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1.  Multidrug-Resistant Plasmodium vivax Associated with Severe and Fatal Malaria: A Prospective Study in Papua, Indonesia 
PLoS Medicine  2008;5(6):e128.
Background
Multidrug-resistant Plasmodium vivax (Pv) is widespread in eastern Indonesia, and emerging elsewhere in Asia-Pacific and South America, but is generally regarded as a benign disease. The aim of the study was to review the spectrum of disease associated with malaria due to Pv and P. falciparum (Pf) in patients presenting to a hospital in Timika, southern Papua, Indonesia.
Methods and Findings
Data were prospectively collected from all patients attending the outpatient and inpatient departments of the only hospital in the region using systematic data forms and hospital computerised records. Between January 2004 and December 2007, clinical malaria was present in 16% (60,226/373,450) of hospital outpatients and 32% (12,171/37,800) of inpatients. Among patients admitted with slide-confirmed malaria, 64% of patients had Pf, 24% Pv, and 10.5% mixed infections. The proportion of malarial admissions attributable to Pv rose to 47% (415/887) in children under 1 y of age. Severe disease was present in 2,634 (22%) inpatients with malaria, with the risk greater among Pv (23% [675/2,937]) infections compared to Pf (20% [1,570/7,817]; odds ratio [OR] = 1.19 [95% confidence interval (CI) 1.08–1.32], p = 0.001), and greatest in patients with mixed infections (31% [389/1,273]); overall p < 0.0001. Severe anaemia (haemoglobin < 5 g/dl) was the major complication associated with Pv, accounting for 87% (589/675) of severe disease compared to 73% (1,144/1,570) of severe manifestations with Pf (p < 0.001). Pure Pv infection was also present in 78 patients with respiratory distress and 42 patients with coma. In total 242 (2.0%) patients with malaria died during admission: 2.2% (167/7,722) with Pf, 1.6% (46/2,916) with Pv, and 2.3% (29/1260) with mixed infections (p = 0.126).
Conclusions
In this region with established high-grade chloroquine resistance to both Pv and Pf, Pv is associated with severe and fatal malaria particularly in young children. The epidemiology of P. vivax needs to be re-examined elsewhere where chloroquine resistance is increasing.
Ric Price and colleagues present data from southern Papua, Indonesia, suggesting that malaria resulting from infection withPlasmodium vivax is associated with substantial morbidity and mortality.
Editors' Summary
Background.
Malaria, a parasitic disease transmitted to people by mosquitoes, is common throughout the tropical and subtropical areas of the world. In sub-Saharan Africa, infections with Plasmodium falciparum cause most of the malaria-associated illness and death. Elsewhere, another related parasite—P. vivax—is often the commonest cause of malaria. Both parasites are injected into the human blood stream when an infected mosquito bites a person. From there, the parasites travel to the liver, where they multiply for 8–9 d and mature into a form of the parasite known as merozoites. These merozoites are released from the liver and invade red blood cells where they multiply rapidly for a couple of days before bursting out and infecting more red blood cells. This cyclical accumulation of parasites in the blood causes a recurring flu-like illness characterized by fevers, headaches, chills, and sweating. Malaria can be treated with antimalarial drugs but, if left untreated, infections with P. falciparum can cause anemia (by destroying red blood cells) and can damage the brain and other vital organs (by blocking the capillaries that supply these organs with blood), complications that can be fatal.
Why Was This Study Done?
Unlike falciparum malaria, vivax malaria is generally regarded as a benign or nonfatal disease even though there have been several reports recently of severe disease and deaths associated with vivax malaria. These reports do not indicate, however, whether P. vivax is responsible for a significant proportion of malarial deaths. Public health officials need to know this information because strains of P. vivax that are resistant to multiple antimalarial drugs are widespread in Indonesia and beginning to emerge elsewhere in Asia and South America. In this study, therefore, the researchers investigate the relative burden of vivax and falciparum malaria in Papua, Indonesia, a region where multidrug-resistant strains of both P. falciparum and P. vivax are common.
What Did the Researchers Do and Find?
The researchers examined data collected from all the patients attending the outpatient and inpatient departments of a hospital that serves a large area in the southern lowlands of Papua, Indonesia between January 2004 and December 2007. Among those inpatients in whom malaria had been confirmed by finding parasites in blood samples, two-thirds were infected with P. falciparum, a quarter with P. vivax, and the rest with a mixture of parasites. Nearly one in four patients infected with P. vivax developed severe malaria compared with roughly one in five patients infected with P. falciparum. However, about one in three patients infected with both parasites developed severe disease. Whichever parasite was responsible for the infection, the proportion of patients with severe disease was greatest among children below the age of five years. Severe anemia was the commonest complication associated with severe malaria caused by both P. vivax and P. falciparum (present in 87% and 73% of cases, respectively). Finally, one in 50 patients with malaria died; the risk of death was the same for patients infected with P. falciparum, P. vivax, or both parasites.
What Do These Findings Mean?
These findings provide important information about the burden of malaria associated with P. vivax infection. They show that in a region where multidrug-resistant strains of both P. falciparum and P. vivax are common, P. vivax infection (as well as P. falciparum infection) is associated with severe and fatal malaria, particularly in young children. The findings also show that infection with a mixture of the two parasites is associated with a higher risk of severe disease than infection with either parasite alone. Most importantly, they show that similar proportions of patients infected with P. falciparum, P. vivax, or a mixture of parasites die. Further studies need to be done in other settings to confirm these findings and to learn more about the pattern of severe malaria associated with P. vivax (in particular, with multidrug-resistant strains). Nevertheless, these findings highlight the need to consider both P. vivax and P. falciparum when implementing measures designed to reduce the malaria burden in regions where these parasites coexist.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050128.
A PLoS Medicine Research in Translation article by Stephen Rogerson further discusses this study and a related PLoS Medicine paper on vivax malaria in a community cohort from Papua New Guinea
The MedlinePlus encyclopedia has a page on malaria (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish)
Vivaxmalaria provides information on topics related to P. vivax
The Malaria Vaccine Initiative also provides a fact sheet on P. vivax malaria
Information is available from the Roll Back Malaria Partnership on the global control of malaria
doi:10.1371/journal.pmed.0050128
PMCID: PMC2429950  PMID: 18563962
2.  Plasmodium vivax and Mixed Infections Are Associated with Severe Malaria in Children: A Prospective Cohort Study from Papua New Guinea  
PLoS Medicine  2008;5(6):e127.
Background
Severe malaria (SM) is classically associated with Plasmodium falciparum infection. Little information is available on the contribution of P. vivax to severe disease. There are some epidemiological indications that P. vivax or mixed infections protect against complications and deaths. A large morbidity surveillance conducted in an area where the four species coexist allowed us to estimate rates of SM among patients infected with one or several species.
Methods and Findings
This was a prospective cohort study conducted within the framework of the Malaria Vaccine Epidemiology and Evaluation Project. All presumptive malaria cases presenting at two rural health facilities over an 8-y period were investigated with history taking, clinical examination, and laboratory assessment. Case definition of SM was based on the World Health Organization (WHO) criteria adapted for the setting (i.e., clinical diagnosis of malaria associated with asexual blood stage parasitaemia and recent history of fits, or coma, or respiratory distress, or anaemia [haemoglobin < 5 g/dl]). Out of 17,201 presumptive malaria cases, 9,537 (55%) had a confirmed Plasmodium parasitaemia. Among those, 6.2% (95% confidence interval [CI] 5.7%–6.8%) fulfilled the case definition of SM, most of them in children <5 y. In this age group, the proportion of SM was 11.7% (10.4%–13.2%) for P. falciparum, 8.8% (7.1%–10.7%) for P. vivax, and 17.3% (11.7%–24.2%) for mixed P. falciparum and P. vivax infections. P. vivax SM presented more often with respiratory distress than did P. falciparum (60% versus 41%, p = 0.002), but less often with anaemia (19% versus 41%, p = 0.0001).
Conclusion
P. vivax monoinfections as well as mixed Plasmodium infections are associated with SM. There is no indication that mixed infections protected against SM. Interventions targeted toward P. falciparum only might be insufficient to eliminate the overall malaria burden, and especially severe disease, in areas where P. falciparum and P. vivax coexist.
In a study carried out in Papua New Guinea, Blaise Genton and colleagues show thatPlasmodium vivax is associated with severe malaria.
Editors' Summary
Background.
Malaria is a parasitic infection that is transmitted to people by infected mosquitoes. Four different parasites cause malaria—Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. Of these, P. vivax is the commonest and most widely distributed, whereas P. falciparum causes the most deaths. All these parasites enter their human host when an infected mosquito takes a blood meal. They then migrate to the liver where they replicate without causing any symptoms. Eight to nine days later, mature parasites are released from the liver cells and invade red blood cells. Here, they multiply rapidly before bursting out and infecting more red blood cells. The recurring flu-like symptoms of malaria are caused by this cyclical increase in parasitemia (parasites in the blood) and should be treated promptly with antimalarial drugs to prevent the development of potentially fatal complications. Infections with P. falciparum in particular can cause anemia by destroying the red blood cells and can damage vital organs (including the brain) by blocking the capillaries that supply them with blood.
Why Was This Study Done?
It is generally believed that P. vivax malaria is rarely fatal. There is even some evidence that infection with P. vivax alone (monoinfection) or with other malaria parasites (mixed infection) provides protection against malarial complications. Recently, however, there have been reports of severe disease and deaths associated with infection by P. vivax alone. Most of these reports do not indicate what proportion of severe malaria cases are caused by P. vivax infections, but if P. vivax is responsible for a significant proportion of malarial deaths, efforts to prevent these deaths will need to target P. vivax as well as P. falciparum. In this study, therefore, the researchers estimate the proportion of cases of severe malaria among patients infected with one or several Plasmodium species in Papua New Guinea, a country where all four species coexist.
What Did the Researchers Do and Find?
The researchers enrolled everyone attending two rural health facilities in the Wosera subdistrict of Papua New Guinea over an eight-year period with symptoms indicative of malaria but without symptoms of any other disease (presumptive malaria cases) into their prospective cohort study. They asked each patient about their symptoms, did a standard physical examination, looked for parasites in their blood, and measured their hemoglobin levels to see whether they were anemic. Out of 17,201 presumptive malaria cases, 483 had severe malaria (defined as parasitemia plus a recent history of fits, coma, breathing problems, or anemia). Most of the patients with severe malaria were less than five years old—children have little immunity to Plasmodium parasites. In this age group, 11.7% of patients infected with P. falciparum, 8.8% of patients infected with P. vivax, and 17.3% of patients infected with both parasites had severe malaria. Patients with severe malaria caused by P. vivax presented with breathing difficulties more often than those infected with P. falciparum, whereas anemia was more common among patients with severe malaria caused by P. falciparum than by P. vivax.
What Do These Findings Mean?
The researchers use these results and data on the numbers of infections with each parasite to calculate that, in this rural region of Papua New Guinea, P. vivax is responsible for one-fifth of severe malaria cases, P. falciparum is responsible for three-quarters of cases, and the rest involve mixed P. falciparum/P. vivax infections. Put another way, these findings suggest that about one in ten children under the age of five years infected with either P. vivax or P. falciparum may develop severe malaria. These findings provide no evidence, however, that mixed infections are protective. Because the diagnosis of severe malaria was not confirmed by outcome data (deaths or permanent disability), additional, more detailed studies are needed to confirm these results. Nevertheless, these findings (and those reported separately in a related article published at the same time in PLoS Medicine) suggest that a significant proportion of the illness associated with malaria may be caused by P. vivax infections. Thus, efforts to reduce or eliminate the malarial burden must target P. vivax as well as P. falciparum in regions where these species coexist.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050127.
A PLoSMedicine Research in Translation article by Stephen Rogerson further discusses this study and a related paper on vivax malaria infection in patients attending a regional hospital in Papua, Indonesia
The MedlinePlus encyclopedia has a page on malaria (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish)
Information is available from the Roll Back Malaria Partnership on global control of malaria and on malaria in Papua New Guinea
Vivaxmalaria provides information for the malaria research community on topics related to Plasmodiumvivax
The Malaria Vaccine Initiative also provides a fact sheet on Plasmodiumvivax malaria
doi:10.1371/journal.pmed.0050127
PMCID: PMC2429951  PMID: 18563961
3.  Major Burden of Severe Anemia from Non-Falciparum Malaria Species in Southern Papua: A Hospital-Based Surveillance Study 
PLoS Medicine  2013;10(12):e1001575.
Ric Price and colleagues use hospital-based surveillance data to estimate the risk of severe anemia and mortality associated with endemic Plasmodium species in southern Papua, Indonesia.
Please see later in the article for the Editors' Summary
Background
The burden of anemia attributable to non-falciparum malarias in regions with Plasmodium co-endemicity is poorly documented. We compared the hematological profile of patients with and without malaria in southern Papua, Indonesia.
