the geographical locations and population characteristics of studies. One final effect (PD-NI) demonstrated modest inconsistency ( H = 3.0) while the rest demonstrated minimal to no inconsistency (H < 3, see Table 2 ), again because of uncertainty around the individual mixed effects.

Sensitivity analysis and publication bias

Heterogeneity was evident when selection criteria were modified to include only children or only P. falciparum infections respectively (with \( \overline{H} \) at 2.35 and 2.29, respectively (Additional file 2 : Figure S1; Additional file 3 : Figure S2). However, the rank of effectiveness of different preventive measures remained unchanged in both analyses except that ITN was less effective than IRS in only P. falciparum and effects were now less precise because numbers of studies were lower.

The comparison-adjusted funnel plot demonstrated little evidence of asymmetry except for the PD-NI comparison, which was in keeping with the fact that there was both considerable heterogeneity and inconsistency across this comparison (Additional file 4 : Figure S3).

This meta-analysis showed that only ITNs had a significant effect in protection against malaria infection. While the effect size for PD was larger, the uncertainty was high, thus making the impact of this intervention uncertain. These findings confirm that impregnated insecticides on ITNs offers better protection than UNs in preventing mosquitoes from taking a blood meal from the host through its excito-repellency effect [ 23 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ]. The insecticides on ITNs may also inhibit mosquitoes from entering a house similar to the effect of IRS. Mortality of mosquitoes in the range of 25–75% has been observed after they enter huts in search of blood meals irrespective of the various different pyrethroids used in ITNs [ 67 ]. Individual studies on efficacy of this intervention have shown that the risk of malaria infection due to ITN use can reduce by up to 39–62% and child mortality by 14–29% [ 24 , 71 ]. Interestingly, the impact of ITNs on child mortality and morbidity have been reported to extend out from areas with the actual ITN use to neighbouring areas because of the impact of the insecticidal nets on the entomological inoculation rate (EIR) of the local vector population [ 72 , 73 , 74 ]. Similarly, mathematical modelling has shown that ITNs can even protect against mosquitoes that feed outdoors [ 75 ]. ITNs have also been reported to protect women in pregnancy and in reducing placental malaria, anaemia, stillbirths and abortions [ 65 ]. Of note, the combination of IRS and ITN has been shown to offer better protection as compared to ITNs alone [ 27 , 41 , 76 , 77 , 78 , 79 ]. Only one of the latter studies was included in our synthesis which compared IRS vs NI where both arms were also given ITNs and the RR was 0.42 (95% CI: 0.34–0.52) suggesting that the effects are independent and additive on malaria prevention [ 41 ]. The other studies did not meet our inclusion criteria because these studies were cross-sectional and pre-post interventional studies but evidence from them was also supportive of this conclusion.

Despite reports of pyrethroid resistance in parts of the world including Africa [ 80 , 81 , 82 , 83 , 84 , 85 ], ITNs treated with pyrethroids continue to provide significant protection against malaria [ 69 , 71 , 86 , 87 ]. ITNs of the LLIN type have insecticides impregnated in the fibres of nets, which are wash resistant for the four- to five-year lifespan of the ITNs. ITBN types of ITNs require insecticides to be impregnated every six months. Due to reduced costs and ease of implementation, the LLINs have gained huge popularity in recent years and given their superiority to IRS in this analysis as well as in previous studies [ 27 , 88 ], this would represent a strong choice in terms of malaria prevention.

The biggest effect size was for PD. This intervention prevents or reduces the incidence of malaria primarily through clearing existing parasitaemia (or reducing it to a level below the fever threshold) and preventing new infections [ 8 , 89 , 90 ]. In our analysis however, we found the least precision for the effect estimate and the most inconsistency, suggesting that the effects varied widely across studies. Whilst the effectiveness of prophylactic drugs has been documented in children and pregnant women in sub-Saharan Africa, it has not been substantiated in other parts of the world [ 38 , 42 , 91 , 92 ], possibly because of the limited ability of drugs to prevent relapse in P. vivax infection [ 8 , 93 , 94 ]. Nevertheless, in our analysis restricted to P . falciparum, the same uncertainty was observed for PDs as in the full dataset. There are other concerns apart from preventive efficacy with the use of drugs as they can also result in impairment of natural immunity, and rebound infections of the children who received chemo-prophylaxis for 1–5 years [ 95 , 96 , 97 , 98 ]. The widespread use of chemoprophylaxis in children and pregnant women could possibly increase the rate of spread of drug resistance [ 99 ].

The preventive measure with the next highest effect estimate was IRS, a critical component of the WHO’s Global Malaria Eradication Program from 1955–1969 and the main intervention attributed to the elimination or dramatic reduction of malaria in parts of Europe, Asia and Latin America [ 27 ]. The basic principle of IRS in vector control is that IRS protects inhabitants against mosquito bites by killing the blood-fed females who rest on the walls after feeding and also protect inhabitants against mosquito bites by diverting the vector from entering a sprayed house an effect known as excito-repellency [ 100 , 101 ]. If the mosquito does enter the house, after biting, the female mosquito eventually rests on sprayed surfaces, where it picks up a lethal dose of insecticide, thus preventing transmission of the parasite to others. In a village with a high percentage coverage of houses with IRS, the mean age of the village mosquito population is expected to be reduced and very few mosquitoes will survive the approximately 12 days required for sporozoite maturation to be able to transmit the parasites [ 71 ]. Thus, IRS reduces malaria transmission at the community level by reducing mosquito longevity and abundance, but it has also been reported to provide household-level protection [ 27 ]. Studies have shown that IRS was more effective with high initial prevalence, multiple rounds of spraying and in regions with a combination of P. falciparum and P. vivax [ 26 ]. Despite all the advantages of IRS, our analysis suggested a consistently better (or at worst equivalent) efficacy for ITNs compared to IRS. Mosquito mortality has been shown to decline after the third month following IRS and by the fifth month, effectiveness reduces by 12% [ 102 ]. Efficacy might wane if walls are replastered or painted following implantation of IRS, and mosquito resistance to insecticides can emerge. In addition, there is a need for trained personnel for application of insecticides, which means IRS might not always be done effectively.

Untreated nets were the least effective in preventing malaria infection as compared to other preventive measures. UNs can offer a barrier against the bite of mosquitoes; however, mosquitoes can rest on the UNs while seeking opportunities to feed on the hosts sleeping under the nets, which can be presented when any part of a host’s body comes in contact with the nets. This happens often when hosts are in a deep sleep, especially under inadequately spaced or small nets. Untreated nets can even offer resting places to mosquitoes in an IRS-sprayed house and thus cannot be recommended given the other alternatives that exist. Finally, torn untreated nets have been shown to offer no additional protection as compared to not using nets [ 45 , 103 ].

A key strength of this analysis is the use of the GPM framework which avoids approximations and assumptions that are not stated explicitly or verified when the method is applied. On the contrary, the multivariate frequentist framework assumes that if there is no common comparator in the network, this then has to be handled by augmenting the dataset with fictional arms with high variance. This is not very objective and requires a decision as to what constitutes a sufficiently high variance [ 104 ]. Another alternative, the Bayesian framework, also has its problems such as requiring prior distributions to be specified for a number of unknown parameters and choices regarding over-dispersed starting values for a number of independent chains so that convergence can be assessed. While we have several choices for the meta-analytic framework, this choice may be less important than other choices regarding the modelling of effects [ 105 ]. Indeed, we were able to use the inverse variance heterogeneity model for direct estimates which has correct error estimation when compared with the random effects model [ 31 ]. Results from a random effects model (using both the multivariate meta-analysis framework as well as the GPM framework) differ slightly from our main results, especially regarding PD, which has spuriously precise estimates using this approach (Additional file 1 : Tables S2, S3).

There are limitations of this study worth noting. Even though clinical and statistical significance was found for ITNs, in reality the effectiveness of interventions (ITN) are dependent on a number of extrinsic factors such as population behaviour and vector aetiology. Studies have shown that ITN use is influenced by social behaviour including education, level of knowledge on malaria, and ease of use [ 106 , 107 ]. In addition, other socio-economic factors such as working and staying overnight in the forest decreases protection despite high proportion of coverage by ITNs [ 108 , 109 , 110 ]. Secondly, different insecticides being used for IRS and ITN over the study period would have impacted the findings of this study and the development of insecticide resistance would undermine the effectiveness of ITNs in preventing malaria. Thirdly, the methods of diagnosis of incident malaria were different in the studies. Since most of these studies were conducted in intense malaria transmission areas, this effect is however likely to be minimal. Fourthly, the vectors were different depending on the region of the study; for instance, the commonest malaria vectors in the Asian region including Anopheles dirus , An. baimaii and An. minimus [ 111 , 112 ], are able to avoid indoor sprayed surfaces because of their exophilic and exophagic characteristics [ 113 , 114 , 115 ] rendering most domicile-based interventions, like ITNs and IRS less effective [ 114 , 116 ]. Of the three main vectors in the African region: An. arabiensis , An. funestus and An. gambiae [ 113 , 117 ], only An. arabiensis shows feeding preferences for both indoors and outdoors while the other two are indoor-feeders [ 117 ]. Other challenges include insecticide resistance [ 118 ]. Finally, the drug types and regimens varied between studies. All of these limitations have the potential to increase heterogeneity between the included studies and make it more difficult to estimate the effects of the different interventions more precisely than what we have reported.

Conclusions

Even though ITNs were found to be the only preventive measure with statistical support for its effectiveness in this study, the role of all malaria control measures are important in the global drive to eliminate malaria. However, when a choice needs to be made for resource allocation, the results reported here tend to favour the use of ITNs.

Abbreviations

Amodiaquine

Confidence interval

Design effect

Dihydroartemisinin-peperaquine

Entomological inoculation rate

Generalized pairwise modelling

Global Technical Strategy for Malaria 2016–2030

Higher confidence interval

Indoor residual spraying

Insecticide-treated curtain

Insecticide-treated net

Inverse variance heterogeneity

Lower confidence interval

Long-lasting insecticidal nets

Malaria infection

No intervention

Prophylactic drugs

Randomized controlled trials

Rapid diagnostic tests

Sulphadoxine-pyrimethamine

Surface under the cumulative ranking curve

Untreated nets

World Health Organization

WHO. World Malaria Report, vol. 2017. Switzerland: World Health Organization, Geneva; 2017.

Google Scholar  

WHO. World Malaria Report, vol. 2015. Switzerland: World Health Organization, Geneva; 2015.

Cotter C, Sturrock HJ, Hsiang MS, Liu J, Phillips AA, Hwang J, et al. The changing epidemiology of malaria elimination: new strategies for new challenges. Lancet. 2013;382(9895):900–11.

Article   PubMed   Google Scholar  

Murray CJ, Rosenfeld LC, Lim SS, Andrews KG, Foreman KJ, Haring D, et al. Global malaria mortality between 1980 and 2010: a systematic analysis. Lancet. 2012;379(9814):413–31.

WHO. Global Technical Strategy for Malaria 2016–2030. World Health Organization, Geneva. Switzerland: WHO Library Cataloguing-in-Publication Data; 2015.

WHO. WHO recommendations for achieving universal coverage with long-lasting insecticidal nets in malaria control. World Health Organization. Switzerland: Geneva; 2014.

Greenwood B. Anti-malarial drugs and the prevention of malaria in the population of malaria endemic areas. Malar J. 2010;9(Suppl. 3):S2.

White NJ. Intermittent presumptive treatment for malaria. PLoS Med. 2005;2(1):e3.

Article   PubMed   PubMed Central   CAS   Google Scholar  

Ronn AM, Msangeni HA, Mhina J, Wernsdorfer WH, Bygbjerg IC. High level of resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine in children in Tanzania. Trans R Soc Trop Med Hyg. 1996;90(2):179–81.

Article   CAS   PubMed   Google Scholar  

Mugittu K, Abdulla S, Falk N, Masanja H, Felger I, Mshinda H, et al. Efficacy of sulfadoxine-pyrimethamine in Tanzania after two years as first-line drug for uncomplicated malaria: assessment protocol and implication for treatment policy strategies. Malar J. 2005;4:55.

Roper C, Pearce R, Nair S, Sharp B, Nosten F, Anderson T. Intercontinental spread of pyrimethamine-resistant malaria. Science. 2004;305(5687):1124.

Gosling RD, Gesase S, Mosha JF, Carneiro I, Hashim R, Lemnge M, et al. Protective efficacy and safety of three antimalarial regimens for intermittent preventive treatment for malaria in infants: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;374(9700):1521–32.

Tan KR, Katalenich BL, Mace KE, Nambozi M, Taylor SM, Meshnick SR, et al. Efficacy of sulphadoxine-pyrimethamine for intermittent preventive treatment of malaria in pregnancy, Mansa, Zambia. Malar J. 2014;13:227.

Clerk CA, Bruce J, Affipunguh PK, Mensah N, Hodgson A, Greenwood B, Chandramohan D. A randomized, controlled trial of intermittent preventive treatment with sulfadoxine-pyrimethamine, amodiaquine, or the combination in pregnant women in Ghana. J Infect Dis. 2008;198(8):1202–11.

Taylor WR, White NJ. Antimalarial drug toxicity: a review. Drug Saf. 2004;27(1):25–61.

Steketee RW, Wirima JJ, Hightower AW, Slutsker L, Heymann DL, Breman JG. The effect of malaria and malaria prevention in pregnancy on offspring birthweight, prematurity, and intrauterine growth retardation in rural Malawi. Am J Trop Med Hyg. 1996;55(Suppl. 1):33–41.

Briand V, Bottero J, Noel H, Masse V, Cordel H, Guerra J, et al. Intermittent treatment for the prevention of malaria during pregnancy in Benin: a randomized, open-label equivalence trial comparing sulfadoxine-pyrimethamine with mefloquine. J Infect Dis. 2009;200(6):991–1001.

Eisele TP, Larsen D, Steketee RW. Protective efficacy of interventions for preventing malaria mortality in children in Plasmodium falciparum endemic areas. Int J Epidemiol. 2010;39(Suppl. 1):i88–101.

Article   PubMed   PubMed Central   Google Scholar  

Wilson AL. A systematic review and meta-analysis of the efficacy and safety of intermittent preventive treatment of malaria in children (IPTc). PLoS One. 2011;6(2):e16976.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Meremikwu MM, Donegan S, Sinclair D, Esu E, Oringanje C. Intermittent preventive treatment for malaria in children living in areas with seasonal transmission. Cochrane Database Syst Rev. 2012;2:Cd003756.

Meremikwu MM, Donegan S, Esu E. Chemoprophylaxis and intermittent treatment for preventing malaria in children. Cochrane Database Syst Rev. 2008;2:Cd003756.

Matangila JR, Mitashi P, Inocencio da Luz RA, Lutumba PT, Van Geertruyden JP. Efficacy and safety of intermittent preventive treatment for malaria in schoolchildren: a systematic review. Malar J. 2015;14:450.

Choi HW, Breman JG, Teutsch SM, Liu S, Hightower AW, Sexton JD. The effectiveness of insecticide-impregnated bed nets in reducing cases of malaria infection: a meta-analysis of published results. Am J Trop Med Hyg. 1995;52(5):377–82.

Lengeler C. Insecticide-treated bed nets and curtains for preventing malaria. Cochrane Database Syst Rev. 2004;2:Cd000363.

Van Remoortel H, De Buck E, Singhal M, Vandekerckhove P, Agarwal SP. Effectiveness of insecticide-treated and untreated nets to prevent malaria in India. Trop Med Int Health. 2015;20(8):972–82.

Kim D, Fedak K, Kramer R. Reduction of malaria prevalence by indoor residual spraying: A meta-regression analysis. Am J Trop Med Hyg. 2012;87(1):117–24.

Pluess B, Tanser FC, Lengeler C, Sharp BL. Indoor residual spraying for preventing malaria. Cochrane Database Syst Rev. 2010;4:Cd006657.

Doi SA, Barendregt JJ. A generalized pairwise modelling framework for network meta-analysis. Int J Evid Based Healthc. 2018;27 [Epub ahead of print]

Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol. 1997;50(6):683–91.

Rucker G, Schwarzer G. Ranking treatments in frequentist network meta-analysis works without resampling methods. BMC Med Res Methodol. 2015;15:58.

Doi SA, Barendregt JJ, Khan S, Thalib L, Williams GM. Advances in the meta-analysis of heterogeneous clinical trials I: The inverse variance heterogeneity model. Contemp Clin Trials. 2015;45(Pt A):130–8.

Smithuis FM, Kyaw MK, Phe UO, van der Broek I, Katterman N, Rogers C, et al. The effect of insecticide-treated bed nets on the incidence and prevalence of malaria in children in an area of unstable seasonal transmission in western Myanmar. Malar J. 2013;12:363.

Chaimani A, Salanti G. Using network meta-analysis to evaluate the existence of small-study effects in a network of interventions. Res Synth Methods. 2012;3(2):161–76.

Liu X, Clark J, Siskind D, Williams GM, Byrne G, Yang JL. SA. A systematic review and meta-analysis of the effects of Qigong and Tai Chi for depressive symptoms. Complement Ther Med. 2015;23(4):516–34.

Beach RF, Ruebush TK 2nd, Sexton JD, Bright PL, Hightower AW, Breman JG, et al. Effectiveness of permethrin-impregnated bed nets and curtains for malaria control in a holoendemic area of western Kenya. Am J Trop Med Hyg. 1993;49(3):290–300.

Charlwood JD, Qassim M, Elnsur EI, Donnelly M, Petrarca V, Billingsley PF, et al. The impact of indoor residual spraying with malathion on malaria in refugee camps in eastern Sudan. Acta Trop. 2001;80(1):1–8.

Cisse B, Sokhna C, Boulanger D, Milet J, Ba el H, Richardson K, et al. Seasonal intermittent preventive treatment with artesunate and sulfadoxine-pyrimethamine for prevention of malaria in Senegalese children: a randomised, placebo-controlled, double-blind trial. Lancet. 2006;367(9511):659–67.

Dicko A, Diallo AI, Tembine I, Dicko Y, Dara N, Sidibe Y, et al. Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide-treated bednet in Mali: a randomised, double-blind, placebo-controlled trial. PLoS Med. 2011;8(2):e1000407.

Fraser-Hurt N, Felger I, Edoh D, Steiger S, Mashaka M, Masanja H, et al. Effect of insecticide-treated bed nets on haemoglobin values, prevalence and multiplicity of infection with Plasmodium falciparum in a randomized controlled trial in Tanzania. Trans R Soc Trop Med Hyg. 1999;93(Suppl. 1):47–51.

Hale BR, Owusu-Agyei S, Fryauff DJ, Koram KA, Adjuik M, Oduro AR, et al. A randomized, double-blind, placebo-controlled, dose-ranging trial of tafenoquine for weekly prophylaxis against Plasmodium falciparum . Clin Infect Dis. 2003;36(5):541–9.

Hamel MJ, Otieno P, Bayoh N, Kariuki S, Were V, Marwanga D, et al. The combination of indoor residual spraying and insecticide-treated nets provides added protection against malaria compared with insecticide-treated nets alone. Am J Trop Med Hyg. 2011;85(6):1080–6.

Konate AT, Yaro JB, Ouedraogo AZ, Diarra A, Gansane A, Soulama I, et al. Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide-treated bednet in Burkina Faso: a randomised, double-blind, placebo-controlled trial. PLoS Med. 2011;8(2):e1000408.

Kweku M, Liu D, Adjuik M, Binka F, Seidu M, Greenwood B, Chandramohan D. Seasonal intermittent preventive treatment for the prevention of anaemia and malaria in Ghanaian children: a randomized, placebo controlled trial. PLoS One. 2008;3(12):e4000.

Marbiah NT, Petersen E, David K, Magbity E, Lines J, Bradley DJ. A controlled trial of lambda-cyhalothrin-impregnated bed nets and/or dapsone/pyrimethamine for malaria control in Sierra Leone. Am J Trop Med Hyg. 1998;58(1):1–6.

Mwangi TW, Ross A, Marsh K, Snow RW. The effects of untreated bednets on malaria infection and morbidity on the Kenyan coast. Trans R Soc Trop Med Hyg. 2003;97(4):369–72.

Nankabirwa JI, Wandera B, Amuge P, Kiwanuka N, Dorsey G, Rosenthal PJ, et al. Impact of intermittent preventive treatment with dihydroartemisinin-piperaquine on malaria in Ugandan schoolchildren: a randomized, placebo-controlled trial. Clin Infect Dis. 2014;58(10):1404–12.

Nevill CG, Watkins WM, Carter JY, Munafu CG. Comparison of mosquito nets, proguanil hydrochloride, and placebo to prevent malaria. BMJ. 1988;297(6645):401–3.

Odhiambo FO, Hamel MJ, Williamson J, Lindblade K, ter Kuile FO, Peterson E, et al. Intermittent preventive treatment in infants for the prevention of malaria in rural western Kenya: a randomized, double-blind placebo-controlled trial. PLoS One. 2010;5(4):e10016.

Pinder M, Jawara M, Jarju LB, Salami K, Jeffries D, Adiamoh M, et al. Efficacy of indoor residual spraying with dichlorodiphenyltrichloroethane against malaria in Gambian communities with high usage of long-lasting insecticidal mosquito nets: a cluster-randomised controlled trial. Lancet. 2015;385(9976):1436–46.

Sesay S, Milligan P, Touray E, Sowe M, Webb EL, Greenwood BM, Bojang KA. A trial of intermittent preventive treatment and home-based management of malaria in a rural area of The Gambia. Malar J. 2011;10:2.

Sexton JD, Ruebush TK 2nd, Brandling-Bennett AD, Breman JG, Roberts JM, Odera JS, Were JB. Permethrin-impregnated curtains and bed-nets prevent malaria in western Kenya. Am J Trop Med Hyg. 1990;43(1):11–8.

Snow RW, Rowan KM, Lindsay SW, Greenwood BM. A trial of bed nets (mosquito nets) as a malaria control strategy in a rural area of The Gambia, West Africa. Trans R Soc Trop Med Hyg. 1988;82(2):212–5.

Kamol-Ratanakul P, Prasittisuk C. The effectiveness of permethrin-impregnated bed nets against malaria for migrant workers in eastern Thailand. Am J Trop Med Hyg. 1992;47(3):305–9.

Luxemburger C, Perea WA, Delmas G, Pruja C, Pecoul B, Moren A. Permethrin-impregnated bed nets for the prevention of malaria in schoolchildren on the Thai-Burmese border. Trans R Soc Trop Med Hyg. 1994;88(2):155–9.

Rowland M, Bouma M, Ducornez D, Durrani N, Rozendaal J, Schapira A, Sondorp E. Pyrethroid-impregnated bed nets for personal protection against malaria for Afghan refugees. Trans R Soc Trop Med Hyg. 1996;90(4):357–61.

Taylor WR, Richie TL, Fryauff DJ, Picarima H, Ohrt C, Tang D, et al. Malaria prophylaxis using azithromycin: a double-blind, placebo-controlled trial in Irian Jaya, Indonesia. Clin Infect Dis. 1999;28(1):74–81.

Sahu SS, Jambulingam P, Vijayakumar T, Subramanian S, Kalyanasundaram M. Impact of alphacypermethrin treated bed nets on malaria in villages of Malkangiri District, Orissa, India. Acta Trop. 2003;89(1):55–66.

Sharma SK, Tyagi PK, Upadhyay AK, Haque MA, Mohanty SS, Raghavendra K, Dash AP. Efficacy of permethrin treated long-lasting insecticidal nets on malaria transmission and observations on the perceived side effects, collateral benefits and human safety in a hyperendemic tribal area of Orissa, India. Acta Trop. 2009;112(2):181–7.

Lwin KM, Phyo AP, Tarning J, Hanpithakpong W, Ashley EA, Lee SJ, et al. Randomized, double-blind, placebo-controlled trial of monthly versus bimonthly dihydroartemisinin-piperaquine chemoprevention in adults at high risk of malaria. Antimicrob Agents Chemother. 2012;56(3):1571–7.

Soleimani-Ahmadi M, Vatandoost H, Shaeghi M, Raeisi A, Abedi F, Eshraghian MR, et al. Field evaluation of permethrin long-lasting insecticide treated nets (Olyset(R)) for malaria control in an endemic area, southeast of Iran. Acta Trop. 2012;123(3):146–53.

Shah NK, Tyagi P, Sharma SK. The impact of artemisinin combination therapy and long-lasting insecticidal nets on forest malaria incidence in tribal villages of India, 2006–2011. PLoS One. 2013;8(2):e56740.

