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1.  Immunological testing for malaria and blood donor deferral: the experience of the Ca’ Granda Polyclinic Hospital in Milan 
Blood Transfusion  2011;9(2):162-166.
Background.
Current European regulations require a deferral period of 6 months or 3 years, depending on the risk of exposure, for prospective blood donors at risk of malaria. This period may be reduced to 4 months if an immunological or molecular genomic test is negative at each donation, but Italian regulations have not adopted this provision. As cases of transfusion-transmitted malaria have been recorded in medical literature in blood donors deferred for 3 years and not tested, the Immunohaematology and Transfusion Centre of the Ca’ Grande Polyclinic Hospital in Milan decided to introduce immunological testing for all donors at risk of malaria.
Materials and methods.
Four hundred and twelve blood donors at risk of malaria, who had lived in a malarial area during the first 5 years of life or for more than 6 consecutive months, were tested for malarial antibodies using an enzyme immunoassay kit. The kit (Malaria EIA, Newmarket, UK) uses four recombinant antigens specific for P. falciparum and P. vivax and with cross-reactivity for P. ovale and P. malariae. The kit detects total immunoglobulin antibodies against P. falciparum and P. vivax and shows 80% cross-reactivity with P. ovale and 67% with P. malariae. Antibody-positive samples were further checked by an immunochromatographic test for P. falciparum, P. vivax, P. ovale and P. malariae antigens and by haemoscopy (thin film and thick smear).
Results.
Italian citizens accounted for 16.8% (69/412) of the whole group of donors examined. We found that 8.7% of the donors who were classified as being at risk of malaria were positive for total immunoglobulin antibodies. Only one Italian citizen resulted positive for the test. The positive candidates were deferred from blood donation. None of the antibody-positive donors was confirmed positive by the immunochromatographic test and by haemoscopy.
Conclusion.
The introduction of a malarial screening test in the assessment of blood donor eligibility may increase the safety of blood donations, but could further reduce blood availability. If immunological testing were to be accepted nationally as a valid method of assessing the risk of malaria, more than 90% of the donors who are currently deferred for 3 years could be accepted 4 months after their last visit to an endemic area, thus increasing the availability of blood
doi:10.2450/2011.0158-09
PMCID: PMC3096859  PMID: 21251462
transfusion-transmitted malaria; enzyme immunoassay; donor’s risk
2.  A case report of transfusion-transmitted Plasmodium malariae from an asymptomatic non-immune traveller 
Malaria Journal  2013;12:439.
Background
The incidence of transfusion-transmitted malaria is very low in non-endemic countries due to strict donor selection. The optimal strategy to mitigate the risk of transfusion-transmitted malaria in non-endemic countries without unnecessary exclusion of blood donations is, however, still debated and asymptomatic carriers of Plasmodium species may still be qualified to donate blood for transfusion purposes.
Case description
In April 2011, a 59-year-old Dutch woman with spiking fevers for four days was diagnosed with a Plasmodium malariae infection. The patient had never been abroad, but nine weeks before, she had received red blood cell transfusion for anaemia. The presumptive diagnosis of transfusion-transmitted quartan malaria was made and subsequently confirmed by retrospective PCR analysis of donor blood samples. The donor was a 36-year-old Dutch male who started donating blood in May 2006. His travel history outside Europe included a trip to Kenya, Tanzania and Zanzibar in 2005, to Thailand in 2006 and to Costa Rica in 2007. He only used malaria prophylaxis during his travel to Africa. The donor did not show any abnormalities upon physical examination in 2011, while laboratory examination demonstrated a thrombocytopenia of 126 × 109/L as the sole abnormal finding since 2007. Thick blood smear analysis and the Plasmodium PCR confirmed an ongoing subclinical P. malariae infection. Chloroquine therapy was started, after which the infection cleared and thrombocyte count normalized. Fourteen other recipients who received red blood cells from the involved donor were traced. None of them developed malaria symptoms.
Discussion
This case demonstrates that P. malariae infections in non-immune travellers may occur without symptoms and persist subclinically for years. In addition, this case shows that these infections pose a threat to transfusion safety when subclinically infected persons donate blood after their return in a non-endemic malaria region.