Methods and Findings
Clinical and laboratory data were linked for all patients presenting to a referral hospital between April 2004 and December 2012. Data were available on patient demographics, malaria diagnosis, hemoglobin concentration, and clinical outcome, but other potential causes of anemia could not be identified reliably. Of 922,120 patient episodes (837,989 as outpatients and 84,131 as inpatients), a total of 219,845 (23.8%) were associated with a hemoglobin measurement, of whom 67,696 (30.8%) had malaria. Patients with P. malariae infection had the lowest hemoglobin concentration (n = 1,608, mean = 8.93 [95% CI 8.81–9.06]), followed by those with mixed species infections (n = 8,645, mean = 9.22 [95% CI 9.16–9.28]), P. falciparum (n = 37,554, mean = 9.47 [95% CI 9.44–9.50]), and P. vivax (n = 19,858, mean = 9.53 [95% CI 9.49–9.57]); p-value for all comparisons <0.001. Severe anemia (hemoglobin <5 g/dl) was present in 8,151 (3.7%) patients. Compared to patients without malaria, those with mixed Plasmodium infection were at greatest risk of severe anemia (adjusted odds ratio [AOR] 3.25 [95% CI 2.99–3.54]); AORs for severe anaemia associated with P. falciparum, P. vivax, and P. malariae were 2.11 (95% CI 2.00–2.23), 1.87 (95% CI 1.74–2.01), and 2.18 (95% CI 1.76–2.67), respectively, p<0.001. Overall, 12.2% (95% CI 11.2%–13.3%) of severe anemia was attributable to non-falciparum infections compared with 15.1% (95% CI 13.9%–16.3%) for P. falciparum monoinfections. Patients with severe anemia had an increased risk of death (AOR = 5.80 [95% CI 5.17–6.50]; p<0.001). Not all patients had a hemoglobin measurement, thus limitations of the study include the potential for selection bias, and possible residual confounding in multivariable analyses.
Conclusions
In Papua P. vivax is the dominant cause of severe anemia in early infancy, mixed P. vivax/P. falciparum infections are associated with a greater hematological impairment than either species alone, and in adulthood P. malariae, although rare, is associated with the lowest hemoglobin concentration. These findings highlight the public health importance of integrated genus-wide malaria control strategies in areas of Plasmodium co-endemicity.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria—a mosquito-borne parasitic disease—is a global public health problem. Five parasites cause malaria—Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. Of these, P. vivax is the commonest and most widely distributed, whereas P. falciparum causes the most deaths—about a million every year. All these parasites enter their human host when an infected mosquito takes a blood meal. The parasites migrate to the liver where they replicate and mature into a parasitic form known as merozoites. After 8–9 days, the merozoites are released from the liver cells and invade red blood cells where they replicate rapidly before bursting out and infecting more red blood cells. Malaria's recurring flu-like symptoms are caused by this cyclical increase in parasites in the blood. Malaria needs to be treated promptly with antimalarial drugs to prevent the development of potentially fatal complications. Infections with P. falciparum in particular can cause anemia (a reduction in red blood cell numbers) and can damage the brain and other vital organs by blocking the capillaries that supply these organs with blood.
Why Was This Study Done?
It is unclear what proportion of anemia is attributable to non-falciparum malarias in regions of the world where several species of malaria parasite are always present (Plasmodium co-endemicity). Public health officials in such regions need to know whether non-falciparum malarias are a major cause of anemia when designing malaria control strategies. If P. vivax, for example, is a major cause of anemia in an area where P. vivax and P. falciparum co-exist, then any malaria control strategies that are implemented need to take into account the biological differences between the parasites. In this hospital-based cohort study, the researchers investigate the burden of severe anemia from the endemic Plasmodium species in southern Papua, Indonesia.
What Did the Researchers Do and Find?
The researchers used hospital record numbers to link clinical and laboratory data for patients presenting to a referral hospital in southern Papua over an 8-year period. The hemoglobin level (an indicator of anemia) was measured in about a quarter of hospital presentations (some patients attended the hospital several times). A third of the presentations who had their hemoglobin level determined (67,696 presentations) had clinical malaria. Patients with P. malariae infection had the lowest average hemoglobin concentration. Patients with mixed species, P. falciparum, and P. vivax infections had slightly higher average hemoglobin levels but all these levels were below the normal range for people living in Papua. Among the patients who had their hemoglobin status assessed, 3.7% had severe anemia. After allowing for other factors that alter the risk of anemia (“confounding” factors such as age), patients with mixed Plasmodium infection were more than three times as likely to have severe anemia as patients without malaria. Patients with P. falciparum, P. vivax, or P. malariae infections were about twice as likely to have severe anemia as patients without malaria. About 12.2% of severe anemia was attributable to non-falciparum infections, 15.1% was attributable to P. falciparum monoinfections, and P. vivax was the dominant cause of severe anemia in infancy. Finally, compared to patients without anemia, patients with severe anemia had nearly a 6-fold higher risk of death.
What Do These Findings Mean?
These findings provide a comparative assessment of the pattern of anemia associated with non-falciparum malarias in Papua and an estimate of the public health importance of these malarias. Although the accuracy of these findings may be affected by residual confounding (for example, the researchers did not consider nutritional status when calculating how much malaria infection increases the risk of anemia) and other limitations of the study design, non-falciparum malarias clearly make a major contribution to the burden of anemia in southern Papua. In particular, these findings reveal the large contribution that P. vivax makes to severe anemia in infancy, show that the hematological (blood-related) impact of P. malariae is most apparent in adulthood, and suggest, in contrast to some previous reports, that mixed P. vivax/P. falciparum infection is associated with a higher risk of severe anemia than monoinfection with either species. These findings, which need to be confirmed in other settings, highlight the public health importance of implementing integrated malaria control strategies that aim to control all Plasmodium species rather than a single species in regions of Plasmodium co-endemicity.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001575.
This study is further discussed in a PLOS Medicine Perspective by Gosling and Hsiang
Information is available from the World Health Organization on malaria (in several languages); the 2012 World Malaria Report provides details of the current global malaria situation
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish), including information on different Plasmodium species and a selection of personal stories about malaria
The Malaria Vaccine Initiative has fact sheets on Plasmodium falciparum malaria and on Plasmodium vivax malaria
MedlinePlus provides links to additional information on malaria and on anemia (in English and Spanish)
Information is available from the WorldWide Antimalarial Resistance Network on antimalarial drug resistance for P. falciparum and P. vivax
doi:10.1371/journal.pmed.1001575
PMCID: PMC3866090  PMID: 24358031
4.  Severe disease in children hospitalized with a diagnosis of Plasmodium vivax in south-eastern Pakistan 
Malaria Journal  2012;11:144.
Background
Infection by Plasmodium vivax has been considered rarely threatening to life, but recent studies challenge this notion. This study documented the frequency and character of severe illness in paediatric patients admitted to a hospital in south-eastern Pakistan with a laboratory-confirmed diagnosis of vivax malaria.
Methods
An observational study of all 180 paediatric patients admitted with any diagnosis of malaria during 2010 was conducted: 128 P. vivax; 48 Plasmodium falciparum; and four mixed infections of these species. Patients were classified as having severe illness with any of the following indicators: Glascow coma scale <11; ≥2 convulsions; haemoglobin <5g/dL; thrombocytes <50,000/mL; blood glucose <45mg%; >70 breaths/min; or intravenous anti-malarial therapy. Additionally, 64 patients with a diagnosis of vivax malaria were treated during 2009, and the 21 of these having severe illness were included in analyses of the frequency and character of severe illness with that diagnosis.
Results
During 2010, 39 (31%) or 37 (77%) patients with a diagnosis of P. vivax or P. falciparum were classified as having severe disease. Including the 2009 records of 64 patients having vivax malaria, a total of 60 (31%) patients with severe illness and a diagnosis of P. vivax were available. Altered mental status (Glascow coma scale score <11; or ≥2 convulsions) dominated at 54% of the 83 indicators of severe illness manifest among the patients with vivax malaria, as was true among the 37 children with a diagnosis of falciparum malaria and being severely ill; 58% of the 72 indicators of severe disease documented among them. No statistically significant difference appeared in frequencies of any other severe disease indicators between patients diagnosed with vivax or falciparum malaria. Despite such similarities, a diagnosis of falciparum malaria nonetheless came with 3.8-fold (95% CI = 1.8-8.1) higher risk of presenting with severe illness, and 8.0-fold (95% CI = 2.1-31) greater likelihood of presenting with three or more severe disease indicators. Two patients did not survive hospitalization, one each with a diagnosis of falciparum or vivax malaria.
Conclusions
Vivax malaria caused a substantial burden of potentially life-threatening morbidity on a paediatric ward in a hospital in south-eastern Pakistan.
doi:10.1186/1475-2875-11-144
PMCID: PMC3480837  PMID: 22551061
Plasmodium vivax; Severe illness; Clinical presentation; Risk; children; Pakistan; Hospital; Plasmodium falciparum
5.  Artemisinin-Naphthoquine versus Artemether-Lumefantrine for Uncomplicated Malaria in Papua New Guinean Children: An Open-Label Randomized Trial 
PLoS Medicine  2014;11(12):e1001773.
In a randomized controlled trial Tim Davis and colleagues investigate Artemisinin-naphthoquine versus artemether-lumefantrine for the treatment of P. falciparum and P. vivax malaria.
Please see later in the article for the Editors' Summary
Background
Artemisinin combination therapies (ACTs) with broad efficacy are needed where multiple Plasmodium species are transmitted, especially in children, who bear the brunt of infection in endemic areas. In Papua New Guinea (PNG), artemether-lumefantrine is the first-line treatment for uncomplicated malaria, but it has limited efficacy against P. vivax. Artemisinin-naphthoquine should have greater activity in vivax malaria because the elimination of naphthoquine is slower than that of lumefantrine. In this study, the efficacy, tolerability, and safety of these ACTs were assessed in PNG children aged 0.5–5 y.
Methods and Findings
An open-label, randomized, parallel-group trial of artemether-lumefantrine (six doses over 3 d) and artemisinin-naphthoquine (three daily doses) was conducted between 28 March 2011 and 22 April 2013. Parasitologic outcomes were assessed without knowledge of treatment allocation. Primary endpoints were the 42-d P. falciparum PCR-corrected adequate clinical and parasitologic response (ACPR) and the P. vivax PCR-uncorrected 42-d ACPR. Non-inferiority and superiority designs were used for falciparum and vivax malaria, respectively. Because the artemisinin-naphthoquine regimen involved three doses rather than the manufacturer-specified single dose, the first 188 children underwent detailed safety monitoring. Of 2,542 febrile children screened, 267 were randomized, and 186 with falciparum and 47 with vivax malaria completed the 42-d follow-up. Both ACTs were safe and well tolerated. P. falciparum ACPRs were 97.8% and 100.0% in artemether-lumefantrine and artemisinin-naphthoquine-treated patients, respectively (difference 2.2% [95% CI −3.0% to 8.4%] versus −5.0% non-inferiority margin, p = 0.24), and P. vivax ACPRs were 30.0% and 100.0%, respectively (difference 70.0% [95% CI 40.9%–87.2%], p<0.001). Limitations included the exclusion of 11% of randomized patients with sub-threshold parasitemias on confirmatory microscopy and direct observation of only morning artemether-lumefantrine dosing.
Conclusions
Artemisinin-naphthoquine is non-inferior to artemether-lumefantrine in PNG children with falciparum malaria but has greater efficacy against vivax malaria, findings with implications in similar geo-epidemiologic settings within and beyond Oceania.
Trial registration
Australian New Zealand Clinical Trials Registry ACTRN12610000913077
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria is a mosquito-borne parasitic disease that kills more than 600,000 people (mainly young children in sub-Saharan Africa) every year. Plasmodium falciparum causes most of these deaths, but P. vivax is the most common and most widely distributed cause of malaria outside sub-Saharan Africa. Infection with malaria parasites causes recurring flu-like symptoms and must be treated promptly with antimalarial drugs to prevent the development of anemia and potentially fatal damage to the brain and other organs. In the past, malaria was treated with “monotherapies” such as chloroquine, but the parasites quickly developed resistance to many of these inexpensive drugs. The World Health Organization now recommends artemisinin combination therapy (ACT) for first-line treatment of malaria in all regions where there is drug-resistant malaria. In ACT, artemisinin derivatives (fast-acting antimalarial drugs that are rapidly cleared from the body) are used in combination with a slower acting, more slowly eliminated partner drug to prevent reemergence of the original infection and to reduce the chances of the malaria parasites becoming resistant to either drug.
Why Was This Study Done?
Because falciparum and vivax malaria respond differently to antimalarial drugs, wherever there is transmission of both types of malaria but limited facilities for species-specific malaria diagnosis—as in Papua New Guinea—compromises have to be made about which ACT should be used for the treatment of malaria. Thus, Papua New Guinea's national guidelines recommend artemether-lumefantrine, which is effective against the more deadly P. falciparum, for first-line treatment of uncomplicated (mild) malaria even though this ACT is ineffective against the more common P. vivax. In this open-label randomized trial (a study in which participants are randomly assigned to receive different drugs but know which drug they are being given), the researchers ask whether an alternative ACT might be preferable for the treatment of uncomplicated malaria in young children in Papua New Guinea by comparing outcomes after treatment with artemether-lumefantrine versus artemisinin-naphthoquine (an ACT that should be more effective against vivax malaria than artemether-lumefantrine because naphthoquine stays in the body longer than lumefantrine). Specifically, the researchers test the non-inferiority of artemisinin-naphthoquine compared to artemether-lumefantrine for the treatment of falciparum malaria (whether artemisinin-naphthoquine is not worse than artemether-lumefantrine) and the superiority of artemisinin-naphthoquine compared to artemether-lumefantrine for the treatment of vivax malaria (whether artemisinin-naphthoquine is better than artemether-lumefantrine).
What Did the Researchers Do and Find?
The researchers assigned nearly 250 children (aged 0.5 to 5 years) with falciparum malaria, vivax malaria, or both types of malaria to receive six doses of artemether-lumefantrine over three days or three daily doses of artemisinin-naphthoquine. They then followed the children to see how many children in each treatment group and with each type of malaria were free of malaria 42 days after treatment (an “adequate clinical and parasitological response”). Among the patients originally infected with P. falciparum, 97.8% of those treated with artemether-lumefantrine and 100% of those treated with artemisinin-naphthoquine were clear of their original P. falciparum infection (though some had acquired a new P. falciparum infection) 42 days after treatment. By contrast, among the patients infected with P. vivax, 30% of those treated with artemether-lumefantrine and 100% of those treated with artemisinin-naphthoquine were clear of P. vivax infection 42 days after treatment. Both ACTs were safe and well tolerated.