Hill N, Zhou HN, Wang P, Guo X, Carneiro I, Moore SJ. A household randomized, controlled trial of the efficacy of 0.03% transfluthrin coils alone and in combination with long-lasting insecticidal nets on the incidence of Plasmodium falciparum and Plasmodium vivax malaria in Western Yunnan Province, China. Malar J. 2014;13:208.

Kroeger A, Mancheno M, Alarcon J, Pesse K. Insecticide-impregnated bed nets for malaria control: varying experiences from Ecuador, Colombia, and Peru concerning acceptability and effectiveness. Am J Trop Med Hyg. 1995;53(4):313–23.

Maxwell CA, Rwegoshora RT, Magesa SM, Curtis CF. Comparison of coverage with insecticide-treated nets in a Tanzanian town and villages where nets and insecticide are either marketed or provided free of charge. Malar J. 2006;5:44.

Gamble C, Ekwaru JP, ter Kuile FO. Insecticide-treated nets for preventing malaria in pregnancy. Cochrane Database Syst Rev. 2006;2:Cd003755.

Sutanto I, Freisleben HJ, Pribadi W, Atmosoedjono S, Bandi A. Purnomo. Efficacy of permethrin-impregnated bed nets on malaria control in a hyperendemic area in Irian Java, Indonesia: influence of seasonal rainfall fluctuations. Southeast Asian J Trop Med Pub Hlth. 1999;30(3):432–9.

CAS   Google Scholar  

Maxwell CA, Myamba J, Njunwa KJ, Greenwood BM, Curtis CF. Comparison of bednets impregnated with different pyrethroids for their impact on mosquitoes and on re-infection with malaria after clearance of pre-existing infections with chlorproguanil-dapsone. Trans R Soc Trop Med Hyg. 1999;93(1):4–11.

Sharma SK, Upadhyay AK, Haque MA, Tyagi PK, Mohanty SS, Raghavendra K, Dash AP. Field evaluation of Olyset nets: a long-lasting insecticidal net against malaria vectors Anopheles culicifacies and Anopheles fluviatilis in a hyperendemic tribal area of Orissa, India. J Med Entomol. 2009;46(2):342–50.

Curtis CF, Jana-Kara B, Maxwell CA. Insecticide-treated nets: impact on vector populations and relevance of initial intensity of transmission and pyrethroid resistance. J Vector Borne Dis. 2003;40(1–2):1–8.

Wangdi K, Gatton ML, Kelly GC, Clements AC. Prevalence of asymptomatic malaria and bed net ownership and use in Bhutan, 2013: a country earmarked for malaria elimination. Malar J. 2014;13:352.

Curtis CF, Maxwell CA, Magesa SM, Rwegoshora RT, Wilkes TJ. Insecticide-treated bed-nets for malaria mosquito control. J Am Mosq Control Assoc. 2006;22(3):501–6.

Gimnig JE, Vulule JM, Lo TQ, Kamau L, Kolczak MS, Phillips-Howard PA, et al. Impact of permethrin-treated bed nets on entomologic indices in an area of intense year-round malaria transmission. Am J Trop Med Hyg. 2003;68(Suppl. 4):16–22.

PubMed   Google Scholar  

Hawley WA, Phillips-Howard PA, ter Kuile FO, Terlouw DJ, Vulule JM, Ombok M, et al. Community-wide effects of permethrin-treated bed nets on child mortality and malaria morbidity in western Kenya. Am J Trop Med Hyg. 2003;68(Suppl. 4):121–7.

Larsen DA, Hutchinson P, Bennett A, Yukich J, Anglewicz P, Keating J, Eisele TP. Community coverage with insecticide-treated mosquito nets and observed associations with all-cause child mortality and malaria parasite infections. Am J Trop Med Hyg. 2014;91(5):950–8.

Govella NJ, Okumu FO, Killeen GF. Insecticide-treated nets can reduce malaria transmission by mosquitoes which feed outdoors. Am J Trop Med Hyg. 2010;82(3):415–9.

West PA, Protopopoff N, Wright A, Kivaju Z, Tigererwa R, Mosha FW, et al. Indoor residual spraying in combination with insecticide-treated nets compared to insecticide-treated nets alone for protection against malaria: a cluster randomised trial in Tanzania. PLoS Med. 2014;11(4):e1001630.

West PA, Protopopoff N, Wright A, Kivaju Z, Tigererwa R, Mosha FW, et al. Enhanced protection against malaria by indoor residual spraying in addition to insecticide treated nets: is it dependent on transmission intensity or net usage? PLoS One. 2015;10(3):e0115661.

Fullman N, Burstein R, Lim SS, Medlin C, Gakidou E. Nets, spray or both? The effectiveness of insecticide-treated nets and indoor residual spraying in reducing malaria morbidity and child mortality in sub-Saharan Africa. Malar J. 2013;12:62.

Kleinschmidt I, Schwabe C, Shiva M, Segura JL, Sima V, Mabunda SJ, Coleman M. Combining indoor residual spraying and insecticide-treated net interventions. Am J Trop Med Hyg. 2009;81(3):519–24.

PubMed   PubMed Central   Google Scholar  

Glunt KD, Abilio AP, Bassat Q, Bulo H, Gilbert AE, Huijben S, et al. Long-lasting insecticidal nets no longer effectively kill the highly resistant Anopheles funestus of southern Mozambique. Malar J. 2015;14:298.

Chandre F, Manguin S, Brengues C, Dossou Yovo J, Darriet F, Diabate A, et al. Current distribution of a pyrethroid resistance gene ( kdr ) in Anopheles gambiae complex from west Africa and further evidence for reproductive isolation of the Mopti form. Parassitologia. 1999;41(1–3):319–22.

CAS   PubMed   Google Scholar  

Etang J, Fondjo E, Chandre F, Morlais I, Brengues C, Nwane P, et al. First report of knockdown mutations in the malaria vector Anopheles gambiae from Cameroon. Am J Trop Med Hyg. 2006;74(5):795–7.

Stump AD, Atieli FK, Vulule JM, Besansky NJ. Dynamics of the pyrethroid knockdown resistance allele in western Kenyan populations of Anopheles gambiae in response to insecticide-treated bed net trials. Am J Trop Med Hyg. 2004;70(6):591–6.

Hargreaves K, Koekemoer LL, Brooke BD, Hunt RH, Mthembu J, Coetzee M. Anopheles funestus resistant to pyrethroid insecticides in South Africa. Med Vet Entomol. 2000;14(2):181–9.

Hargreaves K, Hunt RH, Brooke BD, Mthembu J, Weeto MM, Awolola TS, Coetzee M. Anopheles arabiensis and An. quadriannulatus resistance to DDT in South Africa. Med Vet Entomol. 2003;17(4):417–22.

Wangdi K, Banwell C, Gatton ML, Kelly GC, Namgay R, Clements AC. Malaria burden and costs of intensified control in Bhutan, 2006–14: an observational study and situation analysis. Lancet Glob Health. 2016;4(5):e336–43.

Wamae PM, Githeko AK, Otieno GO, Kabiru EW, Duombia SO. Early biting of the Anopheles gambiae s.s . and its challenges to vector control using insecticide treated nets in western Kenya highlands. Acta Trop. 2015;150:136–42.

Hii JLK, Kanai L, Foligela A, Kan SKP, Burkot TR, Wirtz RA. Impact of permethrin-impregnated mosquito nets compared with DDT house-spraying against malaria transmission by Anopheles farauti and An. punctulatus in the Solomon Islands. Med Vet Entomol. 1993;7(4):333–8.

Cairns M, Carneiro I, Milligan P, Owusu-Agyei S, Awine T, Gosling R, et al. Duration of protection against malaria and anaemia provided by intermittent preventive treatment in infants in Navrongo, Ghana. PLoS One. 2008;3(5):e2227.

Menendez C, Schellenberg D, Macete E, Aide P, Kahigwa E, Sanz S, et al. Varying efficacy of intermittent preventive treatment for malaria in infants in two similar trials: public health implications. Malar J. 2007;6:132.

Mace KE, Chalwe V, Katalenich BL, Nambozi M, Mubikayi L, Mulele CK, et al. Evaluation of sulphadoxine-pyrimethamine for intermittent preventive treatment of malaria in pregnancy: a retrospective birth outcomes study in Mansa, Zambia. Malar J. 2015;14(1):576.

Article   CAS   Google Scholar  

Dicko A, Sagara I, Sissoko MS, Guindo O, Diallo AI, Kone M, et al. Impact of intermittent preventive treatment with sulphadoxine-pyrimethamine targeting the transmission season on the incidence of clinical malaria in children in Mali. Malar J. 2008;7:123.

Ranque S, Badiaga S, Delmont J, Brouqui P. Triangular test applied to the clinical trial of azithromycin against relapses in Plasmodium vivax infections. Malar J. 2002;1:13.

Pukrittayakamee S, Chantra A, Simpson JA, Vanijanonta S, Clemens R, Looareesuwan S, White NJ. Therapeutic responses to different antimalarial drugs in vivax malaria. Antimicrob Agents Chemother. 2000;44(6):1680–5.

Greenwood BM, David PH, Otoo-Forbes LN, Allen SJ, Alonso PL, Armstrong Schellenberg JR, et al. Mortality and morbidity from malaria after stopping malaria chemoprophylaxis. Trans R Soc Trop Med Hyg. 1995;89(6):629–33.

Menendez C, Kahigwa E, Hirt R, Vounatsou P, Aponte JJ, Font F, et al. Randomised placebo-controlled trial of iron supplementation and malaria chemoprophylaxis for prevention of severe anaemia and malaria in Tanzanian infants. Lancet. 1997;350(9081):844–50.

Mockenhaupt FP, Reither K, Zanger P, Roepcke F, Danquah I, Saad E, et al. Intermittent preventive treatment in infants as a means of malaria control: a randomized, double-blind, placebo-controlled trial in northern Ghana. Antimicrob Agents Chemother. 2007;51(9):3273–81.

Chandramohan D, Owusu-Agyei S, Carneiro I, Awine T, Amponsa-Achiano K, Mensah N, et al. Cluster randomised trial of intermittent preventive treatment for malaria in infants in area of high, seasonal transmission in Ghana. BMJ. 2005;331(7519):727–33.

Greenwood B. The use of anti-malarial drugs to prevent malaria in the population of malaria-endemic areas. Am J Trop Med Hyg. 2004;70(1):1–7.

Hamusse SD, Balcha TT, Belachew T. The impact of indoor residual spraying on malaria incidence in East Shoa Zone, Ethiopia. Glob Health Action. 2012;5:11619.

Indoor residual spraying WHO. Use of indoor residual spraying for scaling up global malaria control and elimination. Geneva: World Health Organization; 2006.

Bradley J, Matias A, Schwabe C, Vargas D, Monti F, Nseng G, Kleinschmidt I. Increased risks of malaria due to limited residual life of insecticide and outdoor biting versus protection by combined use of nets and indoor residual spraying on Bioko Island, Equatorial Guinea. Malar J. 2012;11:242.

Lines JD, Myamba J, Curtis CF. Experimental hut trials of permethrin-impregnated mosquito nets and eave curtains against malaria vectors in Tanzania. Med Vet Entomol. 1987;1(1):37–51.

van Valkenhoef G, Lu G, de Brock B, Hillege H, Ades AE, Welton NJ. Automating network meta-analysis. Res Synth Methods. 2012;3(4):285–99.

Senn S, Gavini F, Magrez D, Scheen A. Issues in performing a network meta-analysis. Stat Methods Med Res. 2013;22(2):169–89.

Samadoulougou S, Pearcy M, Ye Y, Kirakoya-Samadoulougou F. Progress in coverage of bed net ownership and use in Burkina Faso 2003–2014: evidence from population-based surveys. Malar J. 2017;16(1):302.

Russell CL, Sallau A, Emukah E, Graves PM, Noland GS, Ngondi JM, et al. Determinants of bed net use in southeast Nigeria following mass distribution of LLINs: implications for social behavior change interventions. PLoS One. 2015;10(10):e0139447.

Van Bortel W, Trung HD, Hoi le X, Van Ham N, Van Chut N, Luu ND, et al. Malaria transmission and vector behaviour in a forested malaria focus in central Vietnam and the implications for vector control. Malar J. 2010;9:373.

Singh N, Singh OP, Sharma VP. Dynamics of malaria transmission in forested and deforested regions of Mandla District, central India (Madhya Pradesh). J Am Mosq Control Assoc. 1996;12(2 Pt 1):225–34.

Grietens KP, Xuan XN, Ribera J, Duc TN, Bortel W, Ba NT, et al. Social determinants of long-lasting insecticidal hammock use among the Ra-glai ethnic minority in Vietnam: implications for forest malaria control. PLoS One. 2012;7(1):e29991.

Dev V, Manguin S. Biology, distribution and control of Anopheles ( Cellia ) minimus in the context of malaria transmission in northeastern India. Parasit Vectors. 2016;9:585.

Zhang S, Guo S, Feng X, Afelt A, Frutos R, Zhou S, Manguin S. Anopheles vectors in mainland China while approaching malaria elimination. Trends Parasitol. 2017;33(11):889–900.

Sinka ME, Bangs MJ, Manguin S, Rubio-Palis Y, Chareonviriyaphap T, Coetzee M, et al. A global map of dominant malaria vectors. Parasit Vectors. 2012;5:69.

Trung HD, Bortel WV, Sochantha T, Keokenchanh K, Briet OJ, Coosemans M. Behavioural heterogeneity of Anopheles species in ecologically different localities in Southeast Asia: a challenge for vector control. Trop Med Int Health. 2005;10(3):251–62.

Manh CD, Beebe NW, Van VN, Quang TL, Lein CT, Nguyen DV, et al. Vectors and malaria transmission in deforested, rural communities in north-central Vietnam. Malar J. 2010;9:259.

Somboon P, Lines J, Aramrattana A, Chitprarop U, Prajakwong S, Khamboonruang C. Entomological evaluation of community-wide use of lambdacyhalothrin-impregnated bed nets against malaria in a border area of north-west Thailand. Trans R Soc Trop Med Hyg. 1995;89(3):248–54.

Sinka ME, Bangs MJ, Manguin S, Coetzee M, Mbogo CM, Hemingway J, et al. The dominant Anopheles vectors of human malaria in Africa, Europe and the Middle East: occurrence data, distribution maps and bionomic précis. Parasit Vectors. 2010;3:117.

Dhiman S, Goswami D, Rabha B, Gopalakrishnan R, Baruah I, Singh L. Malaria epidemiology along Indo-Bangladesh border in Tripura State, India. Southeast Asian J Trop Med Public Health. 2010;41(6):1279–89.

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Acknowledgements

The authors pay tribute to the late Jan Barendregt of Epigear International Pty Ltd, who passed away during preparation of this work.

LFK is funded by an Endeavour Postgraduate Scholarship (#3781_2014), an Australian National University Higher Degree Scholarship, and a Fondo para la Innovación, Ciencia y Tecnología Scholarship (#095-FINCyT-BDE-2014).

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KW, LFK, SARD and ACAC conceived the idea. JC developed citation search and executed it. KW and LFK carried out the data extraction. KW, LFK, SARD and JB carried out data analysis. KW drafted the manuscript. SARD and ACAC helped in the interpretation of the findings and critical revision of manuscript. LFK, JC, JB, MLG, CB and GK were involved in revision of the manuscript. All authors read and approved the final manuscript.

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Additional files

Additional file 1:.

Table S1. Search Strategy. Table S2. Meta-analysis of different control measures against NI using the random effects model under the generalized pairwise modeling (GPM) framework in MetaXL. Table S3. Meta-analysis of different control measures against NI using the random effects model under the frequentist multivariate meta-analysis framework (mvmeta) in Stata. Table S4. Quality scale. Table S5. Summary of the excluded studies. Table S6. Drugs used in the included studies. Table S7. Description of ITN’s used across the studies. Table S8. Description of IRS treatments used across the included studies. Table S9. Quality assessment scores of included studies. (DOCX 56 kb)

Additional file 2:

Figure S1. Results of network meta-analysis of 21 studies with children as a study population. (TIFF 624 kb)

Additional file 3:

Figure S2. Results of network meta-analysis of 28 studies with incidence of Plasmodium falciparum . (TIFF 631 kb)

Additional file 4:

Figure S3. Funnel plot depicting asymmetry for the PD-NI comparison. (TIFF 1482 kb)

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Wangdi, K., Furuya-Kanamori, L., Clark, J. et al. Comparative effectiveness of malaria prevention measures: a systematic review and network meta-analysis. Parasites Vectors 11 , 210 (2018). https://doi.org/10.1186/s13071-018-2783-y

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Secukinumab in the Treatment of Psoriasis: A Narrative Review on Early Treatment and Real-World Evidence

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• Piergiorgio Malagoli 1 ,
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Psoriasis is a chronic, immune-mediated, inflammatory skin disease, associated with multiple comorbidities and psychological and psychiatric disorders. The quality of life of patients with this disease is severely compromised, especially in moderate-to-severe plaque psoriasis. Secukinumab, a fully humanized monoclonal antibody, was the first anti-interleukin (IL)-17 biologic approved for treating psoriasis. Secukinumab demonstrated long-lasting efficacy and a good safety profile in individuals with plaque psoriasis, and it is associated with an improvement in health-related quality of life. While there is evidence that early treatment with systemic therapy can affect disease progression and improve long-term outcomes in other autoimmune diseases, evidence is limited in psoriasis, especially in real-world settings. This review provides an overview of studies describing the effectiveness of secukinumab in the treatment of psoriasis summarizing the literature and focusing on real-world evidence and early intervention.

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Introduction

Psoriasis (PsO) is a common chronic, systemic, immune-mediated inflammatory disease that affects the skin. PsO affects 125 million people worldwide, and its prevalence and incidence vary according to geographic region, gender, and age [ 1 , 2 ]. PsO is associated with several comorbidities, including psoriatic arthritis (PsA), Crohn’s disease (CD), and psychological/psychiatric disorders (e.g., depression, and anxiety). In recent years, also metabolic syndrome, inflammatory bowel disease, diabetes, cardiovascular diseases, malignancies (e.g., lymphoma), and infections have been associated with PsO [ 3 ]. In addition, individuals with PsO are at a higher risk of reduced life expectancy [ 4 ]. Manifestations of the disease may involve itching, stinging, and burning of the skin, which together with extracutaneous clinical manifestations, significantly affects the health-related quality of life (HRQoL) of these patients [ 5 ]. Disease progression is often unpredictable, with different degrees of severity and progression. PsO management can minimize physiological and physical harm by treating patients early in the disease to modify its course, preventing associated comorbidities, reducing risks of negative outcomes, and aiming at remission [ 6 ]. The pathogenesis of psoriasis is influenced by the interleukin (IL)-23/IL-17 pathway, which is involved in the inflammatory processes underlying this chronic skin condition. IL-23 is a cytokine that fosters the production of IL-17; in the pathogenesis of PsO, the T helper 17 pathway and cytokine interleukin 17 (IL-17) play a fundamental role. The mechanism of action of several antipsoriatic treatments currently in use and under development is aimed at blocking IL-17 and its mediated downstream immunological cascade. IL-17 effectors include IL-17A, IL-17C, IL-17E, and IL-17F, which are responsible for the pro-inflammatory feed-forward cycle in plaque psoriasis [ 7 ]. The interplay between IL-17 and IL-23 maintains the chronic inflammatory state characteristic of psoriasis. Monoclonal antibodies targeting interleukin IL-23, like guselkumab and resankizumab, and IL-17, like secukinumab and ixekinumab, showed efficacy in the treatment of moderate-to-severe psoriasis. IL-17 and IL-23 inhibitors are both effective treatments for psoriasis, although they differ in their mechanisms of action and clinical outcomes (Table  1 ). IL-17 inhibitors target the IL-17 cytokine, thus leading to rapid relief of the symptoms due to the direct action on inflammation. IL-23 inhibitors target the IL-23 cytokine, which is key for the production of IL-17, thus providing sustained control [ 8 , 9 ]. Drug survival, defined as the duration of a specific treatment, seems accordingly to be more favorable for IL-23 inhibitors in terms of long-time effectiveness [ 10 , 11 , 12 , 13 , 14 ].

Secukinumab is a fully humanized anti-IL-17A monoclonal antibody that was approved in 2015 by the US Food and Drug Administration and the European Commission as the first biologic for the treatment of moderate-to-severe plaque psoriasis, active psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) [ 15 ]. Secukinumab is indicated and well received for the treatment of moderate-to-severe plaque psoriasis in children > 6 years old, adolescents, and adults who are eligible for systemic therapy. In pediatric plaque psoriasis (adolescents and children from the age of 6 years to 18 years old), the recommended dose of secukinumab is based on body weight, while in adult plaque psoriasis it is 300 mg. Secukinumab is administered by subcutaneous injection with initial dosing at weeks 0, 1, 2, 3, and 4, followed by monthly maintenance dosing [ 16 ]. In adults, a maintenance dose of 300 mg every 2 weeks can provide additional benefits after initial assessment of clinical response. A multicenter, randomized clinical trial evaluated two different dosing regimens (i.e., secukinumab 300 mg every 2 weeks vs secukinumab 300 mg every 4 weeks) in patients with bodyweight > 90 kg [ 17 ]. After 16 weeks, the 2-week dosing demonstrated higher efficacy compared to the 4-week regimen psoriasis area and severity index (PASI) 90, 73.2% vs 55.5%, p  = 0.0003. In multiple phase II and III clinical trials, secukinumab was shown to be superior to placebo and to other biologics, such as etanercept and ustekinumab, in the treatment of moderate-to-severe plaque psoriasis, and its clinical efficacy correlated with large improvements in patients’ quality of life [ 18 ]. Secukinumab also showed a long-term safety profile in multiple phase II and III clinical trials for the treatment of moderate-to-severe plaque PsO. A pooled safety analysis of ten Phase II and III studies showed that secukinumab has a favorable safety profile that is similar between the 300 and the 150 mg doses [ 19 ]. The safety profile of secukinumab was comparable to that of etanercept over 52 weeks in patients with moderate-to-severe plaque psoriasis. Secukinumab also showed a safety profile comparable to ustekinumab in long-term follow-up studies [ 20 ]. A pooled analysis including 21 randomized controlled clinical trials examined the long-term (5 years) safety and tolerability profile of secukinumab for the treatment of moderate-to-severe psoriasis, psoriatic arthritis, and ankylosing spondylitis (AS) [ 21 ]. The study results suggest that secukinumab has a favorable safety profile over a long treatment period in patients with these chronic conditions. In alignment with previous research, the study supports the long-term use of secukinumab in the treatment of PsO, PsA, and AS, as these disorders share IL-17A overexpression [ 15 , 22 ]. However, as reported for other biologics, patients with autoimmune diseases taking IL-17 inhibitors are at increased risk of infections, and the most commonly described adverse events associated with secukinumab are upper respiratory tract infections, neutropenia, candidiasis, and rare cases of new or worsening inflammatory bowel disease [ 19 , 23 , 24 , 25 ]. Of note, secukinumab might have a beneficial effect on the cardiometabolic risks associated with psoriasis as a reduction in systemic inflammation could also contribute to indirectly mitigating the risk of adverse cardiovascular conditions [ 26 , 27 ].

There is evidence that in immune-mediated inflammatory diseases, such as rheumatoid arthritis, early intervention, defined as a time window for the onset of therapy (systemic or biologic) of 6–12–24 months after disease manifestation, with targeted systemic therapy can improve long-term patient outcomes [ 28 ]. Similarly, it has been hypothesized that early intervention with systemic agents in plaque psoriasis may alter the course of the disease, improve cutaneous symptoms, and reduce long-term adverse outcomes [ 28 , 29 ]. Given the high prevalence of this condition in the population and its detrimental impact on patients’ quality of life, evaluating the long-term effectiveness, safety, and comorbidity control of secukinumab in the treatment of psoriasis in a real-world setting is of paramount importance. This review aims to provide a comprehensive overview of the effectiveness of secukinumab in the treatment of psoriasis, also summarizing findings on early interventions (considered as occurring within two years of disease onset) through an analysis of the latest evidence available in the field (Table  2 ).

In July 2022, all the authors met to discuss the available evidence on the use of secukinumab in the early treatment of psoriasis, aiming at having a broader view of its use in clinical practice and at supporting the unmet medical needs of individuals affected or at higher risk of the disease. The authors reviewed the literature available, focusing in particular on real-world evidence.