Since thrombocytopenia was the only abnormality associated with the subclinical malaria infection in the donor, this case illustrates that an unexplained low platelet count after a visit to malaria-endemic countries may be an indicator for asymptomatic malaria even when caused by non-falciparum Plasmodium species.
doi:10.1186/1475-2875-12-439
PMCID: PMC3866504  PMID: 24304475
Malaria; Blood transfusion; Blood safety; Blood donor screening; Plasmodium malariae; Transfusion-transmitted malaria; Blood-borne; Infection; Thrombocytopenia; Asymptomatic malaria; Look-back
3.  Influence of Rapid Malaria Diagnostic Tests on Treatment and Health Outcome in Fever Patients, Zanzibar—A Crossover Validation Study 
PLoS Medicine  2009;6(4):e1000070.
Anders Bjorkman and colleagues report results from a cross-over trial evaluating rapid diagnostic testing for malaria diagnosis in Zanzibar.
Background
The use of rapid diagnostic tests (RDTs) for Plasmodium falciparum malaria is being suggested to improve diagnostic efficiency in peripheral health care settings in Africa. Such improved diagnostics are critical to minimize overuse and thereby delay development of resistance to artemisinin-based combination therapies (ACTs). Our objective was to study the influence of RDT-aided malaria diagnosis on drug prescriptions, health outcomes, and costs in primary health care settings.
Methods and Findings
We conducted a cross-over validation clinical trial in four primary health care units in Zanzibar. Patients of all ages with reported fever in the previous 48 hours were eligible and allocated alternate weeks to RDT-aided malaria diagnosis or symptom-based clinical diagnosis (CD) alone. Follow-up was 14 days. ACT was to be prescribed to patients diagnosed with malaria in both groups. Statistical analyses with multilevel modelling were performed. A total of 1,887 patients were enrolled February through August 2005. RDT was associated with lower prescription rates of antimalarial treatment than CD alone, 361/1005 (36%) compared with 752/882 (85%) (odds ratio [OR] 0.04, 95% confidence interval [CI] 0.03–0.05, p<0.001). Prescriptions of antibiotics were higher after RDT than CD alone, i.e., 372/1005 (37%) and 235/882 (27%) (OR 1.8, 95%CI 1.5–2.2, p<0.001), respectively. Reattendance due to perceived unsuccessful clinical cure was lower after RDT 25/1005 (2.5%), than CD alone 43/882 (4.9%) (OR 0.5, 95% CI 0.3–0.9, p = 0.005). Total average cost per patient was similar: USD 2.47 and 2.37 after RDT and CD alone, respectively.
Conclusions
RDTs resulted in improved adequate treatment and health outcomes without increased cost per patient. RDTs may represent a tool for improved management of patients with fever in peripheral health care settings.
Trial Registration
Clinicaltrials.gov NCT00549003
Please see later in the article for Editors' Summary
Editors' Summary
Background
Every year, nearly one million people (mainly children living in sub-Saharan Africa) die because of malaria, a subtropical and tropical parasitic disease. Although several parasites cause malaria, Plasmodium falciparum is responsible for most of these deaths. Indeed, infection with P. falciparum can be fatal within hours if left untreated. For the past 50 years, the main treatments for P. falciparum malaria have been chloroquine and sulfadoxine/pyrimethamine. Unfortunately, parasitic resistance to both of these “monotherapies” is now widespread and the illness and death caused by P. falciparum in sub-Saharan Africa and elsewhere has been increasing. To combat this increase, the World Health Organization now recommends artemisinin combination therapy (ACT) for P. falciparum malaria in all regions with drug-resistant malaria. In ACT, artemisinin derivatives (new, fast-acting antimalarial drugs) are used in combination with another antimalarial to reduce the chances of P. falciparum becoming resistant to either drug.
Why Was This Study Done?
The chances of P. falciparum becoming resistant to ACT should also be reduced by giving ACT only to people who definitely have malaria. Unfortunately, many people who do not have malaria are given ACT because symptom-based (clinical) diagnosis cannot always distinguish between patients whose fever is caused by malaria and those who have a different infection and who would, therefore, gain more benefit from other treatments. Microscopic detection of parasites in blood smears would greatly improve the accuracy of malaria diagnosis, but this test is rarely available in rural clinics in developing countries. Might the recently developed “rapid diagnostic tests” (RDTs) for P. falciparum provide an alternative way to improve malaria diagnosis and thus reduce the overuse of ACT? In this “cross-over trial,” the researchers investigate the effect of the routine use of an RDT for the diagnosis of malaria on ACT prescribing, health outcomes, and costs in four primary health-care clinics in Zanzibar (part of the United Republic of Tanzania), one of the first regions in sub-Saharan Africa to introduce ACT.