What Do These Findings Mean?
These findings indicate that artemisinin-naphthoquine was non-inferior to artemether-lumefantrine for the treatment of uncomplicated falciparum malaria among young children in Papua New Guinea and had greater efficacy than artemether-lumefantrine against vivax malaria. The accuracy of these findings may be limited by several aspects of the study design. For example, not all the artemether-lumefantrine doses were directly observed, so some children may not have received the full treatment course. Moreover, because all the study participants lived in coastal communities in Papua New Guinea where malaria is highly endemic, treatment responses among children living in areas with lower levels of malaria transmission might be different. Nevertheless, these findings suggest that artemisinin-naphthoquine should be considered alongside other ACTs for the treatment of uncomplicated malaria in regions where there is transmission of multiple Plasmodium species and that artemisinin-naphthoquine may be better than artemether-lumefantrine for the treatment of uncomplicated malaria in young children in regions where P. vivax predominates.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001773.
Information is available from the World Health Organization on malaria (in several languages); the World Malaria Report 2013 provides details on the current global malaria situation, including information on malaria in Papua New Guinea; the World Health Organization's Guidelines for the Treatment of Malaria is available
The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish), including personal stories about malaria
Information is available from the Roll Back Malaria Partnership on the global control of malaria, including information about malaria in Papua New Guinea, malaria in children, and ACTs
The Malaria Vaccine Initiative has a fact sheet on Plasmodium vivax malaria
MedlinePlus provides links to additional information on malaria (in English and Spanish)
More information about this trial is available
doi:10.1371/journal.pmed.1001773
PMCID: PMC4280121  PMID: 25549086
6.  Quantifying the Number of Pregnancies at Risk of Malaria in 2007: A Demographic Study 
PLoS Medicine  2010;7(1):e1000221.
By combining data from the Malaria Atlas Project with country-specific data, Feiko ter Kuile and colleagues provide the first contemporary global estimates of the annual number of pregnancies at risk of malaria.
Background
Comprehensive and contemporary estimates of the number of pregnancies at risk of malaria are not currently available, particularly for endemic areas outside of Africa. We derived global estimates of the number of women who became pregnant in 2007 in areas with Plasmodium falciparum and P. vivax transmission.
Methods and Findings
A recently published map of the global limits of P. falciparum transmission and an updated map of the limits of P. vivax transmission were combined with gridded population data and growth rates to estimate total populations at risk of malaria in 2007. Country-specific demographic data from the United Nations on age, sex, and total fertility rates were used to estimate the number of women of child-bearing age and the annual rate of live births. Subregional estimates of the number of induced abortions and country-specific stillbirths rates were obtained from recently published reviews. The number of miscarriages was estimated from the number of live births and corrected for induced abortion rates. The number of clinically recognised pregnancies at risk was then calculated as the sum of the number of live births, induced abortions, spontaneous miscarriages, and stillbirths among the population at risk in 2007. In 2007, 125.2 million pregnancies occurred in areas with P. falciparum and/or P. vivax transmission resulting in 82.6 million live births. This included 77.4, 30.3, 13.1, and 4.3 million pregnancies in the countries falling under the World Health Organization (WHO) regional offices for South-East-Asia (SEARO) and the Western-Pacific (WPRO) combined, Africa (AFRO), Europe and the Eastern Mediterranean (EURO/EMRO), and the Americas (AMRO), respectively. Of 85.3 million pregnancies in areas with P. falciparum transmission, 54.7 million occurred in areas with stable transmission and 30.6 million in areas with unstable transmission (clinical incidence <1 per 10,000 population/year); 92.9 million occurred in areas with P. vivax transmission, 53.0 million of which occurred in areas in which P. falciparum and P. vivax co-exist and 39.9 million in temperate regions with P. vivax transmission only.
Conclusions
In 2007, 54.7 million pregnancies occurred in areas with stable P. falciparum malaria and a further 70.5 million in areas with exceptionally low malaria transmission or with P. vivax only. These represent the first contemporary estimates of the global distribution of the number of pregnancies at risk of P. falciparum and P. vivax malaria and provide a first step towards a more informed estimate of the geographical distribution of infection rates and the corresponding disease burden of malaria in pregnancy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria, a mosquito-borne parasitic disease, is a major global public-health problem. About half of the world's population is at risk of malaria, which kills about one million people every year. Most of these deaths are caused by Plasmodium falciparum, which thrives in tropical and subtropical regions. However, the most widely distributed type of malaria is P. vivax malaria, which also occurs in temperate regions. Most malaria deaths are among young children in sub-Saharan Africa, but pregnant women and their unborn babies are also very vulnerable to malaria. About 10,000 women and 200,000 babies die annually because of malaria in pregnancy, which can cause miscarriages, preterm births, and low-birth-weight births. Over the past decade, a three-pronged approach has been developed to prevent and control malaria in pregnancy. This approach consists of intermittent preventative treatment of pregnant women with antimalarial drugs, the use of insecticide-treated bed nets to protect pregnant women from the bites of infected mosquitoes, and management of malarial illness among pregnant women.
Why Was This Study Done?
This strategy has begun to reduce the burden of malaria among pregnant women and their babies but the resources available for its introduction are very limited in many of the developing countries where malaria is endemic (always present). Policy makers in these countries need to know the number of pregnancies at risk of malaria so that they can use their resources wisely. However, although the World Health Organization recently estimated that more than 30 million African women living in malaria endemic areas become pregnant and are at risk for malaria each year, there are no comprehensive and contemporary estimates of the number of pregnancies at risk of malaria for endemic areas outside Africa. In this study, the researchers derive global estimates of the number of women who became pregnant in 2007 in areas with P. falciparum and P. vivax transmission.
What Did the Researchers Do and Find?
The researchers estimated the sizes of populations at risk of malaria in 2007 by combining maps of the global limits of P. vivax and P. falciparum transmission with data on population densities. They used data from various sources to calculate the annual number of pregnancies (the sum of live births, induced abortions, miscarriages, and still births) in each country. Finally, they calculated the annual number of pregnancies at risk of malaria in each country by multiplying the number of pregnancies in the entire country by the fraction of the population living within the spatial limits of malaria transmission in that country. In 2007, they calculate, 125.2 million pregnancies occurred in areas with P. falciparum and/or P. vivax transmission. These pregnancies—60% of all pregnancies globally—resulted in 82.6 million live births. 77.4 million at-risk pregnancies occurred in Southeast Asia and the Western Pacific (India had the most pregnancies at risk of both P. falciparum and P. vivax malaria), 30.3 million in Africa, 13.1 million in Europe and the Eastern Mediterranean, and 4.3 million in the Americas. 54.7 million at-risk pregnancies occurred in regions with stable P. falciparum transmission (more than one case of malaria per 10,000 people per year), whereas 70.5 million occurred in areas with low malaria transmission or P. vivax transmission only.
What Do These Findings Mean?
These findings are the first contemporary estimates of the global distribution of the number of pregnancies at risk of P. falciparum and P. vivax malaria. They do not provide any information on the actual incidence of malaria during pregnancy or the health burden on mothers and unborn babies. They simply represent “any risk” of exposure. So, for example, the researchers calculate that only about 5,000 actual malaria infections may occur annually among the 70.5 million at-risk pregnancies in areas with very low malaria transmission or with P. vivax transmission only. Furthermore, these findings do not allow for the seasonality of malaria—pregnancies that occur outside of the transmission season may be at no or very low risk of malaria. Nevertheless, the estimates reported in this study are an important first step towards a spatial map of the burden of malaria in pregnancy and should help policy makers allocate resources for research into and control of this important public-health problem.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000221.
Information is available from the World Health Organization on malaria and on malaria in pregnancy (in several languages)
The US Centers for Disease Control and Prevention also provides information on malaria and on malaria in pregnancy (in English and Spanish)
Information is available from the Roll Back Malaria Partnership on all aspects of global malaria control, including information on malaria in pregnancy
The Malaria in Pregnancy Consortium is undertaking research into the prevention and treatment of malaria in pregnancy and also provides a comprehensive bibliographic database of published and unpublished literature relating to malaria in pregnancy
The Malaria Atlas Project provides maps of malaria transmission around the world
MedlinePlus provides links to additional information on malaria (in English and Spanish)
doi:10.1371/journal.pmed.1000221
PMCID: PMC2811150  PMID: 20126256
7.  The Impact of Phenotypic and Genotypic G6PD Deficiency on Risk of Plasmodium vivax Infection: A Case-Control Study amongst Afghan Refugees in Pakistan 
PLoS Medicine  2010;7(5):e1000283.
Analyses of a case-control study among Afghan refugees in Pakistan find that a G6PD (glucose-6-phosphate dehydrogenase) “Mediterranean” type deficiency confers substantial protection against Plasmodium vivax malaria.
Background
The most common form of malaria outside Africa, Plasmodium vivax, is more difficult to control than P. falciparum because of the latent liver hypnozoite stage, which causes multiple relapses and provides an infectious reservoir. The African (A−) G6PD (glucose-6-phosphate dehydrogenase) deficiency confers partial protection against severe P. falciparum. Recent evidence suggests that the deficiency also confers protection against P. vivax, which could explain its wide geographical distribution in human populations. The deficiency has a potentially serious interaction with antirelapse therapies (8-aminoquinolines such as primaquine). If the level of protection was sufficient, antirelapse therapy could become more widely available. We therefore tested the hypothesis that G6PD deficiency is protective against vivax malaria infection.
Methods and Findings
A case-control study design was used amongst Afghan refugees in Pakistan. The frequency of phenotypic and genotypic G6PD deficiency in individuals with vivax malaria was compared against controls who had not had malaria in the previous two years. Phenotypic G6PD deficiency was less common amongst cases than controls (cases: 4/372 [1.1%] versus controls 42/743 [5.7%]; adjusted odds ratio [AOR] 0.18 [95% confidence interval (CI) 0.06–0.52], p = 0.001). Genetic analysis demonstrated that the G6PD deficiency allele identified (Mediterranean type) was associated with protection in hemizygous deficient males (AOR = 0.12 [95% CI 0.02–0.92], p = 0.041). The deficiency was also protective in females carrying the deficiency gene as heterozygotes or homozygotes (pooled AOR = 0.37 [95% CI 0.15–0.94], p = 0.037).
Conclusions
G6PD deficiency (Mediterranean type) conferred significant protection against vivax malaria infection in this population whether measured by phenotype or genotype, indicating a possible evolutionary role for vivax malaria in the selective retention of the G6PD deficiency trait in human populations. Further work is required on the genotypic protection associated with other types of G6PD deficiency and on developing simple point-of-care technologies to detect it before administering antirelapse therapy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria is a parasitic infection transmitted to people through the bite of an infected mosquito. Although Plasmodium falciparum is responsible for most malaria deaths, P. vivax is the commonest, most widespread cause of malaria outside sub-Saharan Africa. Like other malaria parasites, P. vivax has a complex life cycle. Infected mosquitoes inject a parasitic form known as sporozoites into people where they replicate inside liver cells without causing symptoms. About 8–9 days later, merozoites (another parasitic form) are released from the liver cells and invade red blood cells. Here, they replicate rapidly before bursting out and infecting more red blood cells. This increase in the parasitic burden causes malaria's characteristic symptoms (debilitating and recurring chills and fevers). P. vivax infections are usually treated with chloroquine (although resistance to this drug is now emerging) but patients must also take primaquine, a drug that kills hypnozoites, a form of P. vivax that hibernates in the liver. Hypnozoites can cause a relapse months after the initial bout of malaria and make P. vivax malaria harder to control than P. faciparum malaria.
Why Was This Study Done?
Some mutations (DNA changes) protect their human carriers against specific disease-causing organisms. These mutations occur at high frequencies in populations where these organisms are common. For example, the widespread distribution of mutations that cause a deficiency in an enzyme called glucose-6-phosphate dehydrogenase (G6PD) mirrors the distribution of malaria and the African (A−) form of G6PD deficiency, a type of G6PD deficiency that is common in people of African origin, is known to provide partial protection against severe P. falciparum malaria—P. falciparum does not thrive in G6PD-deficient red blood cells. In areas where P. vivax malaria is common, Mediterranean and Asian variants of G6PD deficiency are more widespread than A− G6PD, so the question is, do these variants protect against P. vivax malaria? In this case-control study (a study in which the characteristics of people with and without a specific condition are compared), the researchers investigate whether G6PD deficiency protects against P. vivax infection in a population of Afghan refugees living in Pakistan.
What Did the Researchers Do and Find?
The researchers enrolled 372 Afghan refugees who had had P. vivax malaria during the previous two years and 743 refugees who had not had malaria over the same period. They measured G6PD activity in the participants' blood to detect “phenotypic” G6PD deficiency (reduced enzyme activity) and looked for the Mediterranean variant of the G6PD gene in the participants (“genotypic” G6PD deficiency). 5.7% of the controls but only 1.1% of the cases had phenotypic G6PD deficiency. Statistical analyses indicated that participants with reduced G6PD levels were about one-fifth as likely to develop P. vivax malaria as those with normal G6PD levels after allowing for other factors that might affect their susceptibility to malaria, an adjusted odds ratio (AOR) of 0.18. The genetic analysis indicated that the Mediterranean G6PD gene variant provided protection against P. vivax infection in men (AOR 0.12) and in women carrying either one or two defective copies of the G6PD gene (AOR 0.37); because the G6PD gene is on the X chromosome, men have only one copy of the gene but women have two copies.
What Do These Findings Mean?