A systematic search of the literature using the Embase database was conducted between inception and June 2022. Without applying restrictions, the terms searched used were the following: “real life setting,” “real world,” “RW,” “real world evidence,” “RWE,” “real life,” “evidence,” “case report,” “case series,” “observational studies,” “observational study,” “prospective observational studies,” “retrospective observational studies,” “retrospective study,” “prospective study,” “secukinumab,” “Cosentyx,” “SEC,” “Italy,” “italian,” “psoriasis,” “PSO,” “early treatment,” “naïve,” “Nail,” “Scalp,” “Palmoplantar Psoriasis,” “problematic area,” “psoriatic arthritis,” “arthritis,” “PSA,” “early PSA,” “naïve,” “quality of life,” “QoL,” “adherence,” “adherence to treatment,” “treatment adherence,” “compliance to therapy,” “therapy compliance,” “adherence to therapy,” “compliance to treatment,” “treatment compliance,” “therapy adherence,” “discontinued,” “discontinue,” “rates of adherence,” “non-adherence,” “Survey,” “questionnaire,” “suspension,” “retention rate,” “Long term use,” “long term,” “naïve,” “biologic-naivety,” “Biologic Disease-Modifying Antirheumatic Drugs,” “bDMARDs,” “DMARDs,” “de novo,” “systemic treatment naïve,” “treatment failure,” “anti-TNFα failure,” and “tnf-inhibitor failure.” The literature search was updated in June 2024 to select additional articles relevant to the topic.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Early Treatment with Secukinumab in PsO

Psoriasis is often not diagnosed or treated in atimely manner, leading to worse clinical outcomes for the patients. Early systemic treatment of immune-mediated inflammatory diseases, such as rheumatoid arthritis and Crohn’s disease, has been shown to improve long-term patient outcomes [ 28 ]. However, to date, there is no universally accepted definition of what constitutes an “early” intervention in PsO treatment as clinicians still need to agree on the criteria to screen patients [ 28 , 29 ]. Girolomoni and colleagues [ 28 ] defined an early intervention as the “time window for the onset of therapy between 6 and 24 months after disease manifestation,” based on observations from other chronic diseases. However, the authors highlighted how immediate treatment at disease onset might favorably impact the long-term course of the disease and halt mental health issues [ 28 ].

There are different clinical trials in the literature exploring the effects of secukinumab early treatment in patients with PsO. A randomized, double-blind, placebo-controlled phase II trial showed that early suppression of the IL-23/IL17 axis in individuals with psoriasis by secukinumab treatment improved plaque histopathology and promoted plaque resolution at week 12 [ 30 ]. In this study, clinical efficacy was associated with histopathological features, immunohistochemistry (IHC) cell counts, and mRNA transcription profile of lesional plaques and non-lesional skin biopsy specimens collected at baseline, weeks 1, 4, 12, and 52. In these patients, the levels of the upstream genes IL-23 and the related IL-17F were reduced, suggesting that secukinumab disrupts the IL-17A-dependent feedback mechanisms that drive plaque chronicity [ 30 ]. A phase II regimen-finding study reported that early and monthly induction therapy with secukinumab 150 mg resulted in significantly higher response rates of Psoriasis Area Severity Index (PASI) 75 than placebo therapy (54.5% and 42.0% vs. 1.5%; p  < 0.001 for both regimens) at week 12; similarly, PASI 90 response rates were significantly higher with early and monthly treatment than with placebo (31.8% and 17.4% vs. 1.5%, respectively; p  < 0.001 for both regimens) [ 31 ]. In a sub-analysis of this study, an improvement in health-related quality of life was observed in patients treated with different secukinumab doses compared to placebo [ 32 ]. The early secukinumab regimen was also associated with improvement in difficult-to-treat areas [ 33 ]. Interestingly, secukinumab showed early response rates in patients who switched from cyclosporine A (CyA) therapy after inadequate response to treatment. A total of 37 patients were treated subcutaneously with 300 mg secukinumab and 41.2% of patients reached PASI 50 by week 2; 82.4% of patients met the primary endpoint PASI 75 at week 16. PASI 90/100 and IGA 0/1 were met by 64.7%, 29.4%, and 70.6%, respectively. Of note, higher response rates were observed in biologic-naive patients than in patients with prior biologic exposure [ 34 ].

The STEPin study was the first trial designed to determine whether early intervention with either standard narrowband UVB (nb-UVB) or secukinumab treatment in patients with new-onset (< 12 months) plaque psoriasis could alter the natural history of the disease [ 35 ]. Results at 52 weeks showed that 91.1% (70/77) of patients in the secukinumab arm achieved a PASI 90 response compared to 42.3% (32/76) in the nb-UVB arm ( p  < 0.0001). This supports the notion that early treatment with secukinumab is more effective than standard treatment with nb-UVB in patients with new-onset moderate-to-severe plaque psoriasis [ 36 ]. Of note, recent and ongoing clinical trials on guselkumab and rizamkizumab are exploring PsO early interventions for newly diagnosed patients [ 37 , 38 ], and additional real-world studies would be key to gaining supportive evidence.

Early administration of secukinumab in biologic-naive patients was shown to improve clinical outcomes compared with biologic-experienced patients also in real-life studies, suggesting that it may be considered as a first-line treatment for psoriatic patients [ 39 , 40 , 41 , 42 , 43 ]. A retrospective analysis of real-world data from 151 patients with moderate-to-severe plaque psoriasis, including patients with palmoplantar psoriasis (PP), found a significant association between positive response to secukinumab and no prior use of biologic therapies [ 40 ]. Similarly, a recent real-world study found that biologic-naive patients who did not have concurrent PsA derived the greatest benefit from treatment with secukinumab [ 41 ]. The study involved 83 patients diagnosed with psoriasis, 25.3% with palmoplantar psoriasis, and the effectiveness of secukinumab and its good retention time were described [ 41 ]. Differences in clinical outcomes were also observed in PsA patients who did not receive biologics versus multi-failure patients when treated with secukinumab [ 42 ]. Patients receiving secukinumab as first-line therapy with a biologic showed improvements in multiple outcomes, such as ASDAS, PASI, and MDA, compared to patients with multiple therapeutic failures.

Data from the PURE registry, a prospective cohort study in 2362 adult patients with moderate-to-severe plaque psoriasis treated with secukinumab or standard therapy, confirmed the early and sustained resolution of erythema and scaling of the skin [ 44 ], also for non-responders [ 45 ].

In conclusion, early treatment with secukinumab can be considered a valuable option not only for the treatment of the early stages of the disease but also in patients with a long history of disease as the early introduction of secukinumab as a primary treatment approach led to better clinical outcomes.

Early Treatment of Difficult-to-Treat Body Areas Can Result in Enhanced Secukinumab Efficacy and Effectiveness

Psoriasis affecting hands, feet, nails, scalp, face, and genitals can be underdiagnosed and difficult to treat. The most common difficult-to-treat areas are the scalp, face, nails, soles, genitals, and palms [ 46 ]. Although the areas commonly affected by PsO in these sites may be limited, the impact on patients’ quality of life is significant, mainly because of the psychosocial consequences. The Palmoplantar Psoriasis Area and Severity index (ppPASI), Nail Psoriasis and Severity Index (NAPSI), and Scalp-modified PASI (S-mPASI) are rating scales specifically designed to measure the impact of the disease in these areas. For patients suffering from PsO in hard-to-treat areas of the body, traditional therapeutic options have limitations, and topical agents may not be effective or well tolerated [ 47 ]. However, to date, several therapeutic options are available for this subclass of patients, depending on the severity and extent of the disease. Recent evidence supported the effectiveness of anti-IL-17 and anti-IL-23 agents for the treatment of difficult-to-treat areas in patients with PsO [ 48 , 49 ], with anti IL-17 agents achieving a better control of scalp psoriasis. In this regard, biologics such as secukinumab are playing an important role [ 50 ]. The randomized controlled trial GESTURE investigated the efficacy and safety of secukinumab 300 mg and 150 mg versus placebo in 205 individuals with PP. At week 16, the percentage of patients achieving clear or nearly clear palms and soles with secukinumab 300 mg and 150 mg was higher compared with placebo (33.3%, 22.1%, and 1.5%, respectively, p  < 0.001). The ppPASI score was significantly reduced with secukinumab 300 mg (54.5%) and 150 mg (35.3%) compared with placebo (4.0%, p  < 0.001) [ 34 ]. Interestingly, a sub-analysis of a randomized double-blind, placebo-controlled treatment finding study showed that secukinumab improves PsO on the hands, feet, and nails when administered as early therapy [ 33 ].

A prospective clinical study was conducted specifically in patients with moderate-to-severe psoriasis of the scalp [ 35 ]. This study was a 24-week, double-blind, phase IIIb trial in which patients with extensive moderate-to-severe scalp psoriasis were randomized in a 1:1 ratio to secukinumab 300 mg or placebo. Results showed that secukinumab was effective and well tolerated in these patients, with the safety profile of secukinumab being consistent with previous studies. At week 12, the Psoriasis Scalp Severity Index (PSSI) 90 was significantly higher with secukinumab 300 mg than with placebo (secukinumab 300 mg 52.9% versus placebo 2.0%, p  < 0.001). In addition, significantly more patients achieved complete remission of scalp psoriasis at week 12 on secukinumab 300 mg than on placebo.

There are few real-world long-term data on the effectiveness and safety of secukinumab in patients with psoriasis in difficult-to-treat areas. A retrospective analysis conducted in 151 patients with chronic plaque psoriasis showed improvement in plaques after 136 weeks of treatment with secukinumab 300 mg. After 8 weeks of treatment with secukinumab, plaques on the scalp, head, nails, suprapubic area, and penis had almost disappeared [ 40 ]. Similarly, a 2-year multicenter, observational study investigated the effectiveness of secukinumab in palmoplantar psoriasis [ 34 ] and showed that secukinumab was effective in the treatment of palmoplantar psoriasis also in the real-world setting, with a significant improvement in the mean PASI, reduced to 78.2% at week 16. The mean palmoplantar PASI (ppPASI) score also improved significantly, but more gradually, with a decrease of 55.0% and 79.3% after 16 and 104 weeks, respectively. About half of the patients completely healed after 40 weeks. Secukinumab was well tolerated, and no relevant treatment-related adverse events were reported [ 51 ]. A single-center, 104-week study evaluated the efficacy of secukinumab in moderate-to-severe chronic plaque psoriasis, including scalp and palmoplantar involvement [ 41 ]. The Physician Global Assessment (PGA), PASI75/90/100, and scalp and palmoplantar PGA were assessed. At week 16, the PASI75/PASI90/PASI100 was observed in 83.8/70.0/46.3% of patients, respectively. Scalp and palmoplantar PGA improved rapidly, with 98.7% and 95.5% achieving clear/almost clear skin at week 16, respectively. In this real-world study, secukinumab was shown to be effective in difficult-to-treat areas with a similar safety profile to clinical trials [ 41 ]. These results were confirmed in a study on 99 patients with psoriasis where receiving 300 mg of secukinumab was found to be save and efficacious, also in patients with difficult to treat manifestations, such as the scalp, over 4 years [ 52 ]. Secukinumab was shown to be safe and effective in real-world clinical practice in patients with PP and palmoplantar pustular psoriasis (PPPP) who did not respond to previous systemic or biologic treatments over a 24-month follow-up period [ 53 ]. Interestingly, statistically significant differences in ppIGA scores were observed at 12 months between therapy-naive patients and patients who had previously received biologics therapy. Secukinumab was found to be more effective in therapy-naive patients than in patients who had previously received biologic therapy [ 53 ]. In addition, the first real-world monocentric study comparing secukinumab and ixekizumab in the treatment of PP and erythrodermic psoriasis (EP) showed that patients treated with ixekizumab reached PASI 90, PASI < 3, and PASI 100 faster than those treated with secukinumab, with no statistically significant difference at 12-week follow-up. At 48 weeks, a statistically significant difference was observed between the two groups (100%, 100%, and 75% of patients treated with ixekizumab achieved PASI 90, PASI < 3, and PASI 100, respectively, versus 31%, 46%, and 23% of patients treated with secukinumab, p  = 0.01). Secukinumab proved effective in the EP group at week-48 follow-up, as PASI 90 and PASI 100 were achieved in 82% and 54% of patients, respectively [ 54 ]. Moreover, a 48-week real-world retrospective study performed on 18 pediatric patients with generalized pustular psoriasis (GPP) receiving secukinumab as first-line treatment showed a significant decrease in the GPPPASI score as well as improvements in Children’s Dermatology Life Quality Index score [ 55 ].

Preventing the Development of Psoriasis Arthritis by Early Treatment of Psoriasis

Psoriatic arthritis (PsA), a chronic inflammatory disease, develops in around 14.0–22.7% of the individuals affected by PsO. Patients with psoriasis are at higher risk of developing PsA than healthy individuals or individuals with other diseases [ 56 ]. The progression from PsO to PsA occurs in a series of phases [ 57 ], with clinically evident disease emerging only at late stages. The transitional phase preceding PsA onset, known as prodromal PsA, is characterized by the spread of the disease from the skin to the joints. The prodromal phase of PsA is difficult to diagnose as characterized by non-specific symptoms, such as inflammatory joint lesions, joint pain, or fatigue [ 58 ]. As a result, PsA is often not diagnosed in a timely manner, resulting in treatment delays and missed prevention opportunities [ 59 ]. The transition phase from PsO to PsA offers the opportunity to identify individuals at increased risk of developing PsA and to implement early treatment and prevention strategies. The current literature suggests that the development of PsA might have its roots in the complex interplay between environmental factors, an individual's phenotype, and genotype. For example, severe psoriasis affecting the nails, scalp, and genitals is associated with the development of PsA in people with systemic conditions [ 60 ]. Patients with PsA have a higher incidence and prevalence of cardiovascular risk factors, such as hypertension, diabetes, hyperlipidemia, and obesity [ 61 ]. These known risk factors could be considered in current clinical practice to implement prevention strategies [ 45 ]; however, research on clinical indicators to identify individuals with psoriasis at higher risk of developing PsA remains limited. A systematic review and meta-analysis [ 45 ] attempted to profile PsO patients at higher risk of developing PsA and identified some potential predictors of PsA development. Skin and nail phenotypes of PsA development included PsO severity and nail pitting. Furthermore, other predictors were having arthralgia and higher categories of body mass index (BMI). This research, while limited by the heterogeneity of the included studies, suggests that these risk factors could support the identification of individuals at higher risk of developing PsA who could receive timely treatment, preventing the disease or worse disease outcome [ 62 ]. Of note, treatment of PsA with biologics before the onset of structural damage prevents impairment of physical function and permanent disability [ 63 , 64 ]. Supporting this evidence, preliminary results on a limited number of individuals suggested that early treatment with biologics in patients with PsO carrying a short-term risk of developing PsA may revert the preclinical manifestations of PsA, such as arthralgia or musculoskeletal pain [ 65 ]. Notably, in recent years the number of studies investigating the real-world effectiveness of secukinumab in PsA has significantly increased. For example, one study reported that secukinumab was effective in reducing disease activity and was safe in both biologic-naive and non-naive PsA patients [ 66 ]. A prospective, multicenter study assessing real-life long-term secukinumab effectiveness and safety showed that after 24 months, biologic-naive patients had a lower PASI ( p  = 0.04), erythrocyte sedimentation rate and C-reactive protein ( p  = 0.03; p  = 0.05), and joint count ( p  = 0.03) compared to biologic-multi-failure patients [ 42 ]. When comparing the effectiveness and safety of secukinumab in biologic-naive patients with those in which TNF inhibitors had failed, DAPSA and ASDAS showed that secukinumab was effective in PsA patients over a 24-month follow-up period [ 67 ]. Another study conducted in patients with axial spondyloarthritis showed that biologic-naive patients had better physical functioning and lower disease activity compared to the TNF inhibitor failure group [BASDAI 2.2 (1.0–3.8) vs 3.9 (2.7–5.0), ASDAS 1.3(1.0–2.2) vs 2.1(1.6–2.9)] at 24 months, with high retention rate [ 68 ]. An analysis of the Italian Lombardy Rheumatology Network (LOHREN) registry found a high 3-year retention rate with secukinumab for both PsA and axSpA [ 69 ]. A recent study in the US on patients with PsA described rapid improvements in disease management and quality of life upon secukinumab treatment [ 70 ]. Secukinumab also confirmed effectiveness and safety in PsA patients in a recent real-life Italian study conducted over 52 weeks [ 71 ]. This evidence was confirmed in other studies conducted in Italian settings [ 42 , 72 , 73 ].

The real-world evidence presented in these studies highlights the effectiveness and safety of secukinumab in the management of PsA and axSpA, with a good patient retention rate. The reduction in disease severity scores and good retention rate observed upon treatment with secukinumab emphasize its potential to provide substantial relief to these patients. These findings encourage a shift towards proactive and early intervention strategies, addressed not only to improving the quality of life of the patients but also aiming at preventing long-term disabilities and comorbidities, and potentially disease onset.

Benefits of Early Treatment with Secukinumab on the QoL of Individuals with PSO

The impact of psoriasis on patients’ health-related quality of life is considerable, as the disease negatively affects physical, emotional, psychological, and economic aspects of life. A survey of psoriasis patients conducted in the US found that the larger the body surface area, the greater the impact on quality of life [ 74 ]. Psoriasis patients report that PsO interferes with daily life activities, such as sleeping, washing, or dressing, and with work-related activities [ 75 , 76 , 77 , 78 ]. Patients frequently experience a pronounced sense of diminished self-esteem regarding their physical appearance, and they frequently contend with societal stigmatization [ 79 ]. This psychological condition triggers coping strategies, such as covering up their lesions or avoiding contact with others, which worsen patients' quality of life [ 74 ]. Finally, patients with psoriasis have a higher financial burden of direct and indirect costs, including the cost of treatments and loss of work productivity [ 5 ].

In a multicenter, retrospective real-world study of Italian psoriasis patients that lasted 84 weeks, secukinumab appeared to rapidly improve patients' quality of life as assessed by the Dermatology Life Quality Index score (DLQI). Specifically, a significant improvement in DLQI was observed after 4 weeks of treatment with secukinumab ( p  < 0.001 compared to baseline), which improved significantly at each follow-up visit. Interestingly, the data were comparable between patients who had never been treated with biologics and those who had been previously treated with biologics [ 80 ]. As further evidence, in a multicenter real-world study, secukinumab showed remarkable effects on patients' quality of life, even when used in combination therapy after the failure of secukinumab monotherapy [ 81 ].

Interestingly, a randomized, double-blind, placebo-controlled phase 2 study has shown that patients with moderate-to-severe plaque psoriasis treated early with secukinumab have a better quality of life compared with patients receiving placebo [ 82 ]. DLQI response was significantly higher with all secukinumab regimens compared with placebo at both 4 and 12 weeks, but the greatest changes were observed with the monthly and early regimens [ 82 ].

Benefits of Early Treatment with Secukinumab in Hard-to-Treat Patient Populations

Secukinumab is safe and effective in the real-life setting, also for patients in whom previous systemic treatments have failed or who have multiple comorbidities, such as older people. A study following patients > 65 years old with moderate-to-severe PsO treated with secukinumab over a 2-year period reported a mean PASI reduction of 85.1% at week 96, with a significant reduction from week 24 (from 11.4 ± 6.3 at baseline to 2.1 ± 1.7 at week 24, p  < 0.001) [ 83 ]. In addition to older patients, biologics are proving to be a favorable therapeutic choice for pediatric patients as they have an excellent efficacy and safety profile compared to conventional systemic medications [ 84 ]. As previously mentioned [ 55 ], in a 48-week real-world retrospective study involving 18 pediatric patients diagnosed with GPP who received secukinumab as their initial treatment, a substantial reduction in the GPPPASI score and a concurrent enhancement in the Children's Dermatology Life Quality Index score were evidenced. Notably, at the end of the 48-week period, 88.9% of the patients attained a GPPASI score of 100, while every patient achieved a Children's Dermatology Life Quality Index score of 0 or 1 [ 55 ]. Moreover, real-world evidence has shown that secukinumab has more favorable outcomes in pediatric patients with GPP compared to acitretin [ 85 ]. These data highlight the effectiveness of secukinumab in all life stages of patients with PsO.

Findings from secukinumab clinical trials were confirmed in a more complicated patient population (e.g., polypharmacy, comorbidities, failure of conventional systemic treatment) in a 2-year, real-world, multicenter retrospective study. Results showed that PASI, BSA, and DLQI scores improved significantly from baseline to each follow-up visit and that no significant differences were observed between naive and biologic-naive or non-naive patients. Treatment was discontinued in 31 of 324 patients (9.5%), 1.8% of these because of adverse events [ 86 ]. A heterogeneous patient population with varying disease severity and comorbidities was enrolled in another real-world, multicenter, retrospective study that lasted 52 weeks. Secukinumab was effective and safe but also showed rapid clinical improvement, particularly in young patients, and in certain subgroups of patients, such as those with obesity and multidrug-resistant patients [ 87 ]. A multicenter, real-world observational study involving 15 Italian referral centers assessed the efficacy and safety of secukinumab in patients with PsO and a history of cancer, usually excluded from clinical trials of biologic treatments. After 48 weeks, 64.7% of patients scored PASI 90 and 38.2% scored PASI 100. Significant improvement was also observed in DLQI, itch, and pain visual analog scale (VAS) scores. Furthermore, the study suggests that secukinumab is safe in psoriatic patients with a history of cancer [ 88 ]. A European, multicenter, retrospective real-world study contributed to the characterization of secukinumab best responders. The study confirmed that secukinumab treatment was more effective in biologic-naive patients than in patients previously treated with biologics. The better response in biologic-naive patients was observed at weeks 24 and 52 [ 89 ].

Conclusions

Biologics therapy is a valuable option for the treatment of moderate-to-severe plaque psoriasis. Secukinumab has long-term clinical efficacy and safety in the treatment of patients with PsO, PsA, and axSpA. While the efficacy of early intervention has been explored and demonstrated in other chronic inflammatory diseases, studies on clinical outcomes of early treatment with secukinumab in individuals with psoriasis are limited. Real-world studies are a valuable resource of information to evaluate the effectiveness of this clinical approach in different groups of patients, with several degrees of disease severity and comorbidities. Real-world data have the advantage of including a broad patient population, often excluded from clinical trials and representative of real-world clinical practice. The analysis of real-world data showed the effectiveness of secukinumab, particularly in biologic-naive patients with a history of diseases. In these patients, early intervention with secukinumab proved to be a valuable treatment option. In addition, secukinumab has a good safety profile, which has been consistently observed in diverse patient cohorts characterized by different comorbidities, such as cancer, liver, and cardiovascular disease, as well as in pediatric and older patients. The cost-benefit ratio of secukinumab could also be better than that of other biologics, considering the sustained clinical response. In addition, secukinumab showed low immunogenicity (< 1%) in psoriasis patients for up to 5 years and patients with PsA exposed for up to 52 weeks [ 90 ]. A systematic review conducted to explore the immunogenicity of several biological agents across inflammatory diseases confirmed an overall rate for secukinumab of 0–1%, lower than the one reported for other biologics, such as infliximab and adalimumab, an IL-17 and tumor necrosis factor inhibitor, respectively [ 91 ]. Although limited, the data in the literature support effectiveness, safety, and utility as a treatment option for psoriasis of secukinumab also in biologic-naive patients, with improvements in clinical outcomes comparable to those reported for biologic-experience patients [ 22 , 31 ]. Furthermore, secukinumab could also be an effective alternative when IL-23 inhibitors do not achieve the desired therapeutic outcomes ( 92 ).

Early intervention with secukinumab in the treatment of PsO can potentially improve the overall prognosis by reducing disease severity or altering the natural history of the disease towards more severe and complicated stages, leading to remission and improving the quality of life of these patients. The early intervention may also lead to a reduction of costs in treating this disease. For all these reasons, additional real-world studies exploring intervention and early intervention with secukinumab in PsO is of utmost importance.

Data Availability

Data sharing is not applicable to this article, as no datasets were generated or analyzed during the current study.

Bu J, Ding R, Zhou L, Chen X, Shen E. Epidemiology of psoriasis and comorbid diseases: a narrative review. Front Immunol. 2022;10:13.

Google Scholar  

Parisi R, Symmons DPM, Griffiths CEM, Ashcroft DM. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Investig Dermatol. 2013;133(2):377–85.

Article   PubMed   CAS   Google Scholar  

de Oliveira MFSP, Rocha BO, Duarte GV. Psoriasis: classical and emerging comorbidities. An Bras Dermatol. 2015;90(1):9–20.

Article   PubMed   PubMed Central   Google Scholar  

Noe MH, Shin DB, Wan MT, Gelfand JM. Objective measures of psoriasis severity predict mortality: a prospective population-based cohort study. J Investig Dermatol. 2018;138(1):228–30.

Article   PubMed   Google Scholar  

Bhosle MJ, Kulkarni A, Feldman SR, Balkrishnan R. Quality of life in patients with psoriasis. Health Qual Life Outcomes. 2006;4(1):35.

Griffiths CEM, Armstrong AW, Gudjonsson JE, Barker JNWN. Psoriasis. The Lancet. 2021;397(10281):1301–15.

Article   CAS   Google Scholar  

Mosca M, Hong J, Hadeler E, Hakimi M, Liao W, Bhutani T. The role of IL-17 cytokines in psoriasis. Immunotargets Ther. 2021;10:409–18.

Article   PubMed   PubMed Central   CAS   Google Scholar  

Xu S, Gao X, Deng J, Yang J, Pan F. Comparative efficacy and safety of biologics in moderate to severe plaque psoriasis: a multiple-treatments meta-analysis. J Deutschen Derma Gesell. 2021;19(1):47–56.

Menter A, Krueger GG, Paek SY, Kivelevitch D, Adamopoulos IE, Langley RG. Interleukin-17 and Interleukin-23: a narrative review of mechanisms of action in psoriasis and associated comorbidities. Dermatol Ther (Heidelb). 2021;11(2):385–400.

Gargiulo L, Ibba L, Malagoli P, Balato A, Bardazzi F, Burlando M, et al. Drug survival of IL-12/23, IL-17 and IL-23 inhibitors for moderate-to-severe plaque psoriasis: a retrospective multicenter real-world experience on 5932 treatment courses – IL PSO (Italian landscape psoriasis). Front Immunol. 2024;11:14.

Mastorino L, Dapavo P, Susca S, Cariti C, Siliquini N, Verrone A, et al. Drug survival and clinical effectiveness of secukinumab, ixekizumab, brodalumab, guselkumab, risankizumab, tildrakizumab for psoriasis treatment. J der Deutschen Dermatologischen Gesellschaft. 2024;22(1):34–42.

Thomas SE, Barenbrug L, Hannink G, Seyger MMB, de Jong EMGJ, van den Reek JMPA. Drug survival of IL-17 and IL-23 inhibitors for psoriasis: a systematic review and meta-analysis. Drugs. 2024;84(5):565–78.

Russo F, Galluzzo M, Stingeni L, Persechino S, Zichichi L, Conti A, et al. Long-term drug survival and effectiveness of secukinumab in patients with moderate to severe chronic plaque psoriasis: 42-month results from the SUPREME 2.0 study. Clin Cosmet Investig Dermatol. 2023;16:3561–74.

Dastoli S, Passante M, Loconsole F, Mortato E, Balato A, Piccolo V, et al. Long-term efficacy and safety of secukinumab in real life: a 240 weeks multicenter study from Southern Italy. J Dermatol Treat. 2023. https://doi.org/10.1080/09546634.2023.2200868 .

Article   Google Scholar  

Kolbinger F, Di Padova F, Deodhar A, Hawkes JE, Huppertz C, Kuiper T, et al. Secukinumab for the treatment of psoriasis, psoriatic arthritis, and axial spondyloarthritis: physical and pharmacological properties underlie the observed clinical efficacy and safety. Pharmacol Ther. 2022;229: 107925.

European Medicines Agency. Cosentyx, INN-secukinumab - European Medicines Agency - Product information [Internet]. [cited 2024 Feb 11]. Available from: https://www.ema.europa.eu/en/documents/product-information/cosentyx-epar-product-information_en.pdf

Augustin M, Reich K, Yamauchi P, Pinter A, Bagel J, Dahale S, et al. Secukinumab dosing every 2 weeks demonstrated superior efficacy compared with dosing every 4 weeks in patients with psoriasis weighing 90 kg or more: results of a randomized controlled trial*. Br J Dermatol. 2022;186(6):942–54.

Frieder J, Kivelevitch D, Menter A. Secukinumab: a review of the anti-IL-17A biologic for the treatment of psoriasis. Ther Adv Chronic Dis. 2018;9(1):5–21.

van de Kerkhof PCM, Griffiths CEM, Reich K, Leonardi CL, Blauvelt A, Tsai TF, et al. Secukinumab long-term safety experience: a pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis. J Am Acad Dermatol. 2016;75(1):83-98.e4.

Papp KA, Griffiths CEM, Gordon K, Lebwohl M, Szapary PO, Wasfi Y, et al. Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from 5 years of follow-up. Br J Dermatol. 2013;168(4):844–54.

Deodhar A, Mease PJ, McInnes IB, Baraliakos X, Reich K, Blauvelt A, et al. Long-term safety of secukinumab in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: integrated pooled clinical trial and post-marketing surveillance data. Arthritis Res Ther. 2019;21(1):111.

Blauvelt A, Chiricozzi A. The immunologic role of il-17 in psoriasis and psoriatic arthritis pathogenesis. Clin Rev Allergy Immunol. 2018;55(3):379–90.

Liang J, Zhang S, Li Q, Yu Y, Chen X, Zhang X. Review of secukinumab-induced adverse events of special interest and its potential pathogenesis. Dermatol Ther. 2022. https://doi.org/10.1111/dth.15599 .

Eshwar V, Kamath A. Assessment of safety profile of secukinumab in real-world scenario using United States food and drug administration adverse event reporting system database. Sci Rep. 2024;14(1):1222.

Sun R, Bustamante M, Gurusamy VK, Lebwohl M, Gottlieb AB, Mease PJ, et al. Safety of secukinumab from 1 million patient-years of exposure: experience from post-marketing setting and clinical trials. Dermatol Ther (Heidelb). 2024;14(3):729–43.

Merola JF, McInnes IB, Deodhar AA, Dey AK, Adamstein NH, Quebe-Fehling E, et al. Effect of secukinumab on traditional cardiovascular risk factors and inflammatory biomarkers: post hoc analyses of pooled data across three indications. Rheumatol Ther. 2022;9(3):935–55.

von Stebut E, Reich K, Thaçi D, Koenig W, Pinter A, Körber A, et al. Impact of secukinumab on endothelial dysfunction and other cardiovascular disease parameters in psoriasis patients over 52 weeks. J Investig Dermatol. 2019;139(5):1054–62.

Girolomoni G, Griffiths CEM, Krueger J, Nestle FO, Nicolas JF, Prinz JC, et al. Early intervention in psoriasis and immune-mediated inflammatory diseases: a hypothesis paper. J Dermatol Treat. 2015;26(2):103–12.

Felix PAO, Sampaio AL, Silva BL, Viana ALP. Early intervention in psoriasis: Where do we go from here? Front Med (Lausanne). 2022;1:9.

Krueger JG, Wharton KA, Schlitt T, Suprun M, Torene RI, Jiang X, et al. IL-17A inhibition by secukinumab induces early clinical, histopathologic, and molecular resolution of psoriasis. J Allergy Clin Immunol. 2019;144(3):750–63.

Rich P, Sigurgeirsson B, Thaci D, Ortonne JP, Paul C, Schopf RE, et al. Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study. Br J Dermatol. 2013;168(2):402–11.

Augustin M, Jullien D, Martin A, Peralta C. Real-world evidence of secukinumab in psoriasis treatment—a meta-analysis of 43 studies. J Eur Acad Dermatol Venereol. 2020;34(6):1174–85.

Paul C, Reich K, Gottlieb AB, Mrowietz U, Philipp S, Nakayama J, et al. Secukinumab improves hand, foot and nail lesions in moderate-to-severe plaque psoriasis: subanalysis of a randomized, double-blind, placebo-controlled, regimen-finding phase 2 trial. J Eur Acad Dermatol Venereol. 2014;28(12):1670–5.

Ohtsuki M, Morita A, Igarashi A, Imafuku S, Tada Y, Fujita H, et al. Secukinumab improves psoriasis symptoms in patients with inadequate response to cyclosporine A: a prospective study to evaluate direct switch. J Dermatol. 2017;44(10):1105–11.

Iversen L, Eidsmo L, Austad J, de Rie M, Osmancevic A, Skov L, et al. Secukinumab treatment in new-onset psoriasis: aiming to understand the potential for disease modification – rationale and design of the randomized, multicenter STEPI n study. J Eur Acad Dermatol Venereol. 2018;32(11):1930–9.

Iversen L, Conrad C, Eidsmo L, Costanzo A, Narbutt J, Pinter A, et al. Secukinumab demonstrates superiority over narrow-band ultraviolet B phototherapy in new-onset moderate to severe plaque psoriasis patients: Week 52 results from the STEPIn study. J Eur Acad Dermatol Venereol. 2023;37(5):1004–16.

Schäkel K, Reich K, Asadullah K, Pinter A, Jullien D, Weisenseel P, et al. Early disease intervention with guselkumab in psoriasis leads to a higher rate of stable complete skin clearance (‘clinical super response’): Week 28 results from the ongoing phase IIIb randomized, double-blind, parallel-group, GUIDE study. J Eur Acad Dermatol Venereol. 2023;37(10):2016–27.

Blauvelt A, Leonardi CL, Gooderham M, Papp KA, Philipp S, Wu JJ, et al. Efficacy and safety of continuous risankizumab therapy vs treatment withdrawal in patients with moderate to severe plaque psoriasis. JAMA Dermatol. 2020;156(6):649.

Strober B, Patil D, McLean RR, Moore-Clingenpeel M, Guo N, Levi E, et al. Utilization trends and impact of secukinumab treatment on clinical outcomes in biologic-naive patients with psoriasis in a US real-world setting. Dermatol Ther (Heidelb). 2022;12(6):1351–65.

Galluzzo M, D’Adamio S, Silvaggio D, Lombardo P, Bianchi L, Talamonti M. In which patients the best efficacy of secukinumab? Update of a real-life analysis after 136 weeks of treatment with secukinumab in moderate-to-severe plaque psoriasis. Expert Opin Biol Ther. 2020;20(2):173–82.

Rompoti N, Katsimbri P, Kokkalis G, Boumpas D, Ikonomidis I, Theodoropoulos K, et al. Real world data from the use of secukinumab in the treatment of moderate-to-severe psoriasis, including scalp and palmoplantar psoriasis: a 104-week clinical study. Dermatol Ther. 2019. https://doi.org/10.1111/dth.13006 .

Ramonda R, Lorenzin M, Carriero A, Chimenti MS, Scarpa R, Marchesoni A, et al. Effectiveness and safety of secukinumab in 608 patients with psoriatic arthritis in real life: a 24-month prospective, multicentre study. RMD Open. 2021;7(1): e001519.

Melgosa Ramos FJ, Mateu Puchades A, Guillén Climent S, Galarreta Pascual M, Saéz Belló M, Martínez Ferrer MA, et al. Long-term secukinumab efficacy and safety in bio-naïve patients with moderate-to-severe cutaneous psoriasis: a real-world retrospective noninterventional multicentric experience (128 patients). JEADV Clin Pract. 2023;2(3):576–82.

Gooderham M, Papp KA, Lynde C, Delorme I, Beecker J, Albrecht L, et al. Sustained effectiveness of secukinumab across different body regions in patients with moderate-to-severe plaque psoriasis from the PURE registry. Dermatol Ther (Heidelb). 2023;13(2):535–53.

Papp KA, Gooderham M, Lynde C, Brassard D, Al-Mohammedi F, Prajapati VH, et al. Effectiveness and safety of secukinumab updosing in patients with moderate to severe plaque psoriasis: data from the PURE registry. Arch Dermatol Res. 2024;316(7):362.

Egeberg A, See K, Garrelts A, Burge R. Epidemiology of psoriasis in hard-to-treat body locations: data from the Danish skin cohort. BMC Dermatol. 2020;20(1):3.

Raharja A, Mahil SK, Barker JN. Psoriasis: a brief overview. Clin Med. 2021;21(3):170–3.

Mastorino L, Burzi L, Frigatti G, Fazio A, Celoria V, Macagno N, et al. Clinical effectiveness of IL-17 and IL-23 inhibitors on difficult-to-treat psoriasis areas (scalp, genital, and palmoplantar sites): a retrospective, observational, single-center, real-life study. Expert Opin Biol Ther. 2023;23(9):929–36.

Mrowietz U, Leonardi CL, Girolomoni G, Toth D, Morita A, Balki SA, et al. Secukinumab retreatment-as-needed versus fixed-interval maintenance regimen for moderate to severe plaque psoriasis: a randomized, double-blind, noninferiority trial (SCULPTURE). J Am Acad Dermatol. 2015;73(1):27–36 ( e1 ).

Merola JF, Qureshi A, Husni ME. Underdiagnosed and undertreated psoriasis: nuances of treating psoriasis affecting the scalp, face, intertriginous areas, genitals, hands, feet, and nails. Dermatol Ther. 2018. https://doi.org/10.1111/dth.12589 .

Galluzzo M, Talamonti M, Atzori L, Bardazzi F, Campanati A, Di Cesare A, et al. Secukinumab for the treatment of palmoplantar psoriasis: a 2-year, multicenter, real-life observational study. Expert Opin Biol Ther. 2022;22(4):547–54.

Kyrmanidou E, Kemanetzi C, Stavros C, Trakatelli MG, Patsatsi A, Madia X, et al. A real-life 208 week single-centred, register-based retrospective study assessing secukinumab survival and long-term efficacy and safety among Greek patients with moderate to severe plaque psoriasis, including difficult-to-treat manifestations such as genitals and scalp. Dermatol Pract Concept. 2024;14(2): e2024119.

Krueger J, Langley R, Nigen S. 35098 Secukinumab versus guselkumab in the treatment of ustekinumab-resistant psoriatic plaques: 16-week randomized, open-label, multicenter ARROW study. J Am Acad Dermatol. 2022;87(3): AB108.

Avallone G, Cariti C, Dapavo P, Ortoncelli M, Conforto L, Mastorino L, et al. Real-life comparison between secukinumab and ixekizumab in the treatment of pustular and erythrodermic psoriasis. J Eur Acad Dermatol Venereol. 2022;36(7):e574–e576.

Ruan SF, Zhang LL, Liu Z, Lin TT, Wang HQ, Xu QY, et al. Real-world data on the clinical use of secukinumab in pediatric generalized pustular psoriasis: a 48-week retrospective study. J Am Acad Dermatol. 2023;88(1):243–6.

Hioki T, Komine M, Ohtsuki M. Diagnosis and intervention in early psoriatic arthritis. J Clin Med. 2022;11(7):2051.

Scher JU, Ogdie A, Merola JF, Ritchlin C. Preventing psoriatic arthritis: focusing on patients with psoriasis at increased risk of transition. Nat Rev Rheumatol. 2019;15(3):153–66.

McArdle A, Pennington S, FitzGerald O. Clinical features of psoriatic arthritis: a comprehensive review of unmet clinical needs. Clin Rev Allergy Immunol. 2018;55(3):271–94.

Haroon M, Gallagher P, FitzGerald O. Diagnostic delay of more than 6 months contributes to poor radiographic and functional outcome in psoriatic arthritis. Ann Rheum Dis. 2015;74(6):1045–50.

Paek SY, Thompson JM, Qureshi AA, Merola JF, Husni ME. Comprehensive assessment of the psoriasis patient (CAPP): a report from the GRAPPA 2015 annual meeting. J Rheumatol. 2016;43(5):961–4.

Radner H, Lesperance T, Accortt NA, Solomon DH. Incidence and prevalence of cardiovascular risk factors among patients with rheumatoid arthritis, psoriasis, or psoriatic arthritis. Arthritis Care Res (Hoboken). 2017;69(10):1510–8.

Zabotti A, De Lucia O, Sakellariou G, Batticciotto A, Cincinelli G, Giovannini I, et al. Predictors, risk factors, and incidence rates of psoriatic arthritis development in psoriasis patients: a systematic literature review and meta-analysis. Rheumatol Ther. 2021;8(4):1519–34.

Coates LC, Moverley AR, McParland L, Brown S, Navarro-Coy N, O’Dwyer JL, et al. Effect of tight control of inflammation in early psoriatic arthritis (TICOPA): a UK multicentre, open-label, randomised controlled trial. The Lancet. 2015;386(10012):2489–98.

Kamata M, Tada Y. Efficacy and safety of biologics for psoriasis and psoriatic arthritis and their impact on comorbidities: a literature review. Int J Mol Sci. 2020;21(5):1690.

Zabotti A, Giovannini I, McGonagle D, De Vita S, Stinco G, Errichetti E. Arthritis interception in patients with psoriasis treated with guselkumab. Dermatol Ther (Heidelb). 2022;12(1):5–8.

Letarouilly JG, Sellam J, Richette P, Dieudé P, Claudepierre P, Richard CM, et al. AB0760 drug survival and efficacy of ustekinumab and secukinumab in psoriatic arthritis: a real-world multicentric cohort of 186 Patients. In: Abstracts accepted for Publication. BMJ Publishing Group Ltd and European League Against Rheumatism; 2019. pp. 1847.2–1848.

Lorenzin M, Carletto A, Foti R, Chimenti MS, Semeraro A, Costa L, et al. FRI0284 Effectiveness and safety of secukinumab in naïve or TNF-inhibitors failure psoriatic arthritis patients in real life: a 24-months prospective multicenter study. Ann Rheum Dis. 2020;79(Suppl 1):730.1-730.

Marzo-Ortega H, Juanola X, Okano T, Schymura Y, Bradley A, Gerwien J, et al. POS0926 Normalisation of high sensitivity CRP versus clinical response to ixekizumab at week 16 in patients with radiographic& non-radiographic axial spondyloaarthritis: results from the coast studies. Ann Rheum Dis. 2021;80(Suppl 1):725–6.

Favalli EG, Marchesoni A, Balduzzi S, Montecucco C, Lomater C, Crepaldi G, et al. FRI0273 Effectiveness and retention rate of secukinumab for psoriatic arthritis and axial spondyloarthritis: real-life data from the Italian Lohren Registry. Ann Rheum Dis. 2020;79(Suppl 1):722.1-723.

Kivitz AJ, Kremer JM, Legerton CW, Pricop L, Singhal A. Efficacy and safety of secukinumab in US patients with psoriatic arthritis: a subgroup analysis of the phase 3 FUTURE studies. Rheumatol Ther. 2024;11(3):675–89.

Molica Colella F, Zizzo G, Parrino V, Filosa MT, Cavaliere R, Fazio F, et al. Effectiveness and safety of secukinumab in ankylosing spondylitis and psoriatic arthritis: a 52-week real-life study in an Italian cohort. Adv Rheumatol. 2023;63(1):15.

Gentileschi S, Rigante D, Sota J, Lopalco G, Giannotta MG, Emmi G, et al. Long-term effectiveness of secukinumab in patients with axial spondyloarthritis. Mediators Inflamm. 2020;31(2020):1–5.

Chimenti MS, Fonti GL, Conigliaro P, Sunzini F, Scrivo R, Navarini L, et al. One-year effectiveness, retention rate, and safety of secukinumab in ankylosing spondylitis and psoriatic arthritis: a real-life multicenter study. Expert Opin Biol Ther. 2020;20(7):813–21.

Gelfand JM, Feldman SR, Stern RS, Thomas J, Rolstad T, Margolis DJ. Determinants of quality of life in patients with psoriasis: a study from the US population. J Am Acad Dermatol. 2004;51(5):704–8.

Finlay AY, Coles EC. The effect of severe psoriasis on the quality of life of 369 patients. Br J Dermatol. 2006;132(2):236–44.

Zagni E, Frassi M, Mariano GP, Fusaro E, Lomater C, Del Medico P, et al. A real-world economic analysis of biologic therapies for psoriatic arthritis in Italy: results of the CHRONOS observational longitudinal study. BMC Health Serv Res. 2022;22(1):1537.

Mantovani L, Medaglia M, Piacentini P, Tricca M, Vena GA, Vozza A, et al. Burden of moderate-to-severe plaque psoriasis and new therapeutic approaches (secukinumab): an Italian perspective. Dermatol Ther (Heidelb). 2016;6(2):151–67.

Colombo D, Bianchi L, Fabbrocini G, Corrao S, Offidani A, Stingeni L, et al. Real-world evidence of biologic treatments in moderate–severe psoriasis in Italy: results of the CANOVA (effectiveness of biologic treatments for plaque psoriasis in Italy: an observational longitudinal study of real-life clinical practice) study. Dermatol Ther. 2022. https://doi.org/10.1111/dth.15166 .

Fortune DG, Richards HL, Griffiths CEM. Psychologic factors in psoriasis: consequences, mechanisms, and interventions. Dermatol Clin. 2005;23(4):681–94.

Megna M, Di Costanzo L, Argenziano G, Balato A, Colasanti P, Cusano F, et al. Effectiveness and safety of secukinumab in Italian patients with psoriasis: an 84 week, multicenter, retrospective real-world study. Expert Opin Biol Ther. 2019;19(8):855–61.

Damiani G, Odorici G, Pacifico A, Morrone A, Conic RRZ, Davidson T, et al. Secukinumab loss of efficacy is perfectly counteracted by the introduction of combination therapy (rescue therapy): data from a multicenter real-life study in a cohort of italian psoriatic patients that avoided secukinumab switching. Pharmaceuticals. 2022;15(1):95.

Augustin M, Abeysinghe S, Mallya U, Qureshi A, Roskell N, McBride D, et al. Secukinumab treatment of plaque psoriasis shows early improvement in DLQI response—results of a phase II regimen-finding trial. J Eur Acad Dermatol Venereol. 2016;30(4):645–9.

Megna M, Camela E, Cinelli E, Fabbrocini G. Real-life efficacy and safety of secukinumab in elderly patients with psoriasis over a 2-year period. Clin Exp Dermatol. 2020;45(7):848–52.

Megna M, Camela E, Battista T, Genco L, Martora F, Noto M, et al. Efficacy and safety of biologics and small molecules for psoriasis in pediatric and geriatric populations. Part I: focus on pediatric patients. Expert Opin Drug Saf. 2023;22(1):25–41.

Miao C, Chen Y, Wang Z, Xiang X, Liu Y, Xu Z. Real-world data on the use of secukinumab and acitretin in pediatric generalized pustular psoriasis. J Dermatol. 2023;50(2):258–61.

Di M.M.L. ACG, and CABP. Secukinumab in real life: a 2-year multicenter retrospective study in Campania region. i. Vol. 324. 8–9 p.

Galluzzo M, Talamonti M, De Simone C, D’Adamio S, Moretta G, Tambone S, et al. Secukinumab in moderate-to-severe plaque psoriasis: a multi-center, retrospective, real-life study up to 52 weeks observation. Expert Opin Biol Ther. 2018;18(7):727–35.

Pellegrini C, Esposito M, Rossi E, Gisondi P, Piaserico S, Dapavo P, et al. Secukinumab in patients with psoriasis and a personal history of malignancy: a multicenter real-life observational study. Dermatol Ther (Heidelb). 2022;12(11):2613–26.

Chiricozzi A, Balato A, Conrad C, Conti A, Dapavo P, Ferreira P, et al. Secukinumab demonstrates improvements in absolute and relative psoriasis area severity indices in moderate-to-severe plaque psoriasis: results from a European, multicentric, retrospective, real-world study. J Dermatol Treat. 2020;31(5):476–83.

Deodhar A, Gladman DD, McInnes IB, Spindeldreher S, Martin R, Pricop L, et al. Secukinumab immunogenicity over 52 weeks in patients with psoriatic arthritis and ankylosing spondylitis. J Rheumatol. 2020;47(4):539–47.

Strand V, Balsa A, Al-Saleh J, Barile-Fabris L, Horiuchi T, Takeuchi T, et al. Immunogenicity of biologics in chronic inflammatory diseases: a systematic review. BioDrugs. 2017;31(4):299–316.

Mastorino L, Roccuzzo G, Dapavo P, Siliquini N, Avallone G, Rubatto M, et al. Switching from IL23 inhibitors to IL17 inhibitors: a safe and effective practice? Dermatol Ther. 2022. https://doi.org/10.1111/dth.15697 .