These findings indicate that Mediterranean-type G6PD deficiency protects against P. vivax malaria infection in this population of Afghan refugees. Although further studies are needed to determine whether other G6PD variants protect against P. vivax malaria, these findings suggest that P. vivax malaria might be responsible for the retention of the G6PD deficiency trait in some human populations. In addition, these findings may have implications for the treatment of P. vivax malaria. Currently, in most places where P. vivax malaria is common, primaquine is not given routinely because primaquine can trigger red blood cell death (hemolytic anemia) in G6PD-deficient people and tests for G6PD deficiency are rarely available. These findings suggest that the risk of exposure to primaquine among people infected with P. vivax might be lower than previously assumed, because G6PD deficiency is less common among P. vivax-infected patients than among the general population. Nevertheless, these findings are unlikely to increase the use of primaquine immediately. Such an increase, the researchers suggest, will only occur if a simple test for G6PD deficiency is developed.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000283.
Information is available from the World Health Organization on malaria (in several languages)
The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish)
Information is available from the Wellcome Trust on all aspects of malaria, including a news item about G6PD deficiency protecting against severe P. falciparum malaria
MedlinePlus provides links to additional information on malaria (in English and Spanish)
The Malaria Vaccine Initiative has a fact sheet on Plasmodium vivax malaria
Vivaxmalaria provides information about P. vivax
More about G6PD deficiency can be found on KidsHealth from the Nemours Children's Health System
doi:10.1371/journal.pmed.1000283
PMCID: PMC2876136  PMID: 20520804
8.  Malaria Burden and Artemisinin Resistance in the Mobile and Migrant Population on the Thai–Myanmar Border, 1999–2011: An Observational Study 
PLoS Medicine  2013;10(3):e1001398.
Francois Nosten and colleagues evaluate malaria prevalence and incidence in the mobile population on the Myanmar side of the border with Thailand between 1999 and 2011, and also assess resistance to artemisinin.
Background
The Shoklo Malaria Research Unit has been working on the Thai–Myanmar border for 25 y providing early diagnosis and treatment (EDT) of malaria. Transmission of Plasmodium falciparum has declined, but resistance to artesunate has emerged. We expanded malaria activities through EDT and evaluated the impact over a 12-y period.
Methods and Findings
Between 1 October 1999 and 30 September 2011, the Shoklo Malaria Research Unit increased the number of cross-border (Myanmar side) health facilities from two to 11 and recorded the number of malaria consultations. Changes in malaria incidence were estimated from a cohort of pregnant women, and prevalence from cross-sectional surveys. In vivo and in vitro antimalarial drug efficacy were monitored. Over this period, the number of malaria cases detected increased initially, but then declined rapidly. In children under 5 y, the percentage of consultations due to malaria declined from 78% (95% CI 76–80) (1,048/1,344 consultations) to 7% (95% CI 6.2–7.1) (767/11,542 consultations), p<0.001. The ratio of P. falciparum/P. vivax declined from 1.4 (95% CI 1.3–1.4) to 0.7 (95% CI 0.7–0.8). The case fatality rate was low (39/75,126; 0.05% [95% CI 0.04–0.07]). The incidence of malaria declined from 1.1 to 0.1 episodes per pregnant women-year. The cumulative proportion of P. falciparum decreased significantly from 24.3% (95% CI 21.0–28.0) (143/588 pregnant women) to 3.4% (95% CI 2.8–4.3) (76/2,207 pregnant women), p<0.001. The in vivo efficacy of mefloquine-artesunate declined steadily, with a sharp drop in 2011 (day-42 PCR-adjusted cure rate 42% [95% CI 20–62]). The proportion of patients still slide positive for malaria at day 3 rose from 0% in 2000 to reach 28% (95% CI 13–45) (8/29 patients) in 2011.
Conclusions
Despite the emergence of resistance to artesunate in P. falciparum, the strategy of EDT with artemisinin-based combination treatments has been associated with a reduction in malaria in the migrant population living on the Thai–Myanmar border. Although limited by its observational nature, this study provides useful data on malaria burden in a strategically crucial geographical area. Alternative fixed combination treatments are needed urgently to replace the failing first-line regimen of mefloquine and artesunate.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
According to latest figures, the World Health Organization estimates that there are over 200 million cases of malaria each year, with over three-quarters of a million deaths. Several Plasmodium parasites cause malaria (the most serious being Plasmodium falciparum) and are transmitted to people through the bites of infected night-flying mosquitoes. Malaria transmission can be prevented by using insecticides to control the mosquitoes and by sleeping under insecticide-treated bed nets. However, in Southeast Asia the effectiveness of these measures is limited. Treating infected people with antimalarial drugs, particularly with artemisinin-based combination treatments (ACTs), is a key strategy in reducing the deaths and disability caused by malaria. However, progress is now threatened by the emergence in Southeast Asia of P. falciparum isolates that are resistant to artesunate (a common component of ACT). This development is concerning, as resistance to the artemisinin family of drugs, of which artesunate is a member, could trigger a resurgence in malaria in many parts of the world and compromise the progress made in the treatment of severe malaria.
Why Was This Study Done?
P. falciparum resistance to artemisinin has been confirmed in the area around the border between Thailand and Myanmar. Malaria control in this border area is particularly challenging, as there is a reservoir of malaria in Myanmar (where the disease burden is higher than in Thailand), frequent population movement, and differences in adequate control measures on the two sides of the border. In this study the authors evaluated malaria prevalence and incidence in the mobile population on the Myanmar side of the border between 1 October 1999 and 30 September 2011 to assess whether increasing access to early diagnosis and treatment with ACT was associated with a decline in the malaria burden.
What Did the Researchers Do and Find?
The Shoklo Malaria Research Unit (SMRU) has been working on the Thai–Myanmar border for 25 years providing early diagnosis and treatment of malaria and has extended its services from two to 11 health care facilities (health posts) on the Myanmar side of the border over the past few years. In order to evaluate any changes in the malaria burden since the expansion of services, the researchers recorded the number of consultations in all SMRU clinics and health posts with confirmed malaria diagnosis and tracked changes in the prevalence of malaria in the population on the Myanmar side of the border (via cross-sectional surveys in villages). The researchers also assessed the incidence of malaria in a cohort of pregnant women living on both sides of the border and monitored antimalarial drug efficacy over this time period.
The researchers found that although the mobile population on the Thai side of the border remained constant, the population in villages covered by the clinics and health posts in the border area increased four-fold. Over the time period, the researchers found that the number of confirmed malaria cases (P. falciparum) increased initially, rising from just over 5,000 in 2000 to a peak of 13,764 in 2006, and then declined to just over 3,500 in 2011. A striking finding was the predominance of infections in young adult males (50,316/90,321; 55.7%). Encouragingly, the percentage of consultations due to malaria in children under five years fell from 78% to 7%, and the incidence of malaria declined from 1.1 to 0.1 episodes per pregnant woman-year. In addition, the proportion of patients admitted to hospital with severe disease was stable, and the number of deaths from malaria remained extremely low, with an overall case fatality rate of 0.05%. The researchers also found that the ratio of P. falciparum to P. vivax infections declined from 1.4 to 0.7, and the prevalence of P. falciparum decreased from 24.3% to 3.4%. However, worryingly, in the small number of patients undertaking drug efficacy tests, the drug efficacy of artesunate declined steadily, with the proportion of patients still infected with malaria at day 3 of treatment increasing from 0% in 2000 to 28% in 2011.
What Do These Findings Mean?
These findings indicate that despite the emergence of resistance to artesunate in P. falciparum, and the decline in the efficacy of ACT, the strategy of early diagnosis and treatment with ACTs has been associated with a reduction in malaria in the population living on the Thai–Myanmar border. Furthermore, these findings suggest that an aggressive strategy based on early detection and treatment of cases, combined with vector control and information, could be the way forward to eliminate malaria. Although there were only a small number of patients involved in drug efficacy tests in 2011, this study shows that alternative fixed combination treatments are needed urgently to replace the failing first-line regimen of mefloquine and artesunate.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001398.
More information about the Shoklo Malaria Research Unit is available
The World Health Organization website has more information about antimalarial drug efficacy and drug resistance
The Bill & Melinda Gates Foundation website tells the malaria resistance story
doi:10.1371/journal.pmed.1001398
PMCID: PMC3589269  PMID: 23472056
9.  Intermittent Preventive Treatment for Malaria in Papua New Guinean Infants Exposed to Plasmodium falciparum and P. vivax: A Randomized Controlled Trial 
PLoS Medicine  2012;9(3):e1001195.
A three-arm randomized trial conducted among infants in Papua New Guinea estimates the preventive effect against malaria episodes of intermittent preventive treatment, in an area where children are exposed to both falciparum and vivax malaria.
Background
Intermittent preventive treatment in infants (IPTi) has been shown in randomized trials to reduce malaria-related morbidity in African infants living in areas of high Plasmodium falciparum (Pf) transmission. It remains unclear whether IPTi is an appropriate prevention strategy in non-African settings or those co-endemic for P. vivax (Pv).
Methods and Findings
In this study, 1,121 Papua New Guinean infants were enrolled into a three-arm placebo-controlled randomized trial and assigned to sulfadoxine-pyrimethamine (SP) (25 mg/kg and 1.25 mg/kg) plus amodiaquine (AQ) (10 mg/kg, 3 d, n = 374), SP plus artesunate (AS) (4 mg/kg, 3 d, n = 374), or placebo (n = 373), given at 3, 6, 9 and 12 mo. Both participants and study teams were blinded to treatment allocation. The primary end point was protective efficacy (PE) against all episodes of clinical malaria from 3 to 15 mo of age. Analysis was by modified intention to treat. The PE (compared to placebo) against clinical malaria episodes (caused by all species) was 29% (95% CI, 10–43, p≤0.001) in children receiving SP-AQ and 12% (95% CI, −11 to 30, p = 0.12) in those receiving SP-AS. Efficacy was higher against Pf than Pv. In the SP-AQ group, Pf incidence was 35% (95% CI, 9–54, p = 0.012) and Pv incidence was 23% (95% CI, 0–41, p = 0.048) lower than in the placebo group. IPTi with SP-AS protected only against Pf episodes (PE = 31%, 95% CI, 4–51, p = 0.027), not against Pv episodes (PE = 6%, 95% CI, −24 to 26, p = 0.759). Number of observed adverse events/serious adverse events did not differ between treatment arms (p>0.55). None of the serious adverse events were thought to be treatment-related, and the vomiting rate was low in both treatment groups (1.4%–2.0%). No rebound in malaria morbidity was observed for 6 mo following the intervention.
Conclusions
IPTi using a long half-life drug combination is efficacious for the prevention of malaria and anemia in infants living in a region highly endemic for both Pf and Pv.
Trial registration
ClinicalTrials.gov NCT00285662
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria is a major global public health problem. Half the world's population is at risk of this parasitic disease, which kills about one million people (mainly young children in sub-Saharan Africa) every year. Most of these deaths are caused by Plasmodium falciparum but P. vivax, the commonest and most widely distributed malaria parasite, is a major cause of malaria-related morbidity (illness and death) in many of the tropical and subtropical regions of the world where malaria is endemic (always present). Malaria is transmitted to people through the bites of night-flying mosquitoes. It can be prevented by controlling the mosquitoes that spread the parasite and by sleeping under insecticide-treated nets to avoid mosquito bites. Prompt treatment of malaria with antimalarial drugs can also reduce malaria transmission. In addition, intermittent preventative treatment (IPT)—the treatment of symptom-free individuals with full therapeutic courses of antimalarial drugs at fixed intervals regardless of their infection status—has been shown to reduce malaria-related morbidity among pregnant women in malaria-endemic areas and among African infants living in areas of high P. falciparum transmission.
Why Was This Study Done?
The World Health Organization recently recommended that, in Africa, IPT should be given during infancy (called IPTi) at the same time as routine immunizations. Because the studies on which this recommendation is based were all carried out in sub-Saharan Africa, in populations where P. falciparum is the predominant parasite and P. vivax is uncommon, it is not known whether IPTi would be an appropriate prevention strategy in non-African settings or in regions where both P. falciparum and P. vivax are endemic. In this randomized placebo-controlled trial, the researchers investigate the efficacy of IPTi in infants living in an area of Papua New Guinea where P. falciparum and P. vivax are both highly endemic. In a randomized placebo-controlled trial, the effects of an intervention and of a placebo (dummy) intervention are compared in groups of individuals chosen through the play of chance.
What Did the Researchers Do and Find?
The researchers assigned more than 1,000 infants to receive sulfadoxine/pyrimethamine (SP) plus amodiaquine (AQ) (SP and AQ are long-lasting antimalarial drugs), SP plus artesunate (AS) (AS is a short-lasting antimalarial), or placebo at 3, 6, 9, and 12 months old. They recorded the number of malaria episodes that occurred among the children between the ages of 3 and 15 months. Then, by comparing the number of episodes occurring among the children receiving SP-AS or SP-AQ with the number occurring among the children receiving placebo, the researchers calculated the protective efficacy of the two drug combinations over the study period. The protective efficacy of IPTi against all clinical malaria episodes (P. falciparum and P. vivax combined) was 29% for SP-AQ, but SP-AS was not associated with a statistically significant reduction in all malaria episodes as compared to placebo. For the two species of malaria separately, the incidence of P. falciparum malaria was 35% lower among the children receiving SP-AQ than among the children receiving placebo, whereas the incidence of P. vivax was reduced by 23%; IPTi with SP-AS provided protection only against P. falciparum malaria (protective efficacy 31%). Importantly, the number of adverse events (possible drug side effects) was similar in all the treatment arms, none of the severe adverse events were treatment-related, and there was no rebound in malaria-related morbidity for six months following the end of the intervention.
What Do These Findings Mean?