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Psocare Unit, IRCCS Policlinico San Donato, 20097, San Donato Milanese (Milan), Italy

Piergiorgio Malagoli

Clinica Dermatologica Universitaria di Torino, ASO Città della Salute e della Scienza, 10126, Turin, Italy

Paolo Dapavo

Dermatology Unit, UOC Dermatologia, Università G.d’Annunzio, 66100, Chieti-Pescara, Italy

Paolo Amerio

Dermatology Unit, Department Medical Sciences and Public Health, University of Cagliari, 09124, Cagliari, Italy

Laura Atzori

Dermatology Unit, University of Campania Luigi Vanvitelli, 81055, Naples, Italy

Anna Balato

Dermatology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy

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Angelo Cattaneo

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Andrea Chiricozzi

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Paolo Gisondi

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Claudio Guarneri

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Serena Lembo

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Giovanni Palazzo

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Aurora Parodi

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Dermatology Unit, Department of Medicine, University of Padova, Padua, Italy

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UOC Dermatologia, Dermatology Unit, “Daniele Innocenzi,” ASL Latina, 04100, Latina, Italy

Department of Health Science Section of Dermatology, University of Florence, 50121, Florence, Italy

Francesca Prignano

Dermatology Unit, Azienda Ospedaliero Universitaria Pisana, Ospedale Santa Chiara, 56126, Pisa, Italy

Marco Romanelli

Department of Health Science, University of Eastern Piedmont, 28100, Novara, Italy

Paola Savoia

Dermatology Section, Department of Medicine and Surgery, University of Perugia, 06123, Perugia, Italy

Luca Stingeni

U.O.S.D. Dermatologica - Centro per la cura della psoriasi, Ospedale A. Perrino, Brindisi, Italy

Massimo Travaglini

Unit of Dermatology, Department of Medical, Surgical and Neurological Sciences, University of Siena, 53100, Siena, Italy

Emanuele Trovato

Dermatology Department, University of Brescia and ASST Spedali Civili Hospital, 25123, Brescia, Italy

Marina Venturini

Dermatology Unit, UOC Dermatologia, Ospedale S A Antonio Abate, ASP Trapani, 91016, Erice, Italy

Leonardo Zichichi

Dermatology Unit, Department of Biomedical Sciences, Humanitas University, 20072, Pieve Emanuele, Italy

Antonio Costanzo

Dermatology Unit, IRCCS Humanitas Research Hospital, 20089, Rozzano, Milano, Italy

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Paolo Amerio, Laura Atzori, Anna Balato, Federico Bardazzi, Luca Bianchi, Angelo Cattaneo, Andrea Chiricozzi, Maurizio Congedo, Antonio Costanzo, Paolo Dapavo, Maria Concetta Fargnoli, Claudia Giofrè, Paolo Gisondi, Claudio Guarneri, Serena Lembo, Francesco Loconsole, Piergiorgio Malagoli, Giampiero Mazzocchetti, Santo Raffaele Mercuri, Pietro Morrone, Anna Maria Offidani, Giovanni Palazzo, Aurora Parodi, Giovanni Pellacani, Stefano Piaserico, Concetta Potenza, Francesca Prignano, Marco Romanelli, Paola Savoia, Luca Stingeni, Massimo Travaglini, Emanuele Trovato, Marina Venturini, Leonardo Zichichiparticipated in the study outline and realization, critically revised the content of the manuscript and agreed to submit the manuscript for publication.

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Correspondence to Antonio Costanzo .

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Paolo Amerio declares the following conflicts of interest: Novartis, Sanofi, Jannsen, Eli Lilly, Galderma. Laura Atzori has been consultant, PI, speaker for Abbvie, Novartis, Janssen, UCB Pharma, Sanofi Genzyme, Lilly, Pfizer, Almirall, BMS. Anna Balato has served on Scientific Boards and/or has received fees for Scientific Consultations from: Abbvie, Amgen, Boehringer Ingelheim, Janssen, Eli-Lilly, Novartis, UCB. Luca Bianchi has been consultant, PI, speaker for Abbvie, Novartis, Janssen, UCB Pharma, Sanofi Genzyme, Lilly, Pfizer, Almirall, Sun Pharma, BMS. Andrea Chiricozzi has served as advisory board member and consultant and has received fees and speaker's honoraria or has participated in clinical trials for AbbVie, Almirall, Bristol Myers Squibb, Leo Pharma, Lilly, Janssen, Novartis, Pfizer and Sanofi Genzyme. Antonio Costanzo has been principal investigator in clinical trials sponsored by and/or and has received personal fees for participation in advisory board from Abbvie, Almirall, Amgen, Boehringer, BMS, Leo Pharma, Lilly, Novartis, Pfizer, UCB and Sanofi, outside the submitted work. Maria Concetta Fargnoli has served on advisory boards, received honoraria for lectures and/or research grants from AMGEN, Almirall, Abbvie, Boehringer-Ingelheim, BMS, Galderma, Kyowa Kyrin, Leo Pharma, Pierre Fabre, UCB, Lilly, Pfizer, Janssen, MSD, Novartis, Sanofi-Regeneron, Sunpharma. Claudia Giofrè has served as advisory board member or has received fees and speaker or has participated in clinical trials for Amgen, Novartis, Janssen, Leo Pharma, Almirall, Abbvie, UCB, Lilly. Paolo Gisondi declares the following conflicts of interest: Amgen, Almirall Abbvie Eli Lilly Novartis Janssen UCB Pierre Fabre Pfizer. Claudio Guarneri declares the following conflicts of interest: Pfizer, Abbvie, Janssen, Novartis, Merck-Serono, Eli-Lilly, Celgene, Leo Pharma, Leo Pharma Denmark, Almirall, Amgen, Sanofi-Aventis, Boehringer-Ingelheim, Bristol Myers Squibb, UCB Pharma. Serena Lembo declares the following conflicts of interest: Pfizer, Abbvie, Janssen, Novartis, Eli-Lilly, Leo Pharma, Almirall, Sanofi-Aventis, UCB Pharma. Santo Raffaele Mercuri SRM has been principal investigator in clinical trials sponsored by and/or has received personal fees for participation in advisory board from Abbvie, Almirall, Amgen, Leopharma, Lilly, Jansenn, Novartis, Sanofi and Ucb, outside the submitted work. Pietro Morrone has served as advisory board member or has received fees and speaker for AbbVie, Almirall,Novartis, Sanofi Genzyme, Lilly, Leo Pharma. Giovanni Palazzo declares the following conflicts of interest: Novartis, Abbvie, Leopharma, Lilly, Pfizer, Janssen. Aurora Parodi declares the following conflicts of interest: Almirall, Abbvia, Amgen, Novartis, Pfizer, Lilly, LEO pharma, Euroimmun, Argx, Menarini, Boehringer. Giovanni Pellacani received institutional grants and/or honoraria for Advisory boards: Abbvie, Galderma, Leo-pharma, Lilly, Pfizer, Novartis, Sanofi, UCB. Stefano Piaserico has been a consultant and/or speaker for Abbvie, Almirall, Amgen, Janssen, LEO Pharma, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Sandoz, andUCB. Francesca Prignano served as consultant, presenter and advisory board member for Abbvie, Novartis, Eli-Lilly, Jannsen-Cilag, Bohringer- Ingelheim, Almirall, Leo-Pharma, UCB, Bristol-Meyers-Squibb. Marco Romanelli: Abbvie, Lilly, Novartis, URGO, ConvaTec. Paola Savoia has served as advisory board member or has received fees and speaker's honoraria or has participated in clinical trials for AbbVie, Almirall, Bristol Myers Squibb, Ganassini, Kyowa Kirin, Janssen, Novartis, Sanofi and Sunpharma. Luca Stingeni has been principal investigator in clinical trials sponsored by and/or and has received personal fees for participation in advisory board from Abbvie, Leo Pharma, Lilly, Novartis, Pfizer, and Sanofi, outside the submitted work. Emanuele Trovato: Speaker for Abbvie, Novartis, Janssen, UCB Pharma, Eli-Lilly, Almirall, Leo Pharma. Marina Venturini has served as advisory board member and consultant and has received fees and speaker's honoraria or has participated in clinical trials for AbbVie, Almirall, Bristol Myers Squibb, Boehringer-Ingelheim, Eli Lilly, Galderma, Janssen, Leo Pharma, Novartis, Pierre Fabre, UCB Pharma. Leonardo Zichichi has been consultant, and speaker for Abbvie, Novartis, Janssen, Sanofi Genzyme, Lilly, Almirall, Sun Pharma.

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Malagoli, P., Dapavo, P., Amerio, P. et al. Secukinumab in the Treatment of Psoriasis: A Narrative Review on Early Treatment and Real-World Evidence. Dermatol Ther (Heidelb) (2024). https://doi.org/10.1007/s13555-024-01255-4

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DOI : https://doi.org/10.1007/s13555-024-01255-4

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Knowledge, Attitude, and Practice towards Malaria among People Attending Mekaneeyesus Primary Hospital, South Gondar, Northwestern Ethiopia: A Cross-Sectional Study

Belaynesh tazebew flatie.

Biology Department, Science College, Bahir Dar University, Ethiopia

Abaineh Munshea

Associated data.

The datasets used and analyzed during the current study are available upon reasonable request from the corresponding author.

Malaria is one of the most severe public health problems worldwide. It is a leading cause of suffering, death, and socioeconomic problem, especially in many developing countries like Ethiopia. To introduce appropriate preventive and control measures, assessment of community's levels of knowledge, attitude, and preventative practices regarding malaria is crucial. This study was aimed at assessing the knowledge, attitude, and practice (KAP) towards malaria and its preventive and control methods among people attending Mekaneeyesus primary hospital, South Gondar, northwestern Ethiopia.

A hospital-based cross-sectional study was conducted from September 2017 to April 2018. A structured questionnaire was administered to collect data on sociodemographic characteristics and KAP of 390 randomly selected individuals. The data collecting tool was pretested before commencing the actual data collection. The data were analyzed using the SPSS version 21 software. P values less than 0.05 were considered statistically significant.

The overall prevalence rate of malaria in the study area was 8.5%. Nearly two-third of the participants had good knowledge (63.1%) and positive attitude (62.6%) scores towards malaria while only half of the participants had (50.8%) good practice score towards malaria prevention and control measures. Sex, age category, family monthly income, residence, and occupational and educational status of the participants were significantly associated with knowledge and practice scores ( P < 0.05). The odds of malaria were 26.93 (CI = 3.67‐197.47, P = 0.001) and 13.09 (CI = 0.93‐183.47, P = 0.036) times higher among individuals who had poor knowledge and poor practice towards malaria, respectively, as compared to individuals who were knowledgeable and had good practice score towards malaria.

The overall knowledge score, attitude, and practice level of respondents towards malaria was relatively good. However, significant proportion of the participants still have misconception about the cause, sign and symptoms, modes of transmission, and practices towards prevention methods of malaria. Thus, health education which is aimed at raising community's awareness about the disease is necessary to address the gaps identified by this study.

1. Introduction

Malaria is a serious mosquito borne infectious disease caused by an obligate intracellular protozoan parasite of the genus Plasmodium . There are five Plasmodium species causing malaria in human, P. falciparum , P. vivax , P. malaria , P. ovale , and P. knowlesi. P. falciparum and P. vivax account for more than 95% of the cases of malaria worldwide. P. falciparum is fatal in its characteristics and responsible for most of the malaria overall deaths [ 1 ].

Despite being preventable and curable, malaria continues to have a devastating impact on people's health and livelihoods around the world. According to the latest world malaria report, there were an estimated 229 million malaria cases and 409,000 deaths globally in 2019 [ 2 ]. Above and beyond such a huge health consequence, malaria imposes a heavy economic burden on individuals, households, and the entire economy [ 3 ]. Sub-Saharan African countries carried a disproportionately high share of the global malaria burden and accounted for 94% of all malaria cases and deaths [ 2 ].

In Ethiopia, about 75% of the land mass is malarious and 68% of the country's population is at risk of malaria due to climatic and ecological conditions favorable for its transmission. Around 4 up to 5 million cases of malaria and 70,000 related deaths are reported annually in Ethiopia [ 4 ]. Malaria still remains to be a leading public health problem and has been one of the main causes of hospitalization and deaths in the country [ 5 , 6 ].

Malaria can easily be prevented through individual and societal combined efforts by keeping the environment safe, effective utilization of long lasting insecticide nets (ITNs), and early diagnosis and prompt treatment [ 7 , 8 ]. Widespread control and elimination measures were implemented through international and national malaria control programs; however, malaria continues to be the most important parasitic disease worldwide. In Ethiopia, the key malaria control strategies are prompt diagnosis and immediate treatment of cases. Besides these, there are other strategies like outbreak investigation and arrest, mosquito vector control, and environmental management. Indoor residual sprays and insecticide-treated nets are also used at a large [ 9 ].

The scope of malaria control is changing worldwide with more emphasis is being placed on community and individual participation in malaria control and prevention measures than on exclusive use of insecticides. In this regard, understanding the level of knowledge, attitude, and practices of individuals and communities towards the disease and its risk factors is crucial to ensure appropriate intervention measures [ 10 ]. Health education can improve participation in malaria control, when such education is designed to address gaps in the knowledge, attitudes, and practice of individuals in the communities [ 11 , 12 ].

Knowledge, attitude, and practice (KAP) studies are a useful method to design and execute malaria prevention and control programs. Several studies have shown that improving community's knowledge, attitudes, and practices can play an effective role in controlling the spread and reducing the burden of malaria [ 13 , 14 ].

Varying reports regarding the knowledge about malaria in different parts of Africa and around the world reveal that gap in the knowledge about the malaria disease condition may lead individuals not to actively participate in the control programs [ 15 ]. The knowledge of the community is far from perfect, and misconceptions are rampant. Despite reasonable knowledge on malaria and its preventive measures, there is a need to improve availability of information through proper community channels. Special attention should be given to illiterate community members. High acceptance of indoor residual spraying and high level of bed net ownership should be taken as an advantage to improve malaria control [ 16 ].

Many of the human behaviors favor malaria transmission stem from broad social, cultural, and economic forces. In addition to these broad social forces, malaria transmission and control are invariably affected by local beliefs, attitudes, and practices [ 17 ]. It is clear that a change in behavior is an important component in malaria prevention and control, but the basis of the behavior elucidated by determining the levels of malaria knowledge, attitude, and practices of the community is even more crucial [ 15 ]. Knowledge in malaria reinforces the capacity of the host to affect transmission intensity through informing attitudes and behavior [ 18 ].

There have been a considerable number of reports about knowledge, attitudes, and practices relating to malaria and its control from different parts of Ethiopia. These reports concluded that misconceptions about the cause and transmission of malaria still exist, and that practices for the control of malaria have been inadequate [ 19 – 25 ]. In this direction, in order to create awareness in particular community, insight into the gaps of knowledge, attitudes, and practices regarding malaria is important. As well, to the best of our knowledge, no study has been conducted about the malaria knowledge, attitudes, and practices (KAP) in the population of Mekaneeyesus, Estie District, South Gondar, northwestern Ethiopia. Thus, this study was aimed at investigating knowledge, attitude, and practice towards malaria among people attending Mekaneeyesus primary hospital, South Gondar, northwestern Ethiopia (a cross-sectional study).

2. Materials and Methods

2.1. study area and design.

A cross-sectional study was conducted from September 2017 to April 2018 to evaluate the levels of knowledge, attitudes, and practices towards malaria among people attending Mekaneeyesus primary hospital, South Gondar, northwestern Ethiopia. Mekaneeyesus is the capital of Estie District. Estie is one of the 105 districts in Amhara Regional state of Ethiopia. Geographically, the study area lies on the coordinates of 11°34′N, latitude and 36°41′E, and longitude and at an altitude range of 1500-4000 meters above sea level (m.a.s.l). The minimum and maximum mean annual rainfall of the area is 1307-1500 mm, and the mean annual minimum and maximum temperature is 8.3°C-25°C. The district exhibits four climate zones: Wurch (upper highlands above 3,200 m a.s.l), Dega (highlands 2,300–3,200 m a.s.l), Woinadega (midlands 1500–2,300 m a.s.l), and Kola (lowlands 500–1500 m a.s.l). The peak times of malaria transmission occur between September and December following the main rainy season from June to August and from April to June.

Estie is about 676 km northwest of Addis Ababa, capital city of the country, and about 110 km north of Bahr Dar, the regional capital. The total area of this district is 132,373.9 km 2 . It has 42 rural and 3 urban kebeles (small administrative unit). Based on figures published by the Central Statistical Agency (CSA) in 2005, Estie has an estimated 403,956 population, of whom 199,325 are men and 204,631 are women; 16,014 (3.96%) of its population are urban dwellers.

2.2. Sample Size Determination and Sampling Techniques

The sample size of the study was determined using single population proportion formula by taking the proportion with confidence interval at 95% and alpha at 5% [ 26 ].

where n is the sample size, z is the z statistic for a level of confidence ( z = 1.96 at 95% CI), d is the precision (if 5%, d = 0.05), and p is the proportion of malaria prevalence ( p = 0.5) which was considered, since there were no similar previous studies in the study areas. Accordingly, the sample size of the study was

In addition, 5% nonresponse rate was added for individuals who fail to participate in the study. Then, the final sample size of the study was 403. Based on these assumptions, the study participants were recruited using simple random sampling technique.

2.3. Inclusion and Exclusion Criteria

Individuals who consented to participate were included in this study, while individuals who cannot communicate due to impairment or severely sick and mentally sick people and those who did not provide consent and assent were excluded from the study.

2.4. Data Collection

2.4.1. questionnaire survey.

A standard KAP questionnaire was compiled and adapted from similar previous studies to collect data on sociodemographic characteristics, knowledge and attitude of the study participants about malaria, its transmission, symptoms, preventive measures, and practices towards ITN ownership and use. The questionnaire was first developed in English and translated into the local language, Amharic, and then translated back to English to check consistency and phrasing of difficult concepts.

The knowledge scores of the participants towards malaria were determined as follows. The response to each correct knowledge question was given a score of 1 while a wrong or unsure response was scored as 0. The original Bloom's cut-off points where a score of 80.0%–100.0% of correct responses meant a good knowledge, a score of 60.0%–79.0% put a scorer in a level of satisfactory knowledge, and a poor knowledge was for the respondents with a score ≤ 59.0% of the correct responses were adapted and modified. Attitude was assessed by Likert's scaling technique. The questions on Likert's scaling had positive and negative responses that ranged from strongly agree (score 5), agree (score 4), undecided (score 3), disagree (score 2), to strongly disagree (score 1). The responses were summed up, and a total score was obtained for each respondent. The mean score was calculated, and respondents with score of greater than or equal to the mean score (4.14) were considered as having positive attitude while those with score of less than the mean score (4.14) were taken as having negative attitude towards malaria.

Practices of the participants were also determined using Likert's scaling method. The scoring system of Likert's type scales with respect to respondents response ranging from never (score 0), sometimes (score 1), to always (score 2) were used. The responses were summed up, and total score was obtained for each respondent, and mean practice score was computed across all the study participants. An individual was claimed as having good practice when his/her overall practice score (1.03) was equal to or more than the mean practice score. However, an individual was considered as having poor practice when his/her overall practice score is less than the mean practice score (1.03).

2.4.2. Laboratory Examination and Parasite Detection

Capillary blood samples were collected by finger pricking using 70% isopropanol and sterile disposable lancet. Immediately, thin film was spread on grease free, frosted end of labeled slide using a smooth edged slide spreader. The thick smear was also prepared on the same slide by spreading larger drop of blood. The thin blood smear was allowed to air dry for 10 minutes and then fixed with absolute methanol for 5 seconds and then air-dried. The thick smears were air-dried for about 30 minutes, not fixed in methanol but dipped in water to dehaemoglobinize. The blood films were stained with 10% Giemsa for 10 minutes [ 27 ]. Finally, the films were examined under the microscope using an oil immersion microscope objective (100x) for detection of Plasmodium spp.

2.5. Data Analysis

The data gathered were double entered in to Microsoft Excel data sheets and were crosschecked and imported into SPSS version 21 for analysis. Descriptive statistics was carried out to measure relative frequencies and percentages of the variables. Frequency distribution tables were used to present sociodemographic variables, knowledge and attitude of respondents related to symptoms, causes, transmission, prevention and control measures of malaria, and practices towards malaria prevention and control methods.

Logistic regression analysis was performed to examine associations between variables by using odds ratio. Variable having significance at P values 0.25 in univariate test was selected and entered for multivariate logistic regression analysis to identify the most important predictors of malaria risk [ 28 ]. Odds ratios (ORs) were calculated with 95% confidence interval (CI). P values less than 0.05 were considered statistically significant.

2.6. Data Quality Control

The questionnaire was compiled and adapted from similar previous malaria indicator survey questionnaires. Before going to the actual data collection, the questionnaire was pretested to ensure the validity of the data collection tool. A pretest was carried out on 19 individuals (5% of the calculated sample size) that were not part of the sample population in the actual study at Mekaneeyesus hospital. The data gathered were double entered in to Microsoft Excel data sheets and were crosschecked and imported into SPSS version 21 for analysis.

2.7. Ethical Consideration

The study protocol of the research was reviewed and approved by the Ethical Review Committee under the research and community service coordinating office of College of Science, Bahir Dar University. Mekaneeyesus primary hospital granted permission for the study to be conducted at the target outpatient department after explaining the objective of the study. Informed written and oral consent was also obtained from the study participants before interview. For those who did not read and understand the consent form, the objectives of the study were explained to them and verbal consent was obtained. For children less than 18 years old, consent was obtained from their parents or guardians.

3.1. Sociodemographic Characteristics

Of the total 403 individuals invited, 390 (97.0%) participated in the study and the remaining 13 (3.0%) individuals who refused to participate were excluded from the study. About 211 (54.1%) of the participants were males, and the remaining 179 (45.9%) were females. The mean age of the sampled population was 31.48 ± 15.62 years, and the highest number of participants (108 (27.7%)) was within the age range of 25-34 years. More than half (242 (62.1%)) of the respondents were urban residents, and majority (186 (47.7%)) were married. The educational background of the study participants varied from those who were illiterate to those who attained the levels of college and above ( Table 1 ).

Sociodemographic characteristics of respondents in Mekaneeyesus hospital, South Gondar, northwestern Ethiopia, 2018.

3.2. Knowledge about Malaria

Amharic version of malaria is known as “webba,” which is the most commonly used term in the study areas. Most of the participants (336 (86.2%)) attributed a mosquito bite as the cause of malaria. Misconceptions regarding the causes of malaria were also reflected in 10 (2.6%) of the subjected who related it with flies, and surprisingly, 44 (11.3%) of the participants did not know the cause of malaria. The majority (320 (82.1%)) of respondents had knowledge how malaria is transmitted, and more than three quarter (294 (75.4%)) of the study subjects implicated anopheles mosquitoes in the transmission of malaria. However, few participants had misconceptions about the mode of malaria transmission, and the remaining 66 (16.9%) did not know how malaria is transmitted ( Table 2 ).

Knowledge of respondents related to cause, sign and symptoms, transmission of malaria, and mosquito breeding areas, Mekaneeyesus hospital, South Gondar, northwestern Ethiopia, 2018.

Two hundred sixty-five (67.9%), 80 (20.5%), 41 (10.5%), and 4(1.0%) of the study participants mentioned that stagnant water, tall grass, bushes, and running water can serve as breeding sites of mosquitoes, respectively. Most (354 (90.8%)) of the respondents identified that mosquitoes bite during night time. Almost all respondents identified the major sign and symptoms of malaria correctly; 386 (99.0%), 382 (97.9%), 383 (98.2%), and 377 (96.7%) mentioned fever, headache, chill and shivering, and loss of appetite as symptoms of malaria, respectively. In the present study, 256 (65.6%) and 251 (64.4%) of study participants identified underfive children and pregnant women as the most susceptible segments of the population to malaria, respectively ( Table 2 ).

In response to knowledge about indoor preventing methods of malaria, most of the respondents (218 (55.9%)) considered using insecticide-treated bed net (ITN) as the best indoor intervention method for preventing and controlling the disease, while only 21.8% of respondents believed that malaria can be prevented using indoor residual spray (IRS), and few of them mentioned fumigation (3(0.8%)) as one of the preventive measures. Regarding the knowledge of the study participants towards the outdoor preventive methods of malaria, majority, 85.6 and 93.1%, of them mentioned that malaria can be prevented by avoiding weeds and stagnant water, respectively, whereas about one in ten (9.5%) mentioned the use of insecticide spray ( Table 2 ).

The respondents of this study had information about malaria from varied sources, of which 255 (65.4%) received information through radio/television, 249 (63.8%) from hospital, 242 (62.1%) from health extension workers, 168 (43.1%) from family, 166 (42.6%) from teachers, and 165 (42.3%) from neighbors/friends ( Figure 1 ).

Sources of information about malaria as reported by respondents in Mekaneeyesus hospital, 2018.

3.3. Attitudes towards Malaria

From the total respondents, 361 (92.5%) agreed the seriousness and threat posed by malaria. The larger proportion (320 (82.2%)) of the subjects agreed that malaria is a preventable disease. The vast majority of participants (351 (90%)) felt worried when mosquitoes are nearby. Most (382 (97.9%)) of the study participants mentioned that they sleep under a mosquito net during the night to prevent themselves from mosquito bite. On the other hand, 360 (92.3%) of respondents agreed on risk incurred when malaria medicine is not taken properly and completely; however, about 4 (1%) and 26 (6.4%) of the study participants disagreed and remain neutral to this statement, respectively ( Table 3 ).

The study participants' response towards attitude questions, Mekaneeyesus hospital, South Gondar, northwestern Ethiopia, 2018.

3.4. Practices towards Malaria

Interestingly, majority of the study participants (320 (82.1%)) responded that they always visit health center/clinic when they or their family members get sick. More than half (216 (55.4%)) of the study participants reported that they always sleep under insecticide-treated mosquito nets, and 170 (43.6%) had the habit of checking the presence of holes/repair in the mosquito nets to avoid the mosquito bite. Nobody (0%) had the practice of constantly draining standing water where anopheles mosquito may breed. Of the total respondents, 268 (68.7%) reported that they sometimes drain stagnant water or moist areas around their residence, while 248 (63.6%) of the respondents preferred trimming bushes where mosquitoes rest and hide during the daytimes ( Table 4 ).

Participants response to good practice questions related to treatment, prevention, and control of malaria, Mekaneeyesus hospital, 2018.

This study revealed that the majority (325 (83.3%)) of respondents had the practice of utilizing bed net while the remaining 65 (16.7%) had no the practice of using ITN. Of total number of the study participants who did not use ITN, about1 0.3% reported that they lack awareness about the use of ITN, while majority of them (64 (16.7%)) reported unavailability of ITN in local markets ( Figure 2 ).

Practice of using ITN among the respondents in Mekaneeyesus hospital, 2018.

3.5. Overall Knowledge, Attitude, and Practice (KAP) Scores of the Study Participants and Its Association with Prevalence of Malaria

Assessment of knowledge score revealed that 246 (63.1%), 92 (23.6%), and 52 (13.3%) of the study participants had good (knowledgeable), satisfactory, and poor knowledge about malaria, respectively. With regard to attitude, nearly two-third (62.6%) of the study participants had positive attitude while the remaining146 (37.4%) had negative attitude towards malaria in terms of its seriousness or threat, prevention, and control. The study participants' overall practice score towards malaria prevention and control was calculated, and practice level was determined by comparing one's practice score against the mean practice score. Accordingly, nearly equal proportion of study participants had good (50.8%) and poor (49.2%) practice towards malaria prevention and control measures ( Table 5 ).

Cross tabulation of Chi-square analyses of association of overall knowledge, attitude, and practice scores of the study participants with the prevalence of malaria.

Out of the 390 microscopically examined blood samples, 33 samples were found positive for malaria infection with the overall prevalence rate of 8.5%. In Chi-square analyses, the prevalence of malaria was significantly associated with the overall KAP scores of the study participants ( P < 0.05) ( Table 5 ).

3.6. Associations of Knowledge and Practice Scores of the Study Participants with Sociodemographic Status

In Chi-square analysis, marital status was not significantly associated with knowledge score of the respondents ( P = 0.129). However, the other sociodemographic and environmental risk factors were significantly associated with knowledge score of the respondents towards malaria ( Table 6 ).

Chi-square analyses of the associations of knowledge scores and practice scores of the study participants with sociodemographic status.

Females were more knowledgeable (69.8%) about malaria than their male counterparts (57.3%). Similarly, significantly higher proportion of females had good practices (57.0%) towards malaria than males (45.5%). Conversely, significantly higher proportion of males (54.5%) had poor practices towards malaria than females (43.0%) ( Table 6 ).

There was a statistically significant association between residence and knowledge score of the participants about the cause, sign and symptoms, modes of transmission, and prevention of malaria ( P = 0.001). In this study, most (75.2%) of urban dwellers had good knowledge score about malaria than their rural counterparts (43.2%), while poor knowledge score about malaria was more evident among rural (24.3%) than urban residents (6.6%). Similarly, there was a statistically significant association between residence and practice score of respondents towards malaria treatment, prevention, and control measures ( P = 0.001). Majority (61.2%) of urban residents had good practices towards malaria than rural (33.8%) residents; on the contrary, larger proportion (66.2%) of participants from rural setting had poor practices towards malaria than urban (38.8%) residents ( Table 6 ).

Educational status of the study participants was significantly associated with the knowledge and practice scores towards malaria ( P = 0.05). There was an increasing tendency in good knowledge and practice scores as educational statuses of the study participants go from uneducated to college and above. The highest good knowledge scores were recorded among those who attained high school (82.9%) and college and above (84.3%) education, who also had the lowest poor knowledge scores, 4.9% and 2.5%, respectively. With regard to practices of respondents towards malaria, the highest good practice score was observed among participants who attained college and above (74.2%) education followed by those who attained secondary (41.5%) and primary school (28.6%) education, while the lowest good practice score towards malaria was recorded among uneducated (20.2%) subjects ( Table 6 ).

This study found a statistically significant association between family monthly income and knowledge and practice scores of the participants towards malaria ( P < 0.05). Individuals with the highest monthly income, 2000 and above Ethiopian birr per month, had the highest of good knowledge (84.3%) and good practice score (70.4%), whereas participants with lowest monthly income had the lowest good knowledge (37.8%) and good practice scores (23.0%) towards malaria ( Table 6 ).

3.7. Multivariate Logistic Regression Analysis of Malaria Prevalence with KAP Scores

In multiple regression analysis, the odds of malaria was significantly twenty seven times higher in individuals who had poor knowledge (AOR = 26.93, 95% CI 3.67-197.47, and P = 0.001) than those who had good knowledge, while statistically nonsignificant three times (AOR = 2.97, 95% CI 0.51-17.46, and P = 0.228) increased risk of malaria infection was detected among participants with satisfactory knowledge score as compared to those with good knowledge score. Prevalence of malaria did not show any significant association with regard to attitude levels of the present participants. On the other hand, the odds of positive malaria diagnosis was thirteen times higher in those who had poor practice than those who had good practice, and it was statistically significant (AOR = 13.09, 95% CI 0.93-183.47, and P = 0.036) ( Table 7 ).

Multivariate logistic regression analysis of malaria prevalence with KAP.

Note: N : total number of study participants; n : positive for Plasmodium infection. a Reference category; COR: crude odds ratio, sig. at 0.25; AOR: adjusted odds ratio, ∗ sig. at P < 0.05.

4. Discussion

Of the total 390 individuals participated in this study, majority (82.1%) mentioned that they know how malaria is transmitted, and 86.2% and 75.4% of them associated mosquito bite as a cause of malaria and means of disease transmission, respectively. This observation supports finding of another study conducted in Tanzania, which reported that more than 80% of participants had knowledge about malaria transmission [ 29 ]. This finding is also comparable with the reports of the studies in Swaziland [ 30 ], Northwest Tanzania [ 16 ], India [ 31 ], and Mexico [ 32 ]. However, finding of this study is higher than the one reported in India [ 10 ] and Nigeria [ 33 ]. Contrary to this finding, study conducted in Shashogo District of Ethiopia reported a very low knowledge level of respondents about the mode of malaria transmission where only 15.6% of the participants associated mosquitoes with malaria [ 34 ]. Besides, studies conducted in Ethiopia such as in Assosa Zone, Western Ethiopia, found that less than half (47.5%) of the study participants mentioned mosquito bites as a mode of malaria transmission, and thirty percent (30%) of them were aware that mosquitoes are the carriers of disease causing microorganism [ 10 ], and a report in Amhara region, Ethiopia, revealed that 32.3% of the study participants implicated mosquito bite in transmission of malaria [ 17 ].

In present study, almost all respondents identified the major sign and symptoms of malaria correctly; 386 (99.0%), 382 (97.9%), 383 (98.2%), and 377 (96.7%) mentioned fever, headache, chill and shivering, and loss of appetite as symptoms of malaria, respectively. This finding is comparable with a finding of study conducted in Karachi [ 35 ] and two other studies conducted in Ethiopia [ 10 , 36 ].

Knowledge about mosquito behaviors, resting and breeding places and feeding time, is important to take appropriate malaria preventive actions and proper use of ITNs. Observations regarding breeding sites of mosquitoes showed that 265 (67.9%) of the study participants associated it with stagnant water. The result is consistent with some other study done in India [ 37 ] and in Shashogo District, Southern Ethiopia [ 34 ]. In our study, the proportion of subjects who knew stagnant water as mosquito breed site is lower as compared with a report of a study conducted in Tepi Town, Sheka zone, Southwestern Ethiopia, in which most (96.4%) of the community members were aware that the mosquito breeds in stagnant water [ 38 ]. However, the present result is higher than a finding reported from India, where less than half (32.7%) of the respondents knew that mosquitoes most commonly breed in stagnant water [ 31 ].

It was also observed that most (354 (90.8%)) of participants in our study identified that mosquitoes bite during night time. This is similar with what was reported in Assosa Zone, Western Ethiopia, where most (95%) of respondents replied that mosquitoes bite in the night [ 10 ]. Participants' knowledge about mosquitoes feeding time in this study is encouraging when compared to 56.5% report from India [ 31 ].

In the present study, 256 (65.6%) and 251 (64.4%) of study participants identified correctly underfive children and pregnant women as the most susceptible group of the population to malaria, respectively. This result concurs with the findings of similar studies conducted in Kenya [ 8 ] and Southwestern Ethiopia [ 30 ]; in both cases, significant proportion of the participants identified underfive children and pregnant women as the most vulnerable segment of the population to malaria. This is mainly due to the fact that children under five years of age have less developed and weak immunity that makes them more vulnerable to diseases compared to adults and pregnant women have semicompromised immunity.

In this study, 361 (92.5%) of the respondents agreed the seriousness and threat posed by malaria and 320 (82.2%) of the subjects agreed with the statement that malaria is preventable disease, which is comparable with the study conducted in Shewa Robit, Ethiopia, in which about 90.58% respondents believed that malaria is preventable disease [ 36 ].

It was also revealed that the majority (325 (83.3%)) of respondents of the current study had the practice of utilizing bed net while the remaining 65 (16.7%) had no the practice of using ITN. Of total number of the study participants who did not use ITN, about 0.3% reported that they lack awareness about the use of ITN, while majority of them (64 (16.7%)) reported unavailability of ITN in local markets. However, nobody reported the expensiveness of ITNs. ITN utilization practice coverage observed in our study is in agreement with 85 and 78% bed net utilization results reported in Karachi [ 35 ] and in Swaziland [ 30 ], respectively. The rate of ITN utilization practice in our study is slightly lower compared to a finding of a study in Colombia, where most of the study population (>90%) had a practice of using ITNs [ 39 ]. The bed net utilization practice observed in the current study is also relatively similar with the one reported from Southern Mexico, in which most (76%) used them bed net all year round [ 32 ]. However, these respondents did not associate bed net utilization with malaria prevention rather with protection against mosquito bite. Another study conducted in Southwestern Ethiopia reported 65.0% bed net utilization rate, which is far less than our finding. Of the remaining 35.0% of the participants who did not use bed net, most (77.0%) replied that they were not lucky to use bed nets due to lack of access, 8.0% associated their failure to use bed net with lack of awareness, and the remaining 15.0% suggested other reasons [ 38 ]. The difference in bed net utilization rates across studies and communities might be due to variations in monthly income, availability of bed net in markets, and unevenness in distribution of bed net, and in some cases, it may due to differences in awareness among the studied communities [ 40 ].

Nearly two-third (63.1%) of the study participants had good knowledge score about malaria. This is lower when compared with a study from Southern Ethiopia, where 74.3% of respondents had good knowledge [ 36 ]. However, it is encouraging when compared to finding of a study conducted in Champasack Province, Lao PDR, where 59.1% of respondents had good knowledge [ 41 ]. Likewise, a report of a study from Mumbai, India, revealed that 53.7% respondents had an average level and very few have high level of knowledge [ 42 ]. Differences in demographic, socioeconomic, educational, and cultural factors among communities and the absence, inaccessibility, or inaccuracy of information about the disease could affect knowledge scores.

This study revealed that 244 (62.6%) of the study participants had positive attitude while remaining 146 (37.4%) had negative attitude towards malaria in terms of its seriousness or threat, prevention, and control. This is lower when compared with the reports of 97.0% and 78.1% positive attitudes of the participants towards malaria prevention in Karachi [ 35 ] and in Amhara National Regional State of Ethiopia [ 17 ], respectively.

In this study, half (50.8%) of the study participants had good practice score towards malaria prevention and control measures. Similar studies done in Sri Lanka [ 43 ] and Southern Ethiopia [ 34 ] reported fairly good practice towards malaria prevention and control measures. Our result is lower when compared to the finding of another study conducted in Southern Ethiopia, where 67.7% of the study participants had good practice in terms of malaria treatment, prevention, and control [ 10 ] and a study from Karachi that reported 59% good practice [ 35 ]. Conversely, a study conducted among population in Paksong District, Champasack Province, LAO PDR, found only 5.7% good practice regarding malaria prevention [ 41 ]. These discrepancies in implementation of good practices towards malaria prevention and control might be due to differences in sociodemographic characteristics (gender, age, educational, and income levels), the community's awareness about malaria, and their attitudes towards malaria prevention and control.

In this study, female participants were found to be more knowledgeable (69.8%) about malaria than their male counterparts (57.3%), suggesting a need for awareness creation towards malaria for the males. This is supported by study conducted in Ha-Lambani, Limpopo Province, South Africa [ 44 ], which also reported that more female participants had knowledge on malaria transmission and symptoms than males. Similarly, significantly higher proportion of females (57.0%) had good practices towards malaria than males (45.5%) ( P = 0.05). Conversely, considerably higher proportion of males (54.5%) had poor practices towards malaria than females (43.0%). This is in conformity with the finding that reported statistically significant association between practice level and gender of participants, in which greater proportion (45.0%) of female participants had good practice towards malaria than males (28.1%); contrarily, substantially higher percentage (71.9%) of male participants had poor practice level towards malaria as compared with female participants (55.0%) [ 45 ]. This could be due to the fact that women in developing countries mainly take the role of looking after their family members. Conversely, our finding does not agree with the findings of studies conducted in Ethiopia [ 46 ] and Cabo Verde [ 47 ].

Participants in age categories 15-24 and 25-34 years old had the highest good knowledge. This is in line with study done by [ 46 ]. The finding of this study contradicts with the reports of studies conducted in Cabo Verde [ 47 ] and Myanmar [ 48 ], which showed an increase in the scores of good knowledge and good practice towards malaria as the ages of the study participants' increase.

In this study, there was a significant increasing tendency in good knowledge and practice scores as educational level of the study participants increases from uneducated to college and above levels ( P = 0.05). The highest good knowledge scores were recorded among those who attained college and above (84.3%) and high school (82.9%) education, who also had the lowest poor knowledge scores, 2.5% and 4.9%, respectively. Likewise, the highest good practice score was observed among participants who attained college and above (74.2%) education followed by those who attained secondary (41.5%) and primary school (28.6%) education, while the lowest good practice score towards malaria was recorded among uneducated (20.2%) subjects. This could be explained by the fact that illiterate people and those with low levels of education might not be able to understand and access health education information conveyed through various mass media appropriately. This could lead to poor knowledge score about malaria, which consecutively affects their action towards malaria prevention and control measures. Our findings are consistent with the studies conducted in Indonesia [ 49 ] and Cameroon [ 50 ].

This study found statistically significant association between family monthly income and knowledge and practice scores of the participants towards malaria ( P < 0.05). Individuals with the highest monthly income, 2000 and above Ethiopian birr per month, had the highest of good knowledge (84.3%) and good practice score (70.4%), whereas participants with lowest monthly income had the lowest good knowledge (37.8%) and good practice scores (23.0%) towards malaria. This can be attributed to an increase in the family monthly income which may lead to increase in the opportunity of accomplishing supplies for protecting. The result of the present study is coincident with the reports of a study in Myanmar [ 48 ].

In this study, there was a statistically significant association between residence and knowledge score of the participants about the cause, sign and symptoms, and methods of transmission and prevention of malaria ( P = 0.001). The finding of this study showed that living in the urban area increased the level of knowledge on malaria. Most (75.2%) of urban dwellers had good knowledge score towards malaria than their rural counterparts (43.2%), while poor knowledge score about malaria was more evident among rural (24.3%) than urban residents (6.6%). This may be due to the fact that women from urban residence may have more exposure and access for education and health-related information via mass media than those from rural areas. This finding is supported by studies done in Ethiopia and Malawi, which state that participants from urban residence were more knowledgeable than rural areas, as rural residence may hinder people to access health information and health literacy [ 51 , 52 ]. However, contrary to our finding, Kimbi and his coworkers in Cameroon found no statistically significant difference in malaria knowledge level between participants from rural (98.04%) and urban (98.97%) areas [ 53 ].

In this study, the odds of malaria infection in individuals who had poor knowledge and poor practice were 26.93 and 13.09 times higher, respectively, as compared to individuals who were knowledgeable and had good practice towards malaria. Similar findings were found in the study done in south-central Ethiopia [ 54 ], but respondent's knowledge about malaria was not significantly associated with malaria risk. It is likely to argue that increased level of knowledge on malaria is associated with reduced risk of malaria. People who have a high level of knowledge are in a better position to protect them against malaria.

5. Conclusion and Recommendation

In this study, the overall knowledge score, attitude, and practice level of the study population towards malaria was relatively good. However, substantial proportion of the participants still have misconception about the cause, sign and symptoms, modes of transmission, and practices towards prevention methods of malaria. Thus, health education which is aimed at raising community's awareness about the disease is necessary to address the gaps identified by this study.

Acknowledgments

All the community members in the study area are deeply acknowledged for their cooperation in this work by providing necessary response to questionnaire. This study was financially supported by Bahir Dar University.

Data Availability

Ethical approval.

The study was reviewed and approved by the Ethical Review Board of Science College, Bahir Dar University.

Conflicts of Interest

The authors declare that they have no competing interests.

Authors' Contributions

Both authors designed the current study and were involved in data collection, analysis and interpretation of the results, and the write-up of the manuscript. The authors read and approved the manuscript.

• Open access
• Published: 19 September 2024

Why becoming a positive deviant for malaria prevention and control: a sequential explanatory mixed methods study in Bugesera district, Rwanda

• Domina Asingizwe 1 , 2 ,
• Malachie Tuyizere 2 ,
• Madeleine Mukeshimana 3 ,
• Theogene Nyandwi 2 ,
• Chris Adrien Kanakuze 4 &
• Emmanuel Hakizimana 5  

Malaria Journal volume  23 , Article number:  284 ( 2024 ) Cite this article

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Malaria continues to be a significant global health challenge, particularly in sub-Saharan African regions. Effective prevention and control strategies are crucial in mitigating its impact. Therefore, assessing the use of malaria preventive measures, treatment-seeking behaviours, and understanding the motivating factors behind positive behaviours/practices and barriers to using malaria preventive and control measures is essential for designing successful intervention programs.

Using a sequential explanatory mixed methods design, a descriptive cross-sectional study was conducted among 382 heads of households in the Mareba sector, Bugesera district, Rwanda. A qualitative study followed with 30 in-depth interviews among the top performers and other community members to explore the motivations and barriers to performing positive behaviours. Descriptive statistics for quantitative data and thematic analysis for qualitative data were used.

This study revealed that among those who own insecticide-treated nets, 234(89.3%) reported that they slept under the bed net the night preceding the survey; 256(67%) had fever cases in the last 24 months preceding the survey; and 214(87%) reported seeking care within 24 h. While almost all 243(98.8%) of participants who had fever case reported that they have taken all medicines as prescribed, however, a large number 263(68.8%) and 148(38.7%) still think that there are people in the community who do not take all malaria medications as prescribed and there are people who share malaria medications in the community, respectively. 82(65.1%) of those who never had a fever case believe that they have been using malaria preventive measures correctly and consistently. This study found that knowledge about malaria, family support, and community mobilization are the top motivating factors to practice positive behaviours while, lack of bet nets, poverty, and lack of time were reported as main barriers.

Interventions that target key motivating factors for adopting positive behaviours in malaria prevention and control should be prioritized. This, in turn, will reduce the disease burden on affected populations. Efforts to overcome barriers in malaria prevention and control should also be participatory. Community involvement should be at the centre of these interventions.

Malaria remains a public health concern globally, especially in developing countries [ 1 ]. In 2022, the global malaria burden reached an estimated 249 million cases, marking a worrisome increase of 5 million cases compared to the previous year [ 1 ]. In 2022, Africa continued to emerge as the epicentre of reported malaria cases and fatalities, comprising 93.6% of global cases and 95.4% of global deaths. Of significant concern is the fact that 78.1% of all malaria deaths on the continent were among children under the age of five, marking a noteworthy decrease from the 90.7% documented in 2000 [ 1 ].

Between 2019 and 2022, several African countries saw a significant rise in malaria cases: Nigeria (5.3 million), Ethiopia (2.4 million), Madagascar (1.5 million), Uganda (1.3 million), Tanzania (1.3 million), Mali (1.1 million), and Mozambique (1 million). In contrast, Rwanda reported a decrease of over 3.8 million cases during the same period [ 1 , 2 ].

The decrease in malaria cases in Rwanda may be linked to nationwide mobilization efforts, including the adoption of interventions, such as indoor residual spraying (IRS), insecticide-treated nets (ITNs), and improved malaria case management [ 3 ]. Additionally, institutional and individual research initiatives in high-endemic areas have involved community engagement, capacity building, and local priority setting [ 4 , 5 ]. Furthermore, research efforts also utilized citizen science to monitor ecological changes and disseminate malaria prevention messages, enhancing the effectiveness of control measures and health literacy [ 6 , 7 ].

Malaria prevention and control are multifaceted endeavours, influenced by an array of factors spanning social, structural, community, and individual levels [ 1 , 2 , 8 ]. At the social and structural level, access to healthcare services, infrastructure, and resources play pivotal roles. Adequate funding for malaria control programmes, availability of diagnostic tools, and distribution of effective medications are vital aspects of this framework [ 8 ]. Community engagement and participation in preventive measures such as ITNs distribution campaigns, IRS initiatives, and community-based health education programs can greatly impact malaria transmission rates [ 9 , 10 ]. On an individual level, factors such as personal behaviours, knowledge, and socioeconomic status heavily influence malaria risk and control efforts. Practices like consistent use of bed nets, seeking prompt treatment upon experiencing symptoms, and adherence to prescribed medication regimens are critical in reducing malaria transmission.

In an attempt to eliminate malaria to achieve universal health coverage, different methods and tools were put in place to achieve this overarching goal. The positive deviance(PD) approach is one among others which focuses on community-driven approaches to behaviours change that are applied to address many health and social problems [ 11 , 12 , 13 ]. Positive deviants are outliers who display uniquely positive behaviours compared to their peers in similar circumstances. This concept originated in early 20th-century sociology, which examined human behaviours and social dynamics [ 11 ]. This approach targets remote and high-risk population and this was tested to be a novel tool for malaria control and elimination [ 13 ].

The effectiveness of Positive Deviance (PD) in malaria control and elimination was tested in Cambodia using a qualitative approach. It was well-received, fostering community empowerment and behaviours change, leading to increased net use among forest goers and greater utilization of public health facilities for malaria diagnosis and treatment [ 12 ]. In Uganda, positive deviants and related drivers concerning the consistent use of bed nets indicated that the drivers identified were proved to play a role in designing an effective social behaviours change programme and other strategies that may support the distribution and use of bed nets [ 14 ]. PD presents the potential to target remote areas where in most cases the current active surveillance activities do not reach, thus, creating a high level of community mobilization [ 15 ].

In Rwanda, to achieve the set target towards malaria elimination, preventive measures and treatment-seeking behaviours among community members need to be determined especially in high endemic regions. Besides, positive deviant actions as well as barriers that hinder positive behaviours among community members towards malaria elimination need to be unpacked by community members themselves. Therefore this study was conducted to address the following research objectives: (1) to assess the use of malaria preventive measures and treatment-seeking behaviours among community members; (2) to identify positive deviants among community members; (3) to explore motivations of their positive behaviours; and (4) to explore barriers that hinder positive behaviours among community members.

Study setting

This study was conducted in the Mareba sector of Bugesera district, a high malaria prevalence area in Rwanda’s Eastern Province. The sector covers 55.91 km 2 and has a population of 29,266, according to the 2022 census. It comprises 10 cells, which are further divided into villages.

Study design

Using a sequential explanatory mixed methods design, a descriptive cross sectional study was conducted. The quantitative approach was used to determine the extent of using malaria control measures and treatment-seeking behaviours among community members in the Mareba sector and also identify positive deviants according to preset criteria. A qualitative study followed to explore the motivations of doing positive behaviours among positive deviance and also explore barriers that hinder positive behaviours among both positive deviants and the rest of the community members.

Study population and sampling

Quantitative phase.

The targeted population encompassed all household heads residing within the Mareba sector, Bugesera district. A total of 382 households were selected. A multistage sampling strategy was adopted for the study. The Mareba sector, which comprises five cells and each cell contains between five to six villages. The village served as a primary sampling unit.