These findings show that IPTi using a combination of long-lasting antimalarial drugs (SP-AQ) can effectively and safely prevent malaria in a non-African population living in a region where P. falciparum and P. vivax are both highly endemic. Importantly, they also show that IPTi with SP-AQ can prevent both P. falciparum and P. vivax malaria. For Papua New Guinea, these findings suggest that SP-AQ is an appropriate drug choice for IPTi, particularly since the replacement of SP-AQ by artemether-lumefantrine as the national first line treatment for malaria will reduce the selection pressure for resistance against SP and AQ. However, although these finding provide proof-of-principle evidence for the efficacy and safety of IPTi, further studies are needed to identify the most effective combinations of long-lasting antimalarial drugs for use in IPTi in other malaria-endemic regions.
Additional Information
Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001195.
Information is available from the World Health Organization on malaria (in several languages); the 2011 World Malaria Report provides details of the current global malaria situation; and the WHO policy recommendation on IPTi for P. falciparum malaria control in Africa is available
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish), including a selection of personal stories about malaria
Information is available from the Roll Back Malaria Partnership on the global control of malaria, including a fact sheet about malaria in children and information on malaria in Papua New Guinea
The IPTi Consortium was established to evaluate IPTi and inform public health policy making
The Malaria Vaccine Initiative has a fact sheet on P. vivax malaria
Vivaxmalaria.com provides information about P. vivax
MedlinePlus provides links to additional information on malaria (in English and Spanish)
doi:10.1371/journal.pmed.1001195
PMCID: PMC3313928  PMID: 22479155
10.  Coma Associated with Microscopy-Diagnosed Plasmodium vivax: A Prospective Study in Papua, Indonesia 
Background
Coma complicates Plasmodium falciparum infection but is uncommonly associated with P. vivax. Most series of vivax coma have been retrospective and have not utilized molecular methods to exclude mixed infections with P. falciparum.
Methods
We prospectively enrolled patients hospitalized in Timika, Indonesia, with a Glasgow Coma Score (GCS) ≤10 and P. vivax monoinfection on initial microscopy over a four year period. Hematological, biochemical, serological, radiological and cerebrospinal fluid (CSF) examinations were performed to identify other causes of coma. Repeat microscopy, antigen detection and polymerase chain reaction (PCR) were performed to exclude infections with other Plasmodium species.
Results
Of 24 patients fulfilling enrolment criteria, 5 had clear evidence for other non-malarial etiologies. PCR demonstrated 10 mixed infections and 3 P. falciparum monoinfections. 6 (25%) patients had vivax monoinfection and no apparent alternative cause, with a median GCS of 9 (range 8–10) and a median coma duration of 42 (range 36–48) hours. CSF leukocyte counts were <10/ul (n = 3); 2 of the 3 patients without CSF examination recovered with antimalarial therapy alone. One patient had a tremor on discharge consistent with a post-malarial neurological syndrome. No patient had other organ dysfunction. The only death was associated with pure P. falciparum infection by PCR. Vivax monoinfection-associated risk of coma was estimated at 1 in 29,486 clinical vivax infections with no deaths. In comparison, the risk of falciparum-associated coma was estimated at 1 in 1,276 clinical infections with an 18.5% mortality rate.
Conclusions
P. vivax-associated coma is rare, occurring 23 times less frequently than that seen with falciparum malaria, and is associated with a high proportion of non-malarial causes and mixed infections using PCR. The pathogenesis of coma associated with vivax malaria, particularly the role of comorbidities, is uncertain and requires further investigation.
Author Summary
An estimated 132 to 391 million cases of Plasmodium vivax occur annually, accounting for up to 50% of malaria cases in South and East Asia. Vivax malaria is called “benign tertian malaria” and is not considered to be associated with life threatening or severe complications. Recently, observational studies and case series or reports have reported features of severe disease normally only seen in falciparum malaria, including coma. However, the majority of these reports did not exclude mixed infections using molecular methods or estimate the risk to the population in an endemic area. In Indonesia Papua, which has a high rate of vivax malaria and drug resistance, we prospectively enrolled all patients with coma and vivax monoinfection by microscopy over a 4 year period. We excluded falciparum malaria by molecular and antigenic methods, and sought evidence for other central nervous system (CNS) infections by cerebrospinal fluid microscopic examination. The majority of patients had evidence of mixed infections with P. falciparum or non-malarial causes of coma, however six patients had clinically significant coma, with no evidence of falciparum malaria or other CNS infections. The study was limited by the absence of bacterial cultures. Our study highlights that P. vivax can be associated with coma, but that this phenomenon is 23 times less frequent than that seen with falciparum malaria and was not associated with a fatal outcome.
doi:10.1371/journal.pntd.0001032
PMCID: PMC3110166  PMID: 21666785
11.  Clinical Features of Children Hospitalized with Malaria—A Study from Bikaner, Northwest India 
Severe Plasmodium vivax malaria in adults has been reported from Bikaner (northwestern India) but the reports on children are scanty. This prospective study was done on 303 admitted children of malaria. The diagnosis was done by peripheral blood smear and rapid diagnostic test. Further confirmation of severe P. vivax monoinfection was done by polymerase chain reaction (PCR). The proportion of P. falciparum, P. vivax, and mixed (P. falciparum and P. vivax) infection was 61.01%, 33.99%, and 4.95%, respectively. Severe disease was present in 49.5% (150/303) children with malaria, with the risk greatest among P. vivax monoinfection (63.1% [65/103]) compared with P. falciparum, either alone (42.7% [79/185]; odds ratio [OR] = 2.3 [95% confidence interval (CI) = 1.40–3.76], P = 0.001) or mixed infections (40% [6/15]; OR = 2.57 [95% CI = 0.88–7.48]). In children < 5 years of age, the proportion of severe malaria attributable to P. vivax rose to 67.4% (31/46) compared with 30.4% (14/46) of P. falciparum (OR = 4.7 [95% CI = 2.6–8.6], P < 0.0001) and 2.2% (1/46) of mixed infection (OR = 92 [95% CI = 24.6–339.9], P < 0.0001). The proportion of patients having severe manifestations, which included severe anemia, thrombocytopenia, cerebral malaria, acute respiratory distress syndrome, hepatic dysfunction, renal dysfunction, abnormal bleeding was significantly high in association with P. vivax monoinfection in 0–5 year age group, while the same was significantly high in association with P. falciparum monoinfection in 5–10 year age group. Similarly P. vivax monoinfection had greatest propensity to cause multiorgan dysfunction in 0–5 year age group (34.1% [17/41], P < 0.0001) in comparison to P. falciparum monoinfection, which had similar propensity in 5–10 year age group (36.8% [35/95], P = 0.039). Plasmodium vivax monoinfection was almost equally serious to cause significant mortality in comparison to P. falciparum (case fatality rate of severe P. vivax was 3.9% versus 3.2% of severe P. falciparum malaria; P = 1.0). This study reaffirms the evidence of severe P. vivax malaria in children in Bikaner.
doi:10.4269/ajtmh.2010.09-0633
PMCID: PMC2963956  PMID: 21036824
12.  Field Evaluation of the ICT Malaria P.f/P.v Immunochromatographic Test for Detection of Plasmodium falciparum and Plasmodium vivax in Patients with a Presumptive Clinical Diagnosis of Malaria in Eastern Indonesia 
Journal of Clinical Microbiology  1999;37(8):2412-2417.
In areas such as eastern Indonesia where both Plasmodium falciparum and Plasmodium vivax occur, rapid antigen detection tests for malaria need to be able to detect both species. We evaluated the new combined P. falciparum-P. vivax immunochromatographic test (ICT Malaria P.f/P.v.) in Radamata Primary Health Centre, Sumba, Indonesia, from February to May 1998 with 560 symptomatic adults and children with a presumptive clinical diagnosis of malaria. Blinded microscopy was used as the “gold standard,” with all discordant and 20% of concordant results cross-checked blindly. Only 50% of those with a presumptive clinical diagnosis of malaria were parasitemic. The ICT Malaria P.f/P.v immunochromatographic test was sensitive (95.5%) and specific (89.8%) for the diagnosis of falciparum malaria, with a positive predictive value (PPV) and a negative predictive value (NPV) of 88.1 and 96.2%, respectively. HRP2 and panmalarial antigen line intensities were associated with parasitemia density for both species. Although the specificity and NPV for the diagnosis of vivax malaria were 94.8 and 98.2%, respectively, the overall sensitivity (75%) and PPV (50%) for the diagnosis of vivax malaria were less than the desirable levels. The sensitivity for the diagnosis of P. vivax malaria was 96% with parasitemias of >500/μl but only 29% with parasitemias of <500/μl. Nevertheless, compared with the test with HRP2 alone, use of the combined antigen detection test would reduce the rate of undertreatment from 14.7 to 3.6% for microscopy-positive patients, and this would be at the expense of only a modest increase in the rate of overtreatment of microscopy-negative patients from 7.1 to 15.4%. Cost remains a major obstacle to widespread use in areas of endemicity.
PMCID: PMC85241  PMID: 10405377
13.  Limitations of microscopy to differentiate Plasmodium species in a region co-endemic for Plasmodium falciparum, Plasmodium vivax and Plasmodium knowlesi 
Malaria Journal  2013;12:8.
Background
In areas co-endemic for multiple Plasmodium species, correct diagnosis is crucial for appropriate treatment and surveillance. Species misidentification by microscopy has been reported in areas co-endemic for vivax and falciparum malaria, and may be more frequent in regions where Plasmodium knowlesi also commonly occurs.
Methods
This prospective study in Sabah, Malaysia, evaluated the accuracy of routine district and referral hospital-based microscopy, and microscopy performed by an experienced research microscopist, for the diagnosis of PCR-confirmed Plasmodium falciparum, P. knowlesi, and Plasmodium vivax malaria.
Results
A total of 304 patients with PCR-confirmed Plasmodium infection were enrolled, including 130 with P. knowlesi, 122 with P. falciparum, 43 with P. vivax, one with Plasmodium malariae and eight with mixed species infections. Among patients with P. knowlesi mono-infection, routine and cross-check microscopy both identified 94 (72%) patients as “P. malariae/P. knowlesi”; 17 (13%) and 28 (22%) respectively were identified as P. falciparum, and 13 (10%) and two (1.5%) as P. vivax. Among patients with PCR-confirmed P. falciparum, routine and cross-check microscopy identified 110/122 (90%) and 112/118 (95%) patients respectively as P. falciparum, and 8/122 (6.6%) and 5/118 (4.2%) as “P. malariae/P. knowlesi”. Among those with P. vivax, 23/43 (53%) and 34/40 (85%) were correctly diagnosed by routine and cross-check microscopy respectively, while 13/43 (30%) and 3/40 (7.5%) patients were diagnosed as “P. malariae/P. knowlesi”. Four of 13 patients with PCR-confirmed P. vivax and misdiagnosed by routine microscopy as “P. malariae/P. knowlesi” were subsequently re-admitted with P. vivax malaria.
Conclusions
Microscopy does not reliably distinguish between P. falciparum, P. vivax and P. knowlesi in a region where all three species frequently occur. Misdiagnosis of P. knowlesi as both P. vivax and P. falciparum, and vice versa, is common, potentially leading to inappropriate treatment, including chloroquine therapy for P. falciparum and a lack of anti-relapse therapy for P. vivax. The limitations of microscopy in P. knowlesi-endemic areas supports the use of unified blood-stage treatment strategies for all Plasmodium species, the development of accurate rapid diagnostic tests suitable for all species, and the use of PCR-confirmation for accurate surveillance.
doi:10.1186/1475-2875-12-8
PMCID: PMC3544591  PMID: 23294844
Plasmodium knowlesi; Malaria; Microscopy; Diagnosis
14.  Severe Plasmodium falciparum and Plasmodium vivax malaria among adults at Kassala Hospital, eastern Sudan 
Malaria Journal  2013;12:148.
Background
There have been few published reports on severe Plasmodium falciparum and Plasmodium vivax malaria among adults in Africa.
Methods
Clinical pattern/manifestations of severe P. falciparum and P. vivax (according to World Health Organization 2000 criteria) were described in adult patients admitted to Kassala Hospital, eastern Sudan.
Results
A total of 139 adult patients (80 males, 57.6%) with a mean (SD) age of 37.2 (1.5) years presented with severe P. falciparum (113, 81.3%) or P. vivax (26, 18.7%) malaria. Manifestations among the 139 patients included hypotension (38, 27.3%), cerebral malaria (23, 16.5%), repeated convulsions (18, 13.0%), hypoglycaemia (15, 10.8%), hyperparasitaemia (14, 10.1%), jaundice (14, 10.1%), severe anaemia (10, 7.2%), bleeding (six, 4.3%), renal impairment (one, 0.7%) and more than one criteria (27, 19.4%). While the geometric mean of the parasite count was significantly higher in patients with severe P. vivax than with severe P. falciparum malaria (5,934.2 vs 13,906.6 asexual stage parasitaemia per μL, p = 0.013), the different disease manifestations were not significantly different between patients with P. falciparum or P. vivax malaria. Three patients (2.2%) died due to severe P. falciparum malaria. One had cerebral malaria, the second had renal impairment, jaundice and hypoglycaemia, and the third had repeated convulsions and hypotension.
Conclusions
Severe malaria due to P. falciparum and P. vivax malaria is an existing entity among adults in eastern Sudan. Patients with severe P. falciparum and P. vivax develop similar disease manifestations.
doi:10.1186/1475-2875-12-148
PMCID: PMC3655045  PMID: 23634728
Plasmodium falciparum; Plasmodium vivax; Severe malaria; Sudan
15.  Is Plasmodium vivax Malaria a Severe Malaria?: A Systematic Review and Meta-Analysis 
Background
Plasmodium vivax is one of the major species of malaria infecting humans. Although emphasis on P. falciparum is appropriate, the burden of vivax malaria should be given due attention. This study aimed to synthesize the evidence on severe malaria in P. vivax infection compared with that in P. falciparum infection.