At the cell level, two villages were selected through simple random sampling, ensuring representative coverage across the sector’s geographic and demographic diversity. Subsequently, at the village level, household lists furnished by village leaders facilitated systematic random sampling to determine the households to be visited, ensuring a methodical and unbiased selection process.

Qualitative phase

The qualitative part involved included 30 in-depth interviews. These included 15 positive deviants to explore motivations of their positive behaviours and 15 other community members to explore barriers that hinder positive behaviours among community members. These participants were purposively selected based on their reported use of malaria preventive measures and ever had fever cases in the last 24 months.

Data collection tools

For the quantitative part, a questionnaire was designed by experts based on study objectives and also on variables collected from similar studies in the literature [ 16 ]. For the qualitative part, an interview guide was developed to identify motivations and barriers to the positive behaviours/practices.

Data collection

Data collection was done in three steps. The first step consisted of determining the baseline information which gives a picture of to what extent community members use malaria control measures, their knowledge about control measures and treatment-seeking behaviours, consulting, visiting, and buying anti-malarial medicine in the pharmacies, and adherence to malaria medicines. In addition to the questionnaire, a standardized checklist was filled based on the observations of the data collector/researcher to check and verify some of the measures already identified with the questionnaire. Data collection took place from November 2022 by three experienced data collectors.

The second step consisted identification of positive deviants (those who have achieved unexpected good behaviours despite being at high risk like others in the same community) based on the findings from both the questionnaire and checklist. The positive deviants were defined as those who never had a fever case in the last 24 months, who do not have bushes and stagnant water around the house, and the bed nets are hung up (observed) after reporting that they have slept in the bed net the night preceding the survey. The least performers were the ones with opposite behaviours of those with positive deviants. These were identified from the data set.

The third step involved interviewing positive deviants and least performers to document the ‘positive deviant’ practices and barriers for the least performers. This was done in April 2023.

Data analysis

Quantitative data were analysed using SPSS software. Descriptive statistics are mainly presented in terms of the consistent use of malaria control measures and treatment-seeking behaviours. Qualitative data were analysed using Atlas ti software. A qualitative content analysis was used to code, interpret, and present qualitative data. To make sure that all codes were captured, an inductive method was used. Audio-recorded data were transcribed and coded to develop themes.

This section is presented in two sections starting with quantitative results.

Quantitative data

Sociodemographic characteristic.

As shown in Table  1 , the mean age of respondents was 43, and female respondents were slightly more 220 (57.6%) than male. Based on the 2015 wealth categorization locally known as Ubudehe categories, ranging from 1 (the poorest) to 4 (the wealthiest), the majority of the study participants 215 (56.3%) were in the third category, while 111(29.1%) were in the second category. Majority 261(68.3%) were married, 266(69.6%) of the respondents were protestants.

Attitude towards malaria prevention and treatment

Table 2 presents the attitude towards malaria prevention and treatment. Overall, there were positive attitudes on the use of malaria preventive measures and positive attitudes were reported by almost all male and female participants. In total, 377 (98.7) reported that sleeping under bed nets every night prevented malaria, 381 (99.7) reported that clearing mosquito breeding sites was important to prevent family members from getting sick from malaria, and all 382(100%) respondents noted that it is important to have indoor residual spraying in their homes. However, 67(17.5) of the participants still believe that the use of bed nets brings bed bugs and other insects into the house compared to only 33(8.6%) who believed that indoor residual spraying brings other insects such as bedbugs, and fleas in their homes. the cost of bed nets was mentioned as a barrier to the majority of the participants 391(76.2%) and 95 (24.9%) reported that lack of bed frame made the use of bed nets difficult. On the other hand, a majority of 275(72%) of the participants also believed that they could buy bet nets in case they do not have enough for their families.

Similar to malaria preventive measures, positive attitudes were reported for malaria treatment. Overall, almost all participants 381(99.7%) believed that it is important to seek care if any family member presents with some of malaria symptoms, it is important to test for malaria before obtaining malaria medications 380(99.5%), and it is important to take all malaria medications as prescribed 377(98.7%). However, more than half 263(68.8%) thought that some people in their community would not take malaria drugs as prescribed by the health provider, and 148 (38.7%) believed that some members of their community shared malaria drugs.

Malaria preventive measures

Table 3 presents the ITNs’ ownership and use of malaria preventive measures. Of all respondents, 262(68.6%) own at least one LLIN and the majority 182(69.5%) got them from the health center while. Only 95 (36.2%) reported having enough bed nets (one bed net for two people). The majority 234(89.3%) reported having slept under the bed net the night preceding the survey. slept under the bed net the night before the survey. However, only a quarter of the respondents own sufficient LLINs. Half of the respondents reported that they sleep under the bed net all the time as for children. Another 105(27.5%) used measures other than bed nets to prevent malaria and those measures include mainly cutting bushes 67(63.8%), clearing stagnant water 64(61%), and closing windows and doors early in the evenings 46(42.8%). As shown in Table  4 , generally the respondents’ home environment was clean as 360(94.2%) had no stagnant water, and 329 (86.1%) had no bushes around their home. However, among those who reported owning bed nets, 218(83.2%) of households had them hung up.

Malaria treatment-seeking behaviours

As shown in Table  5 , in 24 months that preceded the survey, 256(67%) of households visited reported to have suffered fever. 246(96.1%) were taken for treatment, mostly 216(84.4%) at a health facility and community health workers 24(9.4%). For most of the cases, the care was sought either the same day (day of onset of the fever 100(40.7%) or the next day 114(46.3%). During the care for fever, malaria testing was conducted in most of the cases 227 (92.3%). At least 238 (96.7%) received treatment for fever, and 243 (98.8%) confirmed that sick persons took the medicines as they were prescribed. Of those who never had fever cases 126(33%) in the 24 months that preceded the survey, 82(65.1%) respondents reported that they had not fallen sick because they used malaria preventive measures correctly and consistently.

Family support in malaria prevention and care-seeking

Table 6 presents the family support in the dimension of malaria prevention and care seeking. Of all respondents, 231(60.5%) of which 118(53.6%) were female and 113(69.8%) males feel much supported by their families in using malaria preventive measures while 29(7.6%) both male and female combined feel not supported at all. Quite similar proportions were reported for family support in seeking care at the health centre in case a family member has malaria. In addition, the support from a partner or family in getting malaria testing before obtaining medication, and in taking prescribed anti-malarial medication was similarly reported.

Collective actions towards malaria prevention and control

As shown in Table  7 , over half of the study respondents often and very often participate in malaria-related activities among social/community work and in clearing mosquito breeding sites in the village, this is slightly higher among males than females.

Positive deviants among community members and motivation of their positive behaviours

Table 5 indicates that 126(33%) did not have malaria cases in the previous 24 months preceding the survey. Among this, the majority 82(65.1%) believe that they never had malaria cases because they have been using malaria preventive measures correctly and consistently.

Qualitative results

Qualitative findings indicated that motivations of and barriers to practicing positive behaviours.

Motivations

Motivations were divided into the following two main categories that emerged from the analysis: (1) knowledge and understanding of malaria disease as well as; (2) support and mobilization. These are described in detail in the following section.

Knowledge and understanding of malaria disease

Participants who never had a malaria case in the 24 months preceding the survey indicated that knowledge and understanding about malaria disease was a key motivation to use preventive measures consistently. This emerged into two main categories: malaria prevention and consequences associated with malaria.

Malaria prevention

Participants described that malaria is not good at all, therefore, they use malaria preventive measures to prevent it so that their family members will not fall sick. This was described as follows:

“Our motivation to consistently adopt malaria prevention measures stems from the understanding that falling ill is undesirable, and malaria, in particular, poses significant health risks. The continual reliance on medical consultations is not ideal, prompting individuals to seek protection to ensure the well-being of themselves and their families.” (Positive deviant, No 1) “Our efforts in malaria prevention are driven by the desire to safeguard people from falling ill. The motivation behind this initiative is rooted in the realization that illness hinders an individual's ability to manage their affairs effectively.” (Positive deviant, No 2)

Besides, some respondents were motivated to provide protection to young children as a vulnerable group. One participant stated:

“We use preventive measures to protect children from contracting malaria and to prevent any other factors that could lead to their illness.” (Positive deviant, No 15)

Consequences associated with malaria

Participants described malaria as a threat that cause several consequences and you waste much time and resources. Several participants described it as follows:

“My reasons to use to use preventive measures are driven by the clear understanding that malaria, upon affecting an individual, inevitably induces weakness and illness. Taking care of a malaria patient not only consumes valuable time and resources but also hinders me from fulfilling my intended responsibilities……” (Positive deviant, No 1) Another respondent explained: “When you have malaria, it also affects your productivity because if there is no malaria at home, you will not go to for treatment, children go to school well, thus you have time to work for your family”. (Positive deviant, No 19)

Support and mobilization

Apart from knowledge about malaria as a threat and the consequences of malaria, positive deviants also described how support from family members, community members, and local leaders helped them to use malaria preventive measures consistently. These were described as follows:

“The administration promotes maintaining a clean environment as a preventive measure against malaria, and our families actively join in these efforts to collectively minimize the risk of contracting the disease.” (Positive deviant, No 16) “For the past five years, my family has remained malaria-free. Community health workers consistently motivate us to combat stagnant water and trim bushes where mosquitoes hide. These efforts are actively carried out during the village general assembly.” (Positive deviant, No 18)

Barriers that hinder positive behaviours among community members

Participants who reported having had malaria cases, also reported barriers that hinder them to consistently use malaria preventive measures. This emerged into three categories: (1) lack of bed nets; (2) poverty; and (3) lack of time.

Lack of bed nets

Lack of bed nets was clearly reported as a significant factor that hindered its use, hence family members get malaria. This was described by participants as follows:

“The challenge lies in obtaining bed nets as they tend to be expensive. However, obstacles associated with clearing bushes and stagnant water are not significant barriers, as these tasks neither demand a substantial financial investment nor require excessive effort.” (Negative deviant, No 13)

Poverty was explained to be one of the barriers to hinder either buying or replacing the damaged bed nets.

“The primary issue is poverty, as I lack the financial means to replace damaged bed nets.” (Negative Deviant, No 8)

Lack of time

Because of poverty people go to find other means of living and then lack time to clear their home environment. This was explained as follows:

“The sole impediment is poverty, which consequently results in a shortage of time. While one might suggest taking care of these tasks, the reality is that the pressing need to secure food for the family takes precedence. As I mentioned earlier, the desire to maintain a clean home environment is there, but the constraint of time becomes a limiting factor.” (Negative deviant, No 11)

This study was conducted to assess the use of malaria preventive measures and treatment-seeking behaviours among community members, identify positive deviants among community members, explore motivations of their positive behaviours; and explore barriers that hinder positive behaviours among community members.

Generally, study participants reported positive attitudes toward malaria preventive and control measures including the fact that IRS and use of bed nets prevent malaria. These results corroborate with previously published studies [ 17 , 18 ] which reported that the majority of study participants agreed that malaria is a serious and life-threatening disease and believe that everybody can contract malaria. The current results may be because respondents know the consequences of malaria, therefore this has influenced their attitudes. The reported positive attitudes is key as it may lead to the use of these measures to prevent and control malaria.

Besides, the study participants also reported some positive attitudes toward adherence to malaria medicines, and this is similar to what was reported previously in similar studies [ 17 , 18 ]. However, a significant number of respondents believe that there are people in their community who do not take all malaria medications as prescribed and there are people who share malaria medications in the community. This merits attention as it may increase over or under treatment which may in turn increase resistance to medications.

The study findings show that the majority of respondents own the LLINs (they got them from the health center), and most of the respondents 234 (89.3%) slept under bed nets the night preceding the survey as the main preventive measure. This concurs with the findings from other studies [ 19 , 20 ] where a high proportion of participants reported that the use of treated bed nets is the most appropriate measure to protect themselves from mosquito bites. They further ranked this measure as their first choice in the prevention of malaria. From this study, higher ITN ownership and utilization may be allocated to the national effort through the Ministry of Health (MoH) as part of its preventive measures for malaria, where MoH conducts regular mass distribution campaigns of Insecticide-Treated Net (ITN) to rapidly increase and sustain ITN coverage. This is in line with the qualitative findings where positive deviants highlighted family protection from malaria illness, especially children as among the key motivations to use preventive measures.

Good treatment-seeking behaviours have been reported in the current study. Health facilities continue to be the most common place of treatment reported among the study participants and the percentage of those seeking care within 24 h is high. Besides, almost all participants reported that they took all medications as prescribed. The current results are slightly higher than the results reported in a study conducted in Senegal [ 17 ] and lower than those reported in Ghana [ 18 ]. The current findings may be due to the current positive attitudes and also high level of family support reported.

Knowledge about malaria, family support, and community mobilization were reported as the top motivating factors to practice positive behaviours. Understanding the transmission dynamics, symptoms, preventive measures, and treatment options empowers people to take proactive steps to protect themselves and their families. Furthermore, strong familial bonds can serve as a motivating factor for adopting positive practices, such as sleeping under ITNs, seeking timely medical care, and maintaining a clean environment to reduce mosquito breeding sites. Mobilizing communities through collective action and community engagement is instrumental in promoting positive behaviour change related to malaria prevention and control. Community-led initiatives, including health education campaigns, participatory workshops, and community-based distribution of preventive tools, can foster a sense of ownership and responsibility among community members [ 4 , 5 , 6 , 21 ]. By involving local leaders, community health workers, and other stakeholders, these initiatives harness social networks and cultural norms to promote the adoption of malaria prevention behaviours [ 6 ]. Interventions targeting these factors can contribute to significant improvements in malaria-related outcomes, ultimately reducing the burden of the disease on affected populations.

Lack of bet net, poverty, and lack of time were reported as the main barriers to using malaria prevention and control measures. This finding broadly supports the work of other studies in this area which revealed that access to these nets remains a significant challenge in many malaria-endemic regions [ 16 , 22 , 23 ]. Where the ITNs are available, sometimes households face competing financial priorities, leading to suboptimal investment in malaria prevention. Time scarcity and competing demands on individuals' schedules pose significant challenges to engaging in malaria prevention activities. In many low-income settings, individuals are engaged in subsistence agriculture or informal labour, leaving limited time for activities such as seeking preventive healthcare or attending community health education sessions. Addressing these barriers requires multifaceted approaches that encompass not only the provision of free or subsidized mosquito nets but also strategies aimed at community engagement, and behaviours change communication. Sustainable solutions must take into account the complex interplay between socioeconomic factors and health-seeking behaviours to achieve meaningful progress in malaria prevention and control efforts.

This study aimed at assessing the use of malaria preventive measures and treatment seeking behaviours among community members, identifying positive deviants among community members, exploring motivations of their positive behaviours; and exploring barriers that hinder positive behaviours among community members. More than half of the study participants owned an ITN. Among those who own ITNs, the majority reported that they slept under the bed net the night preceding the survey. For treatment-seeking behaviours, more than half had a fever case in the last 24 months preceding the survey and majority reported seeking care within 24 h. While almost all of the participants who had a fever case reported that they had taken all medicines as prescribed, however, a big number still think that there are people in the community who do not take all malaria medications as prescribed and there are people who share malaria medications in the community. This requires careful attention and education about the benefits of taking medications as prescribed. This study found that knowledge about malaria, family support, and community mobilization are the top motivating factors to practice positive behaviours while lack of bet net, poverty, and lack of time were reported as main barriers to using malaria prevention and control measures. In conclusion, interventions targeting key motivating factors that influence the adoption of positive behaviours for malaria prevention and control if well conducted, can contribute to significant improvements in malaria-related outcomes, ultimately reducing the burden of the disease on affected populations. In addition, overcoming barriers to malaria prevention and control should be participatory and involve community members at the center of all interventions.

Availability of data and materials

The datasets used in this study are available from the corresponding author on a reasonable request.

Abbreviations

In-depth interviews

Indoor residual spraying

Insecticide-treated nets

WHO. World malaria report 2023. Geneva: World Health Organization; 2023.

Google Scholar  

WHO. World malaria report 2022. Geneva: World Health Organization; 2022.

Ministry of Health. Rwanda malaria programme mid term review. 2023.

Ingabire CM, Hakizimana E, Kateera F, Rulisa A, Van Den Borne B, Nieuwold I, et al. Using an intervention mapping approach for planning, implementing and assessing a community-led project towards malaria elimination in the Eastern Province of Rwanda. Malar J. 2016;15:594.

Article   PubMed   PubMed Central   Google Scholar  

Ingabire CM, Alaii J, Hakizimana E, Kateera F, Muhimuzi D, Nieuwold I, et al. Community mobilization for malaria elimination: application of an open space methodology in Ruhuha sector, Rwanda. Malar J. 2014;13:167.

Asingizwe D, Poortvliet P, van Vliet AJ, Koenraadt CJ, Ingabire CM, Mutesa L, Leeuwis C. What do people benefit from a citizen science programme? Evidence from a Rwandan citizen science programme on malaria control. Malar J. 2020;19:283.

Asingizwe D, Murindahabi MM, Koenraadt CJ, Poortvliet PM, Van Vliet AJ, Ingabire CM, et al. Co-designing a citizen science program for malaria control in Rwanda. Sustainability. 2019;11:7012.

Article   Google Scholar  

WHO. World malaria report 2021. Geneva: World Health Organization; 2021.

Phok S, Tesfazghi K, Tompsett A, Thavrine B, Ly P, Hassan SE, et al. Behavioural determinants of malaria risk, prevention, and care-seeking behaviours among forest-goers in Cambodia. Malar J. 2022;21:362.

Koenker H, Keating J, Alilio M, Acosta A, Lynch M, Nafo-Traore F. Strategic roles for behaviour change communication in a changing malaria landscape. Malar J. 2014;13:1.

Wolfer TA, Wilson B. Seeking champions for change: a positive deviance approach for social work. Fam Soc. 2019;100:151–63.

Shafique M, Edwards H, De Beyl CZ, Thavrin BK, Min M, Roca-Feltrer A. Positive deviance as a novel tool in malaria control and elimination: methodology, qualitative assessment and future potential. Malar J. 2016;15:91.

Foster BA, Seeley K, Davis M, Boone-Heinonen J. Positive deviance in health and medical research on individual level outcomes–a review of methodology. Ann Epidemiol. 2022;69:48–56.

Article   PubMed   Google Scholar  

Ong KI, Jimba M. Positive deviance leading and coping with social change. In: Baikady R, Sajid SM, Nadesan V, Przeperski J, Islam MR, Gao J, editors. The Palgrave handbook of global social change. Cham: Springer; 2023.

Alzunitan MA, Edmond M, Alsuhaibani MA, Samuelson RJ, Schweizer ML, Marra AR. Positive deviance in infection prevention and control: a systematic literature review. Infect Control Hosp Epidemiol. 2022;43:358–65.

Asingizwe D, Poortvliet P, Koenraadt CJ, Van Vliet AJ, Ingabire CM, Mutesa L, et al. Role of individual perceptions in the consistent use of malaria preventive measures: mixed methods evidence from rural Rwanda. Malar J. 2019;18:270.

Tairou F, Nawaz S, Tahita MC, Herrera S, Faye B, Tine RC. Malaria prevention knowledge, attitudes, and practices (KAP) among adolescents living in an area of persistent transmission in Senegal: results from a cross-sectional study. PLoS ONE. 2022;17: e0274656.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Lopez AR, Brown CA. Knowledge, attitudes and practices regarding malaria prevention and control in communities in the Eastern region, Ghana, 2020. PLoS ONE. 2023;18: e0290822.

Musoke D, Miiro G, Karani G, Morris K, Kasasa S, Ndejjo R, et al. Promising perceptions, divergent practices and barriers to integrated malaria prevention in Wakiso district, Uganda: a mixed methods study. PLoS ONE. 2015;10: e0122699.

Andegiorgish AK, Goitom S, Mesfun K, Hagos M, Tesfaldet M, Habte E, et al. Community knowledge and practice of malaria prevention in Ghindae, Eritrea, a cross-sectional study. Afr Health Sci. 2023;23:241–54.

Asingizwe D, Poortvliet P, Koenraadt CJ, van Vliet AJ, Ingabire CM, Mutesa L, et al. Why (not) participate in citizen science? Motivational factors and barriers to participate in a citizen science program for malaria control in Rwanda. PLoS ONE. 2020;15: e0237396.

Asingizwe D, Poortvliet P, Koenraadt CJ, Van Vliet AJ, Murindahabi MM, Ingabire C, et al. Applying citizen science for malaria prevention in Rwanda: an integrated conceptual framework. NJAS-Wagening J Life Sci. 2018;86:111–22.

Akello AR, Byagamy J, Etajak S, Okadhi CS, Yeka A. Factors influencing consistent use of bed nets for the control of malaria among children under 5 years in Soroti district, North Eastern Uganda. Malar J. 2022;21:363.

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Acknowledgements

Special thanks to Bugesera district and Mareba sector leadership who collaboratively agreed to implement this study in Mareba sector. We also thank the Mareba community members and research assistants for their support and participation in the study.

This research did not receive funding for manuscript publication. However, it is prepared from a research project that was funded by the University of Rwanda. The funding covered research data collection and data analysis.

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Domina Asingizwe

Department of Physiotherapy, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda

Domina Asingizwe, Malachie Tuyizere & Theogene Nyandwi

Nursing Department, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda

Madeleine Mukeshimana

Midwifery Department, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda

Chris Adrien Kanakuze

Malaria and Other Parasitic Diseases, Rwanda Biomedical Center, Kigali, Rwanda

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DA conceived the study, coordinated study implementation, analysed the data, and drafted the manuscript. MT and TN collected data, participated in the data analysis, and drafting of the manuscript. MM, CAK, and EH contributed substantially to the study implementation and revision of the paper. All authors have read and approved the final manuscript.

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Correspondence to Domina Asingizwe .

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Asingizwe, D., Tuyizere, M., Mukeshimana, M. et al. Why becoming a positive deviant for malaria prevention and control: a sequential explanatory mixed methods study in Bugesera district, Rwanda. Malar J 23 , 284 (2024). https://doi.org/10.1186/s12936-024-05108-5

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Received : 17 March 2024

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DOI : https://doi.org/10.1186/s12936-024-05108-5

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The effectiveness of lee silverman voice treatment (lsvt loud) on children’s speech and voice: a scoping review.

1. Introduction

The aim of the study, 2. materials and methods, 2.1. databases and search.

• Date range of publication: the dataset for this study included all available literature without any time restrictions.
• Study design type: only research articles and no review studies.
• Study focuses on a specific disease, condition, or patient population: only children.
• Study focuses mainly on a specific intervention: LSVT LOUD
• Study took place in a certain country/hospital or other context: no restriction of the context.
• Study written in a specific language: we only included studies written in English. However, all the available studies were written in English.

2.2. Eligibility Criteria

2.3. quality assessment for scoping review study, 3.1. quality assessment, 3.2. presentation of studies, 4. discussion, 4.1. key findings.

• Speech function and sound pressure level increased.
• Auditory–perceptual ratings of voice and speech revealed improvement.
• Parents’ and expert listeners’ ratings of voice, perception of vocal loudness, speech, and communication indicated improvement.
• Significant post-treatment increases in average vocal intensity during sustained vowel phonations and sentence repetitions were observed for the preschoolers.
• Increased fractional anisotropy in several motor and association tracts was observed.
• Acoustic data on untrained tasks correlated with FA changes detected.
• Post-treatment changes in connectivity between the left supramarginal gyrus, the right supramarginal gyrus, and the left precentral gyrus for children with cerebral palsy were observed.
• Treatment enhanced the contributions of the feedback system in the speech production network.
• Increased acoustic vowel space was found.
• Articulatory accuracy and single-word intelligibility improved immediately post-treatment.
• Individual and environmental features affected fast-phase and long-phase responses to LSVT LOUD.
• Intensity (dose) is necessary but not sufficient for change.
• Weak responders may require a more extended treatment phase, better timing, and a more prominent desire to communicate successfully. In contrast, strong responders benefit from treatment intensity and saliency and intrinsic and extrinsic rewards for using the trained skills for everyday communication.
• Children with DS tolerated intensive voice treatment without adverse effects and made select meaningful therapeutic gains.

4.2. Strengths and Limitations

5. conclusions, author contributions, institutional review board statement, informed consent statement, data availability statement, conflicts of interest.