Methods/Principal Findings
We searched relevant studies in electronic databases. The main outcomes required for inclusion in the review were mortality, severe malaria (SM) and severe anaemia (SA). The methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale. Overall, 26 studies were included. The main meta-analysis was restricted to the high quality studies. Eight studies (n = 27490) compared the incidence of SM between P. vivax infection and P. falciparum mono-infection; a comparable incidence was found in infants (OR: 0.45, 95% CI:0.04–5.68, I2:98%), under 5 year age group (OR: 2.06, 95% CI: 0.83–5.1, I2:83%), the 5–15 year-age group (OR: 0.6, 95% CI: 0.31–1.16, I2:81%) and adults (OR: 0.83, 95% CI: 0.67–1.03, I2:25%). Six studies reported the incidences of SA in P. vivax infection and P. falciparum mono-infection; a comparable incidence of SA was found among infants (OR: 3.47, 95%:0.64–18.94, I2: 92%), the 5–15 year-age group (OR:0.71, 95% CI: 0.06–8.57, I2:82%). This was significantly lower in adults (OR:0.75, 95% CI: 0.62–0.92, I2:0%). Five studies (n = 71079) compared the mortality rate between vivax malaria and falciparum malaria. A lower rate of mortality was found in infants with vivax malaria (OR:0.61, 95% CI:0.5–0.76, I2:0%), while this was comparable in the 5–15 year- age group (OR: 0.43, 95% CI:0.06–2.91, I2:84%) and the children of unspecified-age group (OR: 0.77, 95% CI:0.59–1.01, I2:0%).
Conclusion
Overall, the present analysis identified that the incidence of SM in patients infected with P. vivax was considerable, indicating that P. vivax is a major cause of SM. Awareness of the clinical manifestations of vivax malaria should prompt early detection. Subsequent treatment and monitoring of complications can be life-saving.
Author Summary
Until recently, vivax malaria has received less attention than falciparum malaria and was deemed neglected. There has been a surge in studies that documented the contribution of Plasmodium vivax to severe malaria in some endemic countries such as Thailand, Brazil, Indonesia, Papua New Guinea and India. We aimed to synthesize the evidence on severe malaria in P. vivax infection compared with that in P. falciparum infection. We searched relevant studies in electronic databases. The combined results of the eight relatively high quality studies showed a comparable incidence between vivax malaria and falciparum malaria in infants, under 5 year age group, the 5–15 year age group and adults. The combined results of the six relatively high quality studies revealed a comparable incidence of severe anaemia between P. vivax infection and P. falciparum mono-infection in both the infants and the 5–15 year age group. Considering that severe malaria and deaths attributable to P. vivax is not a rare event, raised clinical awareness of the manifestations of vivax malaria in patients of any age should prompt early detection of malaria. It is likely that early detection, appropriate treatment commenced in a timely manner and close monitoring of any complications could be life-saving and contribute to the attainment of the global vision of no malaria deaths.
doi:10.1371/journal.pntd.0003071
PMCID: PMC4133404  PMID: 25121491
16.  Reduced Risk of Plasmodium vivax Malaria in Papua New Guinean Children with Southeast Asian Ovalocytosis in Two Cohorts and a Case-Control Study 
PLoS Medicine  2012;9(9):e1001305.
Ivo Mueller and colleagues examined the association of Southeast Asian ovalocytosis with Plasmodium vivax infection by genotyping 1975 children enrolled in three independent epidemiological studies conducted in the Madang area of Papua New Guinea and assessing P. vivax infection and disease in the children.
Background
The erythrocyte polymorphism, Southeast Asian ovalocytosis (SAO) (which results from a 27-base pair deletion in the erythrocyte band 3 gene, SLC4A1Δ27) protects against cerebral malaria caused by Plasmodium falciparum; however, it is unknown whether this polymorphism also protects against P. vivax infection and disease.
Methods and Findings
The association between SAO and P. vivax infection was examined through genotyping of 1,975 children enrolled in three independent epidemiological studies conducted in the Madang area of Papua New Guinea. SAO was associated with a statistically significant 46% reduction in the incidence of clinical P. vivax episodes (adjusted incidence rate ratio [IRR] = 0.54, 95% CI 0.40–0.72, p<0.0001) in a cohort of infants aged 3–21 months and a significant 52% reduction in P. vivax (blood-stage) reinfection diagnosed by PCR (95% CI 22–71, p = 0.003) and 55% by light microscopy (95% CI 13–77, p = 0.014), respectively, in a cohort of children aged 5–14 years. SAO was also associated with a reduction in risk of P. vivax parasitaemia in children 3–21 months (1,111/µl versus 636/µl, p = 0.011) and prevalence of P. vivax infections in children 15–21 months (odds ratio [OR] = 0.39, 95% CI 0.23–0.67, p = 0.001). In a case-control study of children aged 0.5–10 years, no child with SAO was found among 27 cases with severe P. vivax or mixed P. falciparum/P. vivax malaria (OR = 0, 95% CI 0–1.56, p = 0.11). SAO was associated with protection against severe P. falciparum malaria (OR = 0.38, 95% CI 0.15–0.87, p = 0.014) but no effect was seen on either the risk of acquiring blood-stage infections or uncomplicated episodes with P. falciparum. Although Duffy antigen receptor expression and function were not affected on SAO erythrocytes compared to non-SAO children, high level (>90% binding inhibition) P. vivax Duffy binding protein–specific binding inhibitory antibodies were observed significantly more often in sera from SAO than non-SAO children (SAO, 22.2%; non-SAO, 6.7%; p = 0.008).
Conclusions
In three independent studies, we observed strong associations between SAO and protection against P. vivax malaria by a mechanism that is independent of the Duffy antigen. P. vivax malaria may have contributed to shaping the unique host genetic adaptations to malaria in Asian and Oceanic populations.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Hereditary blood disorders are widely prevalent in different regions around the world and the type of disorder depends on the population gene pool. For example, sickle cell disease is indigenous to sub-Saharan Africa, and Southeast Asian ovalocytosis (SAO), as the name suggests, to Southeast Asia and the South West Pacific, particularly Malaysia and Papua New Guinea. In SAO, the red blood cells (erythrocytes) are a different shape (elliptical) from the usual biconcave disc shape due to a genetic defect (caused by band 3 deletion SLC4A1Δ27) in the red blood cell membrane. This defect is carried by up to 35% of people living on the coasts of Papua New Guinea, and as these areas match high malaria endemic areas, it is thought that carrying this defect is associated with improved survival against malaria in these populations—some studies have suggested that SAO is associated with complete protection against cerebral malaria but not other forms of malaria caused by the same type of parasite—P. falciparum.
Why Was This Study Done?
Although P. falciparum gains most attention by the international health community as it causes the most severe types of malaria, recent epidemiological studies suggest that malaria caused by P. vivax can also cause severe illness in some areas of the world where it is highly prevalent. Furthermore, detailed genetic and laboratory studies have suggested that the genetic defect associated with SAO may actually protect against infection from P. vivax malaria. So in this study, the researchers examined the relationship of the SAO genetic defect and P. vivax malaria by doing genetic tests on children in Papua New Guinea—an area in which both conditions are widely prevalent.
What Did the Researchers Do and Find?
The researchers performed genetic tests for the SAO defect in 1,975 children in the Madang area of Papua New Guinea who were participating in three separate malaria studies that were conducted over different time periods: (i) a cohort of 1,121 infants aged 3–21 months participating in a clinical drug trial of intermittent preventative treatment of malaria; (ii) a case-control study of 318 children with severe malaria aged 10 years and under; and (iii) a cohort of 206 children aged 5–14 years who took part in a prospective study to evaluate the time of reinfection with all forms of malaria. Given the different nature of these studies, for example, the effect of intermittent treatment for which the researchers had to make statistical adjustments, the researchers analysed the presence of the SAO genetic defect and the incidence of all forms of malaria separately to calculate the association with SAO and malaria in the participants in each study.
The researchers found that the SAO genetic defect present in 130 infants (11.6%) in the first study and 27 (13.1%) children in the third study. In the case-control study, the researchers found that 28 of the 330 controls (8.5%) had the SAO genetic defect compared to eight of 236 (3.4%) in children with P. falciparum single infections. Overall, the researchers found that the SAO genetic defect was associated with a 43% reduction in risk of clinical P. vivax episodes in the infants in the first study and a 52%–55% reduction in P. vivax reinfection in children in the third study. Furthermore, from the limited data from the second study, the researchers found that none of the children with P. vivax or mixed P. falciparum/P. vivax malaria had the SAO defect, which may indicate a protective effect.
What Do These Findings Mean?
These findings suggest that the SAO genetic defect (SLC4A1Δ27) may have a protective effect against malaria caused by P. vivax in infants and children of different ages in Papua New Guinea. However, although it seems likely that SAO may alter the ability of the malarial parasite to develop within the red blood cell, this study sheds no further light on the way in which the SAO genetic defect may protect against P. vivax infection and disease and so further studies are needed to investigate possible mechanisms. Importantly, these findings suggest that future studies investigating genetic adaptation of diverse populations around the world, particularly in the Asian Pacific region, should include all forms of human malaria, such as P. vivax, and not exclusively focus on P. falciparum.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001305.
Wikipedia has information on Southeast Asian Ovalocytosis (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
WHO provides information on malaria
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish)
MedlinePlus provides links to additional information on malaria and on ovalocytosis
doi:10.1371/journal.pmed.1001305
PMCID: PMC3433408  PMID: 22973182
17.  Plasma Superoxide Dismutase-1 as a Surrogate Marker of Vivax Malaria Severity 
Background
Severe outcomes have been described for both Plasmodium falciparum and P. vivax infections. The identification of sensitive and reliable markers of disease severity is fundamental to improving patient care. An intense pro-inflammatory response with oxidative stress and production of reactive oxygen species is present in malaria. Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and antioxidant agents such as superoxide dismutase-1 (SOD-1) are likely candidate biomarkers for disease severity. Here we tested whether plasma levels of SOD-1 could serve as a biomarker of severe vivax malaria.
Methodology/Principal Findings
Plasma samples were obtained from residents of the Brazilian Amazon with a high risk for P. vivax transmission. Malaria diagnosis was made by both microscopy and nested PCR. A total of 219 individuals were enrolled: non-infected volunteers (n = 90) and individuals with vivax malaria: asymptomatic (n = 60), mild (n = 50) and severe infection (n = 19). SOD-1 was directly associated with parasitaemia, plasma creatinine and alanine amino-transaminase levels, while TNF-alpha correlated only with the later enzyme. The predictive power of SOD-1 and TNF-alpha levels was compared. SOD-1 protein levels were more effective at predicting vivax malaria severity than TNF-alpha. For discrimination of mild infection, elevated SOD-1 levels showed greater sensitivity than TNF-alpha (76% vs. 30% respectively; p<0.0001), with higher specificity (100% vs. 97%; p<0.0001). In predicting severe vivax malaria, SOD-1 levels exhibited higher sensitivity than TNF-alpha (80% vs. 56%, respectively; p<0.0001; likelihood ratio: 7.45 vs. 3.14; p<0.0001). Neither SOD-1 nor TNF-alpha could discriminate P. vivax infections from those caused by P. falciparum.
Conclusion
SOD-1 is a powerful predictor of disease severity in individuals with different clinical presentations of vivax malaria.
Author Summary
Despite being considered a relatively benign disease, Plasmodium vivax infection has been associated with fatal outcomes due to treatment failure or inadequate health care. The identification of sensitive and reliable markers of disease severity is important to improve the quality of patient care. Although not imperative, a good marker should have a close causative relationship with the disease pathogenesis. During acute malaria, an intense inflammatory response and a well-documented oxidative burst are noted. Among the free radicals released, superoxide anions account for the great majority. The present study aimed to evaluate the reliability of using an antioxidant enzyme, responsible for the clearance of superoxide anions, as a marker of vivax malaria severity. Thus, we investigated individuals from an Amazonian region highly endemic for vivax malaria with the goal of predicting infection severity by measuring superoxide dismutase-1 (SOD-1) plasma levels. In addition, we compared the predictive power SOD-1 to that of the tumor necrosis factor (TNF)-alpha. SOD-1 was a more powerful predictor of disease severity than TNF-alpha in individuals with different clinical presentations of vivax malaria. This finding opens up new approaches in the initial screening of severe vivax malaria cases.
doi:10.1371/journal.pntd.0000650
PMCID: PMC2850307  PMID: 20386593
18.  Diagnosing Severe Falciparum Malaria in Parasitaemic African Children: A Prospective Evaluation of Plasma PfHRP2 Measurement 
PLoS Medicine  2012;9(8):e1001297.
Arjen Dondorp and colleagues investigate whether the plasma level of Plasmodium falciparum histidine-rich protein 2 can be used to distinguish between severe malaria and other severe febrile illness in African children with malaria.
Background
In African children, distinguishing severe falciparum malaria from other severe febrile illnesses with coincidental Plasmodium falciparum parasitaemia is a major challenge. P. falciparum histidine-rich protein 2 (PfHRP2) is released by mature sequestered parasites and can be used to estimate the total parasite burden. We investigated the prognostic significance of plasma PfHRP2 and used it to estimate the malaria-attributable fraction in African children diagnosed with severe malaria.