• Duff, M.C.; Proctor, A.; Yairi, E. Prevalence of voice disorders in African American and European American preschoolers. J. Voice 2004 , 18 , 348–353. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Possamai, V.; Hartley, B. Voice disorders in children. Pediatr. Clin. N. Am. 2013 , 60 , 879–892. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Mohammadzadeh, A.; Sandoughdar, N. Prevalence of voice disorders in iranian primary school students. J. Voice 2017 , 31 , 263.e13–263.e18. [ Google Scholar ] [ CrossRef ]
• Campano, M.; Cox, S.R.; Caniano, L.; Koenig, L.L. A Review of voice disorders in school-aged children. J. Voice 2023 , 37 , 301.e1–301.e7. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• McKinnon, D.H.; McLeod, S.; Reilly, S. The prevalence of stuttering, voice, and speech-sound disorders in primary school students in Australia. Lang. Speech Hear. Serv. Sch. 2007 , 38 , 5–15. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Mohamadi, O.; Rahimi-Madiseh, M.; Sedehi, M. The prevalence of stuttering, voice disorder, and speech sound disorders in preschoolers in Shahrekord, Iran. Int. J. Child Youth Fam. Stud. 2016 , 7 , 456. [ Google Scholar ] [ CrossRef ]
• Bhattacharyya, N. The prevalence of pediatric voice and swallowing problems in the U nited S tates. Laryngoscope 2015 , 125 , 746–750. [ Google Scholar ] [ CrossRef ]
• Levy, E.S.; Chang, Y.M.; Ancelle, J.A.; McAuliffe, M.J. Acoustic and perceptual consequences of speech cues for children with dysarthria. J. Speech Lang. Hear. Res. 2017 , 60 , 1766–1779. [ Google Scholar ] [ CrossRef ]
• Mei, C.; Reilly, S.; Reddihough, D.; Mensah, F.; Morgan, A. Motor speech impairment, activity, and participation in children with cerebral palsy. Int. J. Speech Lang. Pathol. 2014 , 16 , 427–435. [ Google Scholar ] [ CrossRef ]
• Rupela, V.; Velleman, S.L.; Andrianopoulos, M.V. Motor speech skills in children with Down syndrome: A descriptive study. Int. J. Speech Lang. Pathol. 2016 , 18 , 483–492. [ Google Scholar ] [ CrossRef ]
• Simões-Zenari, M.; Nemr, K.; Behlau, M. Voice disorders in children and its relationship with auditory, acoustic and vocal behavior parameters. Int. J. Pediatr. Otorhinolaryngol. 2012 , 76 , 896–900. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Adriaansen, A.; Meerschman, I.; Van Lierde, K.; D’Haeseleer, E. Effects of voice therapy in children with vocal fold nodules: A systematic review. Int. J. Lang. Commun. Disord. 2022 , 57 , 1160–1193. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• McAllister, A.; Sjölander, P. Children’s voice and voice disorders. In Seminars in Speech and Language ; Thieme Medical Publishers: New York, NY, USA, 2013; pp. 71–79. [ Google Scholar ]
• Nip, I.S.B.; Garellek, M. Voice quality of children with cerebral palsy. J. Speech Lang. Hear. Res. 2021 , 64 , 3051–3059. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Nordberg, A.; Miniscalco, C.; Lohmander, A. Consonant production and overall speech characteristics in school-aged children with cerebral palsy and speech impairment. Int. J. Speech Lang. Pathol. 2014 , 16 , 386–395. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Nip, I.S.B.; Arias, C.R.; Morita, K.; Richardson, H. Initial observations of lingual movement characteristics of children with cerebral palsy. J. Speech Lang. Hear. Res. 2017 , 60 , 1780–1790. [ Google Scholar ] [ CrossRef ]
• Allison, K.M.; Hustad, K.C. Impact of sentence length and phonetic complexity on intelligibility of 5-year-old children with cerebral palsy. Int. J. Speech Lang Pathol. 2014 , 16 , 396–407. [ Google Scholar ] [ CrossRef ]
• Novak, A. The voice of children with Down’s syndrome. Folia Phoniatr. Logop. 1972 , 24 , 182–194. [ Google Scholar ] [ CrossRef ]
• Moura, C.P.; Cunha, L.M.; Vilarinho, H.; Cunha, M.J.; Freitas, D.; Palha, M.; Pueschel, S.M.; Pais-Clemente, M. Voice parameters in children with down syndrome. J. Voice 2008 , 22 , 34–42. [ Google Scholar ] [ CrossRef ]
• Hseu, A.F.; Spencer, G.P.; Jo, S.; Clark, R.; Nuss, R.C. Laryngeal pathologies in dysphonic children with Down Syndrome. Int. J. Pediatr. Otorhinolaryngol. 2022 , 157 , 111118. [ Google Scholar ] [ CrossRef ]
• Chin, C.J.; Khami, M.M.; Husein, M. A general review of the otolaryngologic manifestations of Down Syndrome. Int. J. Pediatr. Otorhinolaryngol. 2014 , 78 , 899–904. [ Google Scholar ] [ CrossRef ]
• Braden, M.; Abbott, K.V. Advances in pediatric voice therapy. Perspect. ASHA Spéc. Interest Groups 2018 , 3 , 68–76. [ Google Scholar ] [ CrossRef ]
• Braden, M.; Thibeault, S.L. Outcomes of voice therapy in children with benign vocal fold lesions. Int. J. Pediatr. Otorhinolaryngol. 2020 , 136 , 110121. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Fujiki, R.B.; Thibeault, S.L. Pediatric voice therapy: How many sessions to discharge? Am. J. Speech Lang. Pathol. 2022 , 31 , 2663–2674. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Hseu, A.F.; Spencer, G.; Woodnorth, G.; Kagan, S.; Kawai, K.; Nuss, R.C. Barriers to voice therapy in dysphonic children. J. Voice 2023 , 37 , 410–414. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Trani, M.; Ghidini, A.; Bergamini, G.; Presutti, L. Voice therapy in pediatric functional dysphonia: A prospective study. Int. J. Pediatr. Otorhinolaryngol. 2007 , 71 , 379–384. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Salderay, Z.E.; Yılmaz, M.; Altınyay, Ş.; Gölaç, H.; Gökdoğan, Ç. The effect of an indirect voice therapy approach on the voice of children with vocal fold nodules: A prospective cohort study. J. Voice 2022 , 38 , 858–863. [ Google Scholar ] [ CrossRef ]
• Van Stan, J.H.; Roy, N.; Awan, S.; Stemple, J.; Hillman, R.E. A taxonomy of voice therapy. Am. J. Speech Lang. Pathol. 2015 , 24 , 101–125. [ Google Scholar ] [ CrossRef ]
• Behrman, A.; Rutledge, J.; Hembree, A.; Sheridan, S. Vocal hygiene education, voice production therapy, and the role of patient adherence: A treatment effectiveness study in women with phonotrauma. J. Speech Lang. Hear. Res. 2008 , 51 , 350–366. [ Google Scholar ] [ CrossRef ]
• Carding, P.N.; Horsley, I.A.; Docherty, G.J. A study of the effectiveness of voice therapy in the treatment of 45 patients with nonorganic dysphonia. J. Voice 1999 , 13 , 72–104. [ Google Scholar ] [ CrossRef ]
• Holmberg, E.B.; Hillman, R.E.; Hammarberg, B.; Södersten, M.; Doyle, P. Efficacy of a behaviorally based voice therapy protocol for vocal nodules. J. Voice 2001 , 15 , 395–412. [ Google Scholar ] [ CrossRef ]
• Dromey, C.; Nissen, S.L.; Roy, N.; Merrill, R.M. Articulatory changes following treatment of muscle tension dysphonia: Preliminary acoustic evidence. J. Speech Lang. Hear. Res. 2008 , 51 , 196–208. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Roy, N.; Bless, D.M.; Heisey, D.; Ford, C.N. Manual circumlaryngeal therapy for functionaldysphonia: An evaluation of short- and long-term treatment outcomes. J. Voice 1997 , 11 , 321–331. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Mathieson, L.; Hirani, S.; Epstein, R.; Baken, R.; Wood, G.; Rubin, J. Laryngeal Manual Therapy: A Preliminary Study to Examine its Treatment Effects in the Management of Muscle Tension Dysphonia. J. Voice 2009 , 23 , 353–366. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Mathieson, L. The evidence for laryngeal manual therapies in the treatment of muscle tension dysphonia. Curr. Opin. Otolaryngol. Head Neck Surg. 2011 , 19 , 171–176. Available online: https://journals.lww.com/co-otolaryngology/fulltext/2011/06000/the_evidence_for_laryngeal_manual_therapies_in_the.8.aspx (accessed on 22 August 2024). [ CrossRef ] [ PubMed ]
• Sabol, J.W.; Lee, L.; Stemple, J.C. The value of vocal function exercises in the practice regimen of singers. J. Voice 1995 , 9 , 27–36. [ Google Scholar ] [ CrossRef ]
• Stemple, J.C.; Lee, L.; D’Amico, B.; Pickup, B. Efficacy of vocal function exercises as a method of improving voice production. J. Voice 1994 , 8 , 271–278. [ Google Scholar ] [ CrossRef ]
• Verdolini, K.; Druker, D.G.; Palmer, P.M.; Samawi, H. Laryngeal adduction in resonant voice. J. Voice 1998 , 12 , 315–327. [ Google Scholar ] [ CrossRef ]
• Yiu, E.M.-L.; Lo, M.C.; Barrett, E.A. A systematic review of resonant voice therapy. Int. J. Speech Lang. Pathol. 2017 , 19 , 17–29. [ Google Scholar ] [ CrossRef ]
• Kotby, M.N.; El-Sady, S.R.; Basiouny, S.E.; Abou-Rass, Y.A.; Hegazi, M.A. Efficacy of the accent method of voice therapy. J. Voice 1991 , 5 , 316–320. [ Google Scholar ] [ CrossRef ]
• Bassiouny, S. Efficacy of the Accent Method of Voice Therapy. Folia Phoniatr. Logop. 1998 , 50 , 146–164. [ Google Scholar ] [ CrossRef ]
• Kotby, M.N.; Fex, B. The accent method: Behavior readjustment voice therapy. Logoped. Phoniatr. Vocol. 1998 , 23 , 39–43. [ Google Scholar ]
• Verdolini-Marston, K.; Burke, M.K.; Lessac, A.; Glaze, L.; Caldwell, E. Preliminary study of two methods of treatment for laryngeal nodules. J. Voice 1995 , 9 , 74–85. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Ramig, L.O.; Countryman, S.; Thompson, L.L.; Horii, Y. Comparison of two forms of intensive speech treatment for parkinson disease. J. Speech Lang. Hear. Res. 1995 , 38 , 1232–1251. [ Google Scholar ] [ CrossRef ]
• Ramig, L.O.; Sapir, S.; Fox, C.; Countryman, S. Changes in vocal loudness following intensive voice treatment (LSVT ) in individuals with Parkinson’s disease: A comparison with untreated patients and normal age-matched controls. Mov. Disord. 2001 , 16 , 79–83. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Yuan, F.; Guo, X.; Wei, X.; Xie, F.; Zheng, J.; Huang, Y.; Huang, Z.; Chang, Z.; Li, H.; Guo, Y.; et al. Lee Silverman Voice Treatment for dysarthria in patients with Parkinson’s disease: A systematic review and meta-analysis. Eur. J. Neurol. 2020 , 27 , 1957–1970. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sapir, S.; Ramig, L.O.; Spielman, J.L.; Fox, C. Formant Centralization ratio: A proposal for a new acoustic measure of dysarthric speech. J. Speech Lang. Hear. Res. 2010 , 53 , 114–125. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Saffarian, A.; Shavaki, Y.A.; Shahidi, G.A.; Hadavi, S.; Jafari, Z. Lee Silverman voice treatment (LSVT) mitigates voice difficulties in mild Parkinson’s disease. Med. J. Islam. Repub. Iran. 2019 , 33 , 5. [ Google Scholar ] [ CrossRef ]
• Constantinescu, G.; Theodoros, D.; Russell, T.; Ward, E.; Wilson, S.; Wootton, R. Treating disordered speech and voice in Parkinson’s disease online: A randomized controlled non-inferiority trial. Int. J. Lang. Commun. Disord. 2011 , 46 , 1–16. [ Google Scholar ] [ CrossRef ]
• Spielman, J.; Mahler, L.; Halpern, A.; Gilley, P.; Klepitskaya, O.; Ramig, L. Intensive voice treatment (LSVT ® LOUD) for Parkinson’s disease following deep brain stimulation of the subthalamic nucleus. J. Commun. Disord. 2011 , 44 , 688–700. [ Google Scholar ] [ CrossRef ]
• Dumer, A.I.; Oster, H.; McCabe, D.; Rabin, L.A.; Spielman, J.L.; Ramig, L.O.; Borod, J.C. Effects of the lee silverman voice treatment (LSVT ® LOUD) on hypomimia in Parkinson’s disease. J. Int. Neuropsychol. Soc. 2014 , 20 , 302–312. [ Google Scholar ] [ CrossRef ]
• Theodoros, D.G.; Hill, A.J.; Russell, T.G. Clinical and quality of life outcomes of speech treatment for Parkinson’s disease delivered to the home via telerehabilitation: A noninferiority randomized controlled trial. Am. J. Speech-Lang. Pathol. 2016 , 25 , 214–232. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• El Sharkawi, A.; Ramig, L.; Logemann, J.A.; Pauloski, B.R.; Rademaker, A.W.; Smith, C.H.; Pawlas, A.; Baum, S.; Werner, C. Swallowing and voice effects of Lee Silverman Voice Treatment (LSVT ® ): A pilot study. J. Neurol. Neurosurg. Psychiatry 2002 , 72 , 31–36. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Spielman, J.L.; Borod, J.C.; Ramig, L.O. The effects of intensive voice treatment on facial expressiveness in Parkinson disease: Preliminary data. Cogn. Behav. Neurol. 2003 , 16 , 177–188. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Fox, C.M.; Ramig, L.O.; Ciucci, M.R.; Sapir, S.; McFarland, D.H.; Farley, B.G. The science and practice of LSVT/LOUD: Neural plasticity-principled approach to treating individuals with Parkinson disease and other neurological disorders. Semin. Speech Lang. 2006 , 27 , 283–299. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Fox, C.M.; Boliek, C.A. Intensive voice treatment (LSVT LOUD) for children with spastic cerebral palsy and dysarthria. J. Speech Lang. Hear. Res. 2012 , 55 , 930–945. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Langlois, C.; Tucker, B.V.; Sawatzky, A.N.; Reed, A.; Boliek, C.A. Effects of an intensive voice treatment on articulatory function and speech intelligibility in children with motor speech disorders: A phase one study. J. Commun. Disord. 2020 , 86 , 106003. [ Google Scholar ] [ CrossRef ]
• Boliek, C.A.; Halpern, A.; Hernandez, K.; Fox, C.M.; Ramig, L. Intensive Voice Treatment (Lee Silverman Voice Treatment [LSVT LOUD]) for Children With Down Syndrome: Phase I Outcomes. J. Speech Lang. Hear. Res. 2022 , 65 , 1228–1262. [ Google Scholar ]
• Reed, A.; Cummine, J.; Bakhtiari, R.; Fox, C.M.; Boliek, C.A. Changes in White Matter Integrity following Intensive Voice Treatment (LSVT LOUD ® ) in Children with Cerebral Palsy and Motor Speech Disorders. Dev. Neurosci. 2017 , 39 , 460–471. [ Google Scholar ] [ CrossRef ]
• McDonnell, M.N.; Rischbieth, B.; Schammer, T.T.; Seaforth, C.; Shaw, A.J.; Phillips, A.C. Lee Silverman Voice Treatment (LSVT)-BIG to improve motor function in people with Parkinson’s disease: A systematic review and meta-analysis. Clin. Rehabil. 2018 , 32 , 607–618. [ Google Scholar ] [ CrossRef ]
• Tricco, A.C.; Lillie, E.; Zarin, W.; O’Brien, K.K.; Colquhoun, H.; Levac, D.; Moher, D.; Peters, M.D.; Horsley, T.; Weeks, L.; et al. PRISMA extension for scoping reviews (PRISMA-ScR): Checklist and explanation. Ann. Intern. Med. 2018 , 169 , 467–473. [ Google Scholar ] [ CrossRef ]
• Pollock, D.; Peters, M.D.; Khalil, H.; McInerney, P.; Alexander, L.; Tricco, A.C.; Evans, C.; de Moraes, B.; Godfrey, C.M.; Pieper, D.; et al. Recommendations for the extraction, analysis, and presentation of results in scoping reviews. JBI Évid. Synth. 2023 , 21 , 520–532. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Narayana, S.; Franklin, C.; Peterson, E.; Hunter, E.J.; Robin, D.A.; Halpern, A.; Spielman, J.; Fox, P.T.; Ramig, L.O. Immediate and long-term effects of speech treatment targets and intensive dosage on Parkinson’s disease dysphonia and the speech motor network: Randomized controlled trial. Hum. Brain Mapp. 2022 , 43 , 2328–2347. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Levy, E.S.; Ramig, L.O.; Camarata, S.M. The Effects of Two Speech Interventions on Speech Function in Pediatric Dysarthria. J. Med. Speech-Lang. Pathol. 2013 , 20 , 82–87. Available online: www.cengage.com/community/JMSLP (accessed on 22 August 2024).
• Watts, C.R. Preliminary experimental evidence supports the need for further research into the effects of LSVT LOUD on voice and speech function in children with spastic cerebral palsy. Evid.-Based Commun. Assess. Interv. 2013 , 7 , 139–144. [ Google Scholar ] [ CrossRef ]
• Fortin, A.J.; Hamel, A.; Asselin-Giguère, F.; Poulin, S.; McFarland, D.H. Report on the Impact of LSVT LOUD in Improving Communication of a Preschool Child and a Young Adult With Cerebral Palsy Rapport clinique de l’impact du protocole LSVT LOUD pour améliorer la communication d’un enfant d’âge préscolaire et d’un jeune adulte ayant une paralysie cérébrale. Can. J. Speech-Lang. Pathol. Audiol. 2023 , 47 , 125–140. Available online: www.cjslpa.ca (accessed on 22 August 2024).
• Bakhtiari, R.; Cummine, J.; Reed, A.; Fox, C.M.; Chouinard, B.; Cribben, I.; Boliek, C.A. Changes in brain activity following intensive voice treatment in children with cerebral palsy. Hum. Brain Mapp. 2017 , 38 , 4413–4429. [ Google Scholar ] [ CrossRef ]
• Levy, E.S. Implementing two treatment approaches to childhood dysarthria. Int. J. Speech-Lang. Pathol. 2014 , 16 , 344–354. [ Google Scholar ] [ CrossRef ]
• Boliek, C.A.; Fox, C.M. Individual and environmental contributions to treatment outcomes following a neuroplasticity-principled speech treatment (LSVT LOUD) in children with dysarthria secondary to cerebral palsy: A case study review. Int. J. Speech-Lang. Pathol. 2014 , 16 , 372–385. [ Google Scholar ] [ CrossRef ]
• Boliek, C.A.; Fox, C.M. Therapeutic effects of intensive voice treatment (LSVT LOUD ® ) for children with spastic cerebral palsy and dysarthria: A phase I treatment validation study. Int. J. Speech-Lang. Pathol. 2017 , 19 , 601–615. [ Google Scholar ] [ CrossRef ]
• Arksey, H.; O’Malley, L. Scoping studies: Towards a methodological framework. Int. J. Soc. Res. Methodol. 2005 , 8 , 19–32. [ Google Scholar ] [ CrossRef ]
• Levac, D.; Colquhoun, H.; O’Brien, K.K. Scoping studies: Advancing the methodology. Implement. Sci. 2010 , 5 , 69. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Peters, M.D.J.; Marnie, C.; Tricco, A.C.; Pollock, D.; Munn, Z.; Alexander, L.; McInerney, P.; Godfrey, C.M.; Khalil, H. Updated methodological guidance for the conduct of scoping reviews. JBI Évid. Synth. 2020 , 18 , 2119–2126. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• López-Nieto, L.; Compañ-Gabucio, L.M.; Torres-Collado, L.; la Hera, M.G.-D. Scoping Review on Play-Based Interventions in Autism Spectrum Disorder. Children 2022 , 9 , 1355. [ Google Scholar ] [ CrossRef ]
• Papadopoulos, A.; Prentza, A.; Voniati, L.; Tafiadis, D.; Trimmis, N.; Plotas, P. Assessing the Impact of Bilingualism on the Linguistic Skills of Children with Autism Spectrum Disorder (ASD) in Greece: A Scoping Review. Medicina 2024 , 60 , 894. Available online: https://www.mdpi.com/1648-9144/60/6/894 (accessed on 22 August 2024). [ CrossRef ] [ PubMed ]
• Higgins, J.P. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1. 0 [updated March 2011]. The Cochrane Collaboration. 2011. Available online: www.cochrane-handbook.org (accessed on 22 August 2024).
• Wilson, E.M.; Abbeduto, L.; Camarata, S.M.; Shriberg, L.D. Estimates of the prevalence of speech and motor speech disorders in adolescents with Down syndrome. Clin. Linguist. Phon. 2019 , 33 , 772–789. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Gilhuber, C.S.; Raulston, T.J.; Galley, K. Language and communication skills in multilingual children on the autism spectrum: A systematic review. Autism 2023 , 27 , 1516–1531. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Fox, C.; Ebersbach, G.; Ramig, L.; Sapir, S. LSVT LOUD and LSVT BIG: Behavioral treatment programs for speech and body movement in Parkinson disease. Park. Dis. 2012 , 2012 , 391946. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Martel Sauvageau, V.; Roy, J.P.; Langlois, M.; Macoir, J. Impact of the LSVT on vowel articulation and coarticulation in Parkinson’s disease. Clin. Linguist. Phon. 2015 , 29 , 424–440. [ Google Scholar ] [ CrossRef ]
• Levy, E.S.; Leone, D.; Moya-Gale, G.; Hsu, S.C.; Chen, W.; Ramig, L.O. Vowel intelligibility in children with and without dysarthria: An exploratory study. Commun. Disord. Q. 2016 , 37 , 171–179. [ Google Scholar ] [ CrossRef ]
• Boyd, E.V. The Effects of LSVT ® LOUD and LSVT ® CLEAR on Vowel Production in STN-DBS Subjects with Idiopathic Parkinson’s Disease. Master’s Thesis, University of Colorado at Boulder, Boulder, CO, USA, 2006. [ Google Scholar ]
• Narayana, S.; Fox, P.T.; Zhang, W.; Franklin, C.; Robin, D.A.; Vogel, D.; Ramig, L.O. Neural correlates of efficacy of voice therapy in Parkinson’s disease identified by performance–correlation analysis. Hum. Brain Mapp. 2010 , 31 , 222–236. [ Google Scholar ] [ CrossRef ]
• Kleim, J.A.; Hogg, T.M.; VandenBerg, P.M.; Cooper, N.R.; Bruneau, R.; Remple, M. Cortical synaptogenesis and motor map reorganization occur during late, but not early, phase of motor skill learning. J. Neurosci. 2004 , 24 , 628–633. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Schertz, M.; Gordon, A.M. Changing the model: A call for a re-examination of intervention approaches and translational research in children with developmental disabilities. Dev. Med. Child Neurol. 2009 , 51 , 6–7. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Adkins, D.L.; Boychuk, J.; Remple, M.S.; Kleim, J.A. Motor training induces experience-specific patterns of plasticity across motor cortex and spinal cord. J. Appl. Physiol. 2006 , 101 , 1776–1782. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Braza, M.D.; Sakash, A.; Natzke, P.; Hustad, K.C. Longitudinal change in speech rate and intelligibility between 5 and 7 years in children with cerebral palsy. Am. J. Speech Lang. Pathol. 2019 , 28 , 1139–1151. [ Google Scholar ] [ CrossRef ]
• Mahler, L.A.; Jones, H.N. Intensive treatment of dysarthria in two adults with Down syndrome. Dev. Neurorehabilit. 2012 , 15 , 44–53. [ Google Scholar ] [ CrossRef ]

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Papadopoulos, A.; Voniati, L.; Ziavra, N.; Tafiadis, D. The Effectiveness of Lee Silverman Voice Treatment (LSVT LOUD) on Children’s Speech and Voice: A Scoping Review. Brain Sci. 2024 , 14 , 937. https://doi.org/10.3390/brainsci14090937

Papadopoulos A, Voniati L, Ziavra N, Tafiadis D. The Effectiveness of Lee Silverman Voice Treatment (LSVT LOUD) on Children’s Speech and Voice: A Scoping Review. Brain Sciences . 2024; 14(9):937. https://doi.org/10.3390/brainsci14090937

Papadopoulos, Angelos, Louiza Voniati, Nafsika Ziavra, and Dionysios Tafiadis. 2024. "The Effectiveness of Lee Silverman Voice Treatment (LSVT LOUD) on Children’s Speech and Voice: A Scoping Review" Brain Sciences 14, no. 9: 937. https://doi.org/10.3390/brainsci14090937

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