Methods and Findings
Admission plasma PfHRP2 was measured prospectively in African children (from Mozambique, The Gambia, Kenya, Tanzania, Uganda, Rwanda, and the Democratic Republic of the Congo) aged 1 month to 15 years with severe febrile illness and a positive P. falciparum lactate dehydrogenase (pLDH)-based rapid test in a clinical trial comparing parenteral artesunate versus quinine (the AQUAMAT trial, ISRCTN 50258054). In 3,826 severely ill children, Plasmadium falciparum PfHRP2 was higher in patients with coma (p = 0.0209), acidosis (p<0.0001), and severe anaemia (p<0.0001). Admission geometric mean (95%CI) plasma PfHRP2 was 1,611 (1,350–1,922) ng/mL in fatal cases (n = 381) versus 1,046 (991–1,104) ng/mL in survivors (n = 3,445, p<0.0001), without differences in parasitaemia as assessed by microscopy. There was a U-shaped association between log10 plasma PfHRP2 and risk of death. Mortality increased 20% per log10 increase in PfHRP2 above 174 ng/mL (adjusted odds ratio [AOR] 1.21, 95%CI 1.05–1.39, p = 0.009). A mechanistic model assuming a PfHRP2-independent risk of death in non-malaria illness closely fitted the observed data and showed malaria-attributable mortality less than 50% with plasma PfHRP2≤174 ng/mL. The odds ratio (OR) for death in artesunate versus quinine-treated patients was 0.61 (95%CI 0.44–0.83, p = 0.0018) in the highest PfHRP2 tertile, whereas there was no difference in the lowest tertile (OR 1.05; 95%CI 0.69–1.61; p = 0.82). A limitation of the study is that some conclusions are drawn from a mechanistic model, which is inherently dependent on certain assumptions. However, a sensitivity analysis of the model indicated that the results were robust to a plausible range of parameter estimates. Further studies are needed to validate our findings.
Conclusions
Plasma PfHRP2 has prognostic significance in African children with severe falciparum malaria and provides a tool to stratify the risk of “true” severe malaria-attributable disease as opposed to other severe illnesses in parasitaemic African children.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Malaria is a life-threatening disease caused by parasites that are transmitted to people through the bites of infected mosquitoes. In 2010, malaria caused an estimated 655,000 deaths worldwide, mostly in Africa, where according to the World Health Organization, one African child dies every minute from the disease. There are four Plasmodium parasite species that cause malaria in humans, with one species, Plasmodium falciparum, causing the most severe disease. However, diagnosing severe falciparum malaria in children living in endemic areas is problematic, as many semi-immune children may have the malaria parasites in their blood (described as being parasitaemic) but do not have clinical disease. Therefore, a positive malaria blood smear may be coincidental and not be diagnostic of severe malaria, and unfortunately, neither are the clinical symptoms of severe malaria, such as shock, acidosis, or coma, which can also be caused by other childhood infections. For these reasons, the misdiagnosis of falciparum malaria in severely ill children is an important problem in sub-Saharan Africa, and may result in unnecessary child deaths.
Why Was This Study Done?
Previous studies have suggested that a parasite protein—P. falciparum histidine-rich protein-2 (PfHRP2)—is a measure of the total number of parasites in the patient. Unlike the circulating parasites detected on a blood film, which do not represent the parasites that get stuck in vital organs, PfHRP2 is distributed equally through the total blood plasma volume, and so can be considered a measure of the total parasite burden in the previous 48 hours. So in this study, the researchers assessed the prognostic value of plasma PfHRP2 in African children with severe malaria and whether this protein could distinguish children who really do have severe malaria from those who have severe febrile illness but coincidental parasitaemia, who may have another infection.
What Did the Researchers Do and Find?
The researchers assessed levels of plasma PfHRP2 in 3,826 out of a possible 5,425 African children who participated in a large multinational trial (in Mozambique, The Gambia, Rwanda, Tanzania, Kenya, Uganda, and the Democratic Republic of Congo) that compared the anti-malarial drugs quinine and artesunate for the treatment of severe malaria. All children had a clinical diagnosis of severe malaria confirmed by a rapid diagnostic test, and the researchers used clinical signs to define the severity of malaria. The researchers assessed the relationship between plasma PfHRP2 concentrations and risk of death taking other well established predictors of death, such as coma, convulsions, hypoglycaemia, respiratory distress, and shock, into account.
The researchers found that PfHRP2 was detectable in 3,800/3,826 (99%) children with severe malaria and that the average plasma PfHRP2 levels was significantly higher in the 381 children who died from malaria than in children who survived (1,611 ng/mL versus 1,046 ng/mL). Plasma PfHRP2 was also significantly higher in children with severe malaria signs and symptoms such as coma, acidosis, and severe anaemia. Importantly, the researchers found that high death rates were associated with either very low or very high values of plasma PfHRP2: the odds (chance) of death were 20% higher per unit increase in PfHRP2 above a specific threshold (174 ng/ml), but below this concentration, the risk of death increased with decreasing levels, probably because at lower levels disease was caused by a severe febrile disease other than malaria, like septicemia. Finally, the researchers found that in children within the highest PfHRP2 tertile, the chance of death when treated with the antimalarial drug artesunate versus quinine was 0.61 but that there was no difference in death rates in the lowest tertile, which supports that patients with very low plasma PfHRP2 have a different severe febrile illness than malaria. The researchers use mathematical modeling to provide cut-off values for plasma PfHRP2 denoting the proportion of patients with a diagnosis other than severe malaria.
What Do These Findings Mean?
These findings suggest that in areas of moderate or high malaria transmission where a high proportion of children are parasitaemic, plasma PfHRP2 levels taken on admission to hospital can differentiate children at highest risk of death from severe falciparum malaria from those likely to have alternative causes of severe febrile illness. Therefore, plasma PfHRP2 could be considered a valuable additional diagnostic tool and prognostic indicator in African children with severe falciparum malaria. This finding is important for clinicians treating children with severe febrile illnesses in malaria-endemic countries: while high levels of plasma PfHRP2 is indicative of severe malaria which needs urgent antimalarial treatment, low levels suggest that another severe infective disease should be considered, warranting additional investigations and urgent treatment with antibiotics.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001297.
A previous small study in PLOS ONE explores the relationship between plasma PfHRP2 and severe malaria in Tanzanian children
The WHO website and the website of Malaria No More have comprehensive information about malaria
doi:10.1371/journal.pmed.1001297
PMCID: PMC3424256  PMID: 22927801
19.  Congenital Malaria in China 
Abstract
Background
Congenital malaria, in which infants are directly infected with malaria parasites from their mother prior to or during birth, is a potentially life-threatening condition that occurs at relatively low rates in malaria-endemic regions. It is recognized as a serious problem in Plasmodium falciparum–endemic sub-Saharan Africa, where recent data suggests that it is more common than previously believed. In such regions where malaria transmission is high, neonates may be protected from disease caused by congenital malaria through the transfer of maternal antibodies against the parasite. However, in low P. vivax–endemic regions, immunity to vivax malaria is low; thus, there is the likelihood that congenital vivax malaria poses a more significant threat to newborn health. Malaria had previously been a major parasitic disease in China, and congenital malaria case reports in Chinese offer valuable information for understanding the risks posed by congenital malaria to neonatal health. As most of the literature documenting congenital malaria cases in China are written in Chinese and therefore are not easily accessible to the global malaria research community, we have undertaken an extensive review of the Chinese literature on this subject.
Methods/Principal Findings
Here, we reviewed congenital malaria cases from three major searchable Chinese journal databases, concentrating on data from 1915 through 2011. Following extensive screening, a total of 104 cases of congenital malaria were identified. These cases were distributed mainly in the eastern, central, and southern regions of China, as well as in the low-lying region of southwest China. The dominant species was P. vivax (92.50%), reflecting the malaria parasite species distribution in China. The leading clinical presentation was fever, and other clinical presentations were anaemia, jaundice, paleness, diarrhoea, vomiting, and general weakness. With the exception of two cases, all patients were cured with antimalarial drugs such as chloroquine, quinine, artemether, and artesunate.
Conclusions
The symptoms of congenital malaria vary significantly between cases, so clear and early diagnosis is difficult. We suggest that active surveillance might be necessary for neonates born to mothers with a history of malaria.
doi:10.1371/journal.pntd.0002622
PMCID: PMC3953009  PMID: 24626148
20.  Combining Parasite Lactate Dehydrogenase-Based and Histidine-Rich Protein 2-Based Rapid Tests To Improve Specificity for Diagnosis of Malaria Due to Plasmodium knowlesi and Other Plasmodium Species in Sabah, Malaysia 
Journal of Clinical Microbiology  2014;52(6):2053-2060.
Plasmodium knowlesi causes severe and fatal malaria in Malaysia. Microscopic misdiagnosis is common and may delay appropriate treatment. P. knowlesi can cross-react with “species-specific” parasite lactate dehydrogenase (pLDH) monoclonal antibodies used in rapid diagnostic tests (RDTs) to detect P. falciparum and P. vivax. At one tertiary-care hospital and two district hospitals in Sabah, we prospectively evaluated two combination RDTs for malaria diagnosis by using both a pan-Plasmodium-pLDH (pan-pLDH)/P. falciparum-specific-pLDH (Pf-pLDH) RDT (OptiMAL-IT) and a non-P. falciparum VOM-pLDH/Pf-HRP2 RDT (CareStart). Differential cross-reactivity among these combinations was hypothesized to differentiate P. knowlesi from other Plasmodium monoinfections. Among 323 patients with PCR-confirmed P. knowlesi (n = 193), P. falciparum (n = 93), and P. vivax (n = 37) monoinfections, the VOM-pLDH individual component had the highest sensitivity for nonsevere (35%; 95% confidence interval [CI], 27 to 43%) and severe (92%; CI, 81 to 100%) P. knowlesi malaria. CareStart demonstrated a P. knowlesi sensitivity of 42% (CI, 34 to 49%) and specificity of 74% (CI, 65 to 82%), a P. vivax sensitivity of 83% (CI, 66 to 93%) and specificity of 71% (CI, 65 to 76%), and a P. falciparum sensitivity of 97% (CI, 90 to 99%) and specificity of 99% (CI, 97 to 100%). OptiMAL-IT demonstrated a P. knowlesi sensitivity of 32% (CI, 25 to 39%) and specificity of 21% (CI, 15 to 29%), a P. vivax sensitivity of 60% (CI, 42 to 75%) and specificity of 97% (CI, 94 to 99%), and a P. falciparum sensitivity of 82% (CI, 72 to 89%) and specificity of 39% (CI, 33 to 46%). The combination of CareStart plus OptiMAL-IT for P. knowlesi using predefined criteria gave a sensitivity of 25% (CI, 19 to 32%) and specificity of 97% (CI, 92 to 99%). Combining two RDT combinations was highly specific for P. knowlesi malaria diagnosis; however, sensitivity was poor. The specificity of pLDH RDTs was decreased for P. vivax and P. falciparum because of P. knowlesi cross-reactivity and cautions against their use alone in areas where P. knowlesi malaria is endemic. Sensitive P. knowlesi-specific RDTs and/or alternative molecular diagnostic tools are needed in areas where P. knowlesi malaria is endemic.
doi:10.1128/JCM.00181-14
PMCID: PMC4042751  PMID: 24696029
21.  Clinical spectrum and treatment outcome of severe malaria caused by Plasmodium vivax in 18 children from northern India 
Pathogens and Global Health  2013;107(4):210-214.
Objective
The study was intended to document the clinical profile and treatment outcome of severe malaria caused by Plasmodium vivax (P.vivax) in children hospitalized in a tertiary care centre of northern India.
Methods
This prospective observational study was performed among children admitted with severe malaria at a tertiary care referral hospital of northern India from January 2012 to December 2012. Information was recorded pertaining to clinical symptoms at presentation, examination findings, biochemical and hematological investigation, and treatment outcome. Presence of malarial parasite on thick and thin smears and/or positive parasite lactate dehydrogenase (p-LDH) based rapid malaria antigen test was considered diagnostic of ‘malaria’. Based on the etiology, children were categorized into three groups: P.vivax, Plasmodium falciparum (P. falciparum) and mixed infection. Children diagnosed with ‘severe malaria’ (World Health Organization, 2000), were started on intravenous artesunate followed by artemether-lumefantrine combination.
Results
Thirty-five children with a diagnosis of severe malaria were enrolled [18 (51.4%) P. vivax, nine (25.7%) mixed infection, eight (22.8%) P. falciparum]. Clinical features of severe vivax malaria (n = 18) were abnormal sensorium [9 (50%)], multiple seizures [8 (44.4%)], jaundice [5 (27.8%)], severe anaemia [5 (27.8%)], and shock [3 (16.7%)]. Two children [2/18 (11.1%)] infected with P. vivax had died of cerebral malaria, acute respiratory distress syndrome, shock, and metabolic acidosis. The clinical presentation and outcome of severe vivax malaria was found to be similar to severe malaria caused by P. falciparum and mixed infection, except for higher chances of severe anaemia among the children infected with P. falciparum (P = 0.04).
Conclusion
The present study highlights P. vivax as an increasingly recognized causative agent for severe malaria in children from Rohtak, with similar clinical presentation and outcome to that caused by P. falciparum.
doi:10.1179/2047773213Y.0000000096
PMCID: PMC4001474  PMID: 23816514
Malaria; Plasmodium vivax; Plasmodium falciparum; Severe malaria; India
22.  Temporal trends in severe malaria in Chittagong, Bangladesh 
Malaria Journal  2012;11:323.
Background
Epidemiological data on malaria in Bangladesh are sparse, particularly on severe and fatal malaria. This hampers the allocation of healthcare provision in this resource-poor setting. Over 85% of the estimated 150,000-250,000 annual malaria cases in Bangladesh occur in Chittagong Division with 80% in the Chittagong Hill Tracts (CHT). Chittagong Medical College Hospital (CMCH) is the major tertiary referral hospital for severe malaria in Chittagong Division.
Methods
Malaria screening data from 22,785 inpatients in CMCH from 1999–2011 were analysed to investigate the patterns of referral, temporal trends and geographical distribution of severe malaria in Chittagong Division, Bangladesh.
Results
From 1999 till 2011, 2,394 malaria cases were admitted, of which 96% harboured Plasmodium falciparum and 4% Plasmodium vivax. Infection was commonest in males (67%) between 15 and 34 years of age. Seasonality of malaria incidence was marked with a single peak in P. falciparum transmission from June to August coinciding with peak rainfall, whereas P. vivax showed an additional peak in February-March possibly representing relapse infections. Since 2007 there has been a substantial decrease in the absolute number of admitted malaria cases. Case fatality in severe malaria was 18% from 2008–2011, remaining steady during this period.
A travel history obtained in 226 malaria patients revealed only 33% had been to the CHT in the preceding three weeks. Of all admitted malaria patients, only 9% lived in the CHT, and none in the more remote malaria endemic regions near the Indian border.
Conclusions
The overall decline in admitted malaria cases to CMCH suggests recent control measures are successful. However, there are no reliable data on the incidence of severe malaria in the CHT, the most endemic area of Bangladesh, and most of these patients do not reach tertiary health facilities. Improvement of early treatment and simple supportive care for severe malaria in remote areas and implementation of a referral system for cases requiring additional supportive care could be important contributors to further reducing malaria-attributable disease and death in Bangladesh.
doi:10.1186/1475-2875-11-323
PMCID: PMC3544696  PMID: 22970881
Malaria; Bangladesh; Epidemiology; Incidence; Severe; Falciparum; Vivax
23.  Plasmodium vivax Invasion of Human Erythrocytes Inhibited by Antibodies Directed against the Duffy Binding Protein 
PLoS Medicine  2007;4(12):e337.
Background
Plasmodium vivax invasion requires interaction between the human Duffy antigen on the surface of erythrocytes and the P. vivax Duffy binding protein (PvDBP) expressed by the parasite. Given that Duffy-negative individuals are resistant and that Duffy-negative heterozygotes show reduced susceptibility to blood-stage infection, we hypothesized that antibodies directed against region two of P. vivax Duffy binding protein (PvDBPII) would inhibit P. vivax invasion of human erythrocytes.
Methods and Findings
Using a recombinant region two of the P. vivax Duffy binding protein (rPvDBPII), polyclonal antibodies were generated from immunized rabbits and affinity purified from the pooled sera of 14 P. vivax–exposed Papua New Guineans. It was determined by ELISA and by flow cytometry, respectively, that both rabbit and human antibodies inhibited binding of rPvDBPII to the Duffy antigen N-terminal region and to Duffy-positive human erythrocytes. Additionally, using immunofluorescent microscopy, the antibodies were shown to attach to native PvDBP on the apical end of the P. vivax merozoite. In vitro invasion assays, using blood isolates from individuals in the Mae Sot district of Thailand, showed that addition of rabbit anti-PvDBPII Ab or serum (antibodies against, or serum containing antibodies against, region two of the Plasmodium vivax Duffy binding protein) (1:100) reduced the number of parasite invasions by up to 64%, while pooled PvDBPII antisera from P. vivax–exposed people reduced P. vivax invasion by up to 54%.
Conclusions
These results show, for what we believe to be the first time, that both rabbit and human antibodies directed against PvDBPII reduce invasion efficiency of wild P. vivax isolated from infected patients, and suggest that a PvDBP-based vaccine may reduce human blood-stage P. vivax infection.
Christopher King and colleagues found that both rabbit and human antibodies inhibited binding of rPvDBPII to the Duffy antigen N-terminal region and to Duffy-positive human erythrocytes, suggesting that a PvDBP-based vaccine may reduce blood stage Plasmodium vivax infection.
Editors' Summary
Background.
Malaria is a parasitic infection transmitted to people through the bite of an infected mosquito. Four different parasites cause malaria—the commonest and most widely distributed of these is Plasmodium vivax. Infections with P. vivax are rarely fatal, but they cause debilitating chills and fevers that recur every other day if untreated. Like other malaria parasites, P. vivax has a complex life cycle. Infected mosquitoes inject a form of the parasite known as sporozoites into people. The sporozoites replicate inside liver cells without causing any symptoms. Then, 8–9 d later, merozoites (another form of the parasite) are released from the liver cells and invade young red blood cells. Here, they replicate rapidly before bursting out and infecting more red blood cells. The characteristic symptoms of malaria are caused by this cyclical increase in the parasite burden. P. vivax infections are usually treated with chloroquine, but patients must also take a second drug called primaquine. This drug kills hypnozoites, a form of the parasite that hibernates in the liver and that can cause a relapse many months after the initial bout of malaria.
Why Was This Study Done?
P. vivax is becoming resistant to chloroquine and, although other antimalarial drugs still kill it, a vaccine that would limit the severity of P. vivax infections by blocking its ability to invade red blood cells is urgently needed. The invasion of red blood cells by P. vivax depends on an interaction between the Duffy antigen (a protein on the surface of human red blood cells) and the Duffy binding protein (PvDBP), which is expressed by merozoites. People who lack the Duffy antigen are resistant to blood-stage infections of P. vivax. Similarly, people who express half the normal amount of Duffy antigen on their red blood cells have reduced susceptibility to these infections. In this study, the researchers investigated whether antibodies (proteins made by the immune system that recognize foreign proteins) directed against PvDBP inhibit the invasion of human red blood cells by P. vivax.
What Did the Researchers Do and Find?
The researchers injected a fragment of PvDBP called PvDBPII into rabbits and purified the part of the blood that contains antibodies from the animals. They also isolated antibodies to PvDBPII from the blood of several Papua New Guineans who had been exposed to P. vivax. Both types of antibodies bound to PvDBPII in test tubes and to PvDBP expressed on P. vivax merozoites. Then, the researchers showed that both types of antibody inhibited the binding of PvDBPII to Duffy antigen when the antigen was in solution and when it was present on human red blood cells. Finally, to test the ability of the antibodies to inhibit red blood cell invasion by P. vivax, the researchers established short-term cultures of the parasite from blood taken from infected adults living in Thailand. Addition of the rabbit or human antibodies to these cultures inhibited parasite invasion of red blood cells by more than 50%.
What Do These Findings Mean?
These findings show, for what is believed to be the first time, that antibodies recognizing a fragment of PvDBP can partly inhibit the invasion of red blood cells by P. vivax merozoites. The results with the human antibodies are particularly important as they strongly suggest that a PvDBP-based vaccine might provide protection against blood-stage P. vivax infections. Whether the level of inhibition of invasion seen in this study will be sufficient to reduce the clinical severity of these infections will only become clear, however, when a vaccine is tested in people. The findings also indicate that short-term P. vivax cultures can be used to test whether antibodies that recognize other merozoite proteins also inhibit invasion. Unlike P. falciparum (the other major malarial parasite), P. vivax cannot be grown continuously in the laboratory. These short-term cultures will at last provide vaccine developers with a way to evaluate antigens as candidates for inclusion in P. vivax vaccines.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040337.
MedlinePlus encyclopedia page on malaria (in English and Spanish)
Information from the US Centers for Disease Control and Prevention on malaria (in English and Spanish)
Vivaxmalaria, information for the malaria research community on topics related to Plasmodium vivax
Information from the Malaria Vaccine Initiative about malaria and malaria vaccines, including a fact sheet on Plasmodium vivax malaria
doi:10.1371/journal.pmed.0040337
PMCID: PMC2140086  PMID: 18092885
24.  Parasite Biomass-Related Inflammation, Endothelial Activation, Microvascular Dysfunction and Disease Severity in Vivax Malaria 
PLoS Pathogens  2015;11(1):e1004558.
Plasmodium vivax can cause severe malaria, however its pathogenesis is poorly understood. In contrast to P. falciparum, circulating vivax parasitemia is low, with minimal apparent sequestration in endothelium-lined microvasculature, and pathogenesis thought unrelated to parasite biomass. However, the relationships between vivax disease-severity and total parasite biomass, endothelial autocrine activation and microvascular dysfunction are unknown. We measured circulating parasitemia and markers of total parasite biomass (plasma parasite lactate dehydrogenase [pLDH] and PvLDH) in adults with severe (n = 9) and non-severe (n = 53) vivax malaria, and examined relationships with disease-severity, endothelial activation, and microvascular function. Healthy controls and adults with non-severe and severe falciparum malaria were enrolled for comparison. Median peripheral parasitemia, PvLDH and pLDH were 2.4-fold, 3.7-fold and 6.9-fold higher in severe compared to non-severe vivax malaria (p = 0.02, p = 0.02 and p = 0.015, respectively), suggesting that, as in falciparum malaria, peripheral P. vivax parasitemia underestimates total parasite biomass, particularly in severe disease. P. vivax schizonts were under-represented in peripheral blood. Severe vivax malaria was associated with increased angiopoietin-2 and impaired microvascular reactivity. Peripheral vivax parasitemia correlated with endothelial activation (angiopoietin-2, von-Willebrand-Factor [VWF], E-selectin), whereas markers of total vivax biomass correlated only with systemic inflammation (IL-6, IL-10). Activity of the VWF-cleaving-protease, ADAMTS13, was deficient in proportion to endothelial activation, IL-6, thrombocytopenia and vivax disease-severity, and associated with impaired microvascular reactivity in severe disease. Impaired microvascular reactivity correlated with lactate in severe vivax malaria. Findings suggest that tissue accumulation of P. vivax may occur, with the hidden biomass greatest in severe disease and capable of mediating systemic inflammatory pathology. The lack of association between total parasite biomass and endothelial activation is consistent with accumulation in parts of the circulation devoid of endothelium. Endothelial activation, associated with circulating parasites, and systemic inflammation may contribute to pathology in vivax malaria, with microvascular dysfunction likely contributing to impaired tissue perfusion.
Author Summary
How vivax parasites cause severe malaria is not known. In contrast to falciparum parasites, the number of vivax parasites circulating in peripheral blood is low, and there is thought to be little sequestration of parasitized red cells within endothelium-lined small blood vessels in vital organs. Total parasite burden (circulating plus hidden) and activation and dysfunction of the endothelial cells lining blood vessels all contribute to severe disease in falciparum malaria, but have not been evaluated in severe vivax malaria. We measured parasite lactate dehydrogenase (pLDH) and P. vivax-pLDH (PvLDH) as proxies of total parasite biomass and found that, as in falciparum malaria, the total biomass of vivax parasites is underestimated by counting parasites circulating in peripheral blood, suggesting a hidden burden of vivax parasites. Markers of total vivax biomass were strongly associated with illness-severity and inflammatory cytokines, suggesting that this hidden burden is capable of contributing to generalised inflammation and hence severe disease. Number of peripheral vivax parasites, but not total biomass, correlated with activation of endothelial cells, suggesting that the hidden vivax-infected red cells may accumulate in parts of organs without endothelium, such as the slow-circulation of the spleen or non-blood-vessel parts of the bone marrow. Severe vivax malaria was associated with increased endothelial activation and impaired microvascular function, suggesting that these processes also contribute to impaired blood flow and disease.
doi:10.1371/journal.ppat.1004558
PMCID: PMC4287532  PMID: 25569250
25.  Severity in Plasmodium vivax malaria claiming global vigilance and exploration – a tertiary care centre-based cohort study 
Malaria Journal  2014;13(1):304.
Background
Mounting reports on severe Plasmodium vivax malaria from across the globe have raised concerns among the scientific community. However, the risk of P. vivax resulting in complicated malaria and mortality is not as firmly established as it is with Plasmodium falciparum. This study was conducted to determine the severity proportion and factors associated with severity in cases of vivax and falciparum malaria.
Methods
Adult patients microscopically diagnosed to have P. vivax/P. falciparum infections from the year 2007-2011 were evaluated based on their hospital records. Severe malaria was defined as per the World Health Organization’s guidelines. Comparison was made across species and binary logistic regression was used to determine risk factors of severity.
Results
Of 922 malaria cases included in the study, P. vivax was the largest (63.4%, 95% confidence interval (CI) 60.3-66.5%) infecting species, followed by P. falciparum (34.4%, 95% CI 31.3-37.5%) and their mixed infection (2.2%, 95% CI 1.3-3.2%). Severity in P. vivax and P. falciparum was noted to be 16.9% (95% CI 13.9-19.9%) and 36.3% (95% CI 31.0-41.6%) respectively. Plasmodium falciparum had significantly higher odds [adjusted odds ratio (95% CI), 2.80 (2.04-3.83)] of severe malaria than P. vivax. Rising respiratory rate [1.29 (1.15-1.46)], falling systolic blood pressure [0.96 (0.93-0.99)], leucocytosis [12.87 (1.43-115.93)] and haematuria [59.36 (13.51-260.81)] were the independent predictors of severity in P. vivax. Increasing parasite index [2.97 (1.11-7.98)] alone was the independent predictor of severity in P. falciparum. Mortality in vivax and falciparum malaria was 0.34% (95% CI -0.13-0.81%) and 2.21% (95% CI 0.59-3.83%), respectively. Except hyperparasitaemia and shock, other complications were associated (P < 0.05) with mortality in falciparum malaria. Pulmonary oedema/acute respiratory distress syndrome was associated (P = 0.003) with mortality in vivax malaria. Retrospective design of this study possesses inherent limitations.
Conclusions
Plasmodium vivax does cause severe malaria and mortality in substantial proportion but results in much lesser amalgamations of multi-organ involvements than P. falciparum. Pulmonary oedema/acute respiratory distress syndrome in P. vivax infection could lead to mortality and therefore should be diagnosed and treated promptly. Mounting complications and its broadening spectrum in ‘not so benign’ P. vivax warrants global vigilance for any probable impositions.
Electronic supplementary material
The online version of this article (doi:10.1186/1475-2875-13-304) contains supplementary material, which is available to authorized users.
doi:10.1186/1475-2875-13-304
PMCID: PMC4248447  PMID: 25107355
Plasmodium vivax; Plasmodium falciparum; Malaria; Vivax malaria; Falciparum malaria; Parasitaemia; Severity; Cerebral malaria; Anti-malarials

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