What Did the Researchers Do and Find?
Each clinic used RDT-aided symptom-based clinical diagnosis of malaria (the RDT arm of the trial) and symptom-based clinical diagnosis (the CD arm) in alternate weeks to decide whether patients attending with fever had malaria. ACT was prescribed to everyone diagnosed with malaria; during RDT weeks only patients with positive RDT results were prescribed ACT. During the trial, 36% of the 1,005 patients in the RDT arm were prescribed ACT compared to 85% of the 882 patients in the CD arm. 37% and 27% of the RDT and CD arm patients, respectively, were prescribed antibiotics and fewer RDT-arm patients than CD-arm patients returned to the clinic because they still felt ill. The overall cost per patient was similar in both arms. The researchers also report that 23% of the antimalarial treatments given to patients in the RDT arm and 80% of those given to patients in the CD arm were given to people with no microscopically detectable parasites in their blood. Importantly, none of the 26 patients in the RDT group who had positive smears but who were not treated with antimalarial drugs because of a negative RDT result developed severe malaria.
What Do These Findings Mean?
These findings suggest that the replacement of clinical diagnosis alone with RDT-aided diagnosis may reduce the number of people prescribed ACT who do not have malaria and may increase the number of patients given antibiotics for nonmalarial illnesses without increasing costs. However, while the health-care workers involved in this study only prescribed ACT to those patients in the RDT arm who had a positive RDT result (as stipulated in the trial protocol), evidence from other studies suggests that health-care workers often give antimalarials to patients with negative RDT results. Consequently, these findings may not be generalizable to other clinics. Nevertheless, it is reassuring that none of the patients who had malaria that was detected by blood smear but that was missed by RDT subsequently developed severe malaria. This finding, if replicated, might persuade health-care workers to trust RDT results rather than prescribing ACT to everyone with a fever “just in case.”
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000070.
This study is further discussed in a PLoS Medicine Perspective by Zeno Bisoffi and colleagues
The MedlinePlus encyclopedia contains a page on malaria (in English and Spanish)
Information is available from the World Health Organization on malaria (in several languages) and on rapid diagnostic tests for malaria. Their 2008 World Malaria Report includes information about global efforts to control malaria and the latest information on malaria in the United Republic of Tanzania
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish)
Information is available from the Roll Back Malaria Partnership on its approach to the global control of malaria and on artemisinin-based combination therapies
doi:10.1371/journal.pmed.1000070
PMCID: PMC2667629  PMID: 19399156
4.  Modelling the Impact of Artemisinin Combination Therapy and Long-Acting Treatments on Malaria Transmission Intensity 
PLoS Medicine  2008;5(11):e226.
Background
Artemisinin derivatives used in recently introduced combination therapies (ACTs) for Plasmodium falciparum malaria significantly lower patient infectiousness and have the potential to reduce population-level transmission of the parasite. With the increased interest in malaria elimination, understanding the impact on transmission of ACT and other antimalarial drugs with different pharmacodynamics becomes a key issue. This study estimates the reduction in transmission that may be achieved by introducing different types of treatment for symptomatic P. falciparum malaria in endemic areas.
Methods and Findings
We developed a mathematical model to predict the potential impact on transmission outcomes of introducing ACT as first-line treatment for uncomplicated malaria in six areas of varying transmission intensity in Tanzania. We also estimated the impact that could be achieved by antimalarials with different efficacy, prophylactic time, and gametocytocidal effects. Rates of treatment, asymptomatic infection, and symptomatic infection in the six study areas were estimated using the model together with data from a cross-sectional survey of 5,667 individuals conducted prior to policy change from sulfadoxine-pyrimethamine to ACT. The effects of ACT and other drug types on gametocytaemia and infectiousness to mosquitoes were independently estimated from clinical trial data. Predicted percentage reductions in prevalence of infection and incidence of clinical episodes achieved by ACT were highest in the areas with low initial transmission. A 53% reduction in prevalence of infection was seen if 100% of current treatment was switched to ACT in the area where baseline slide-prevalence of parasitaemia was lowest (3.7%), compared to an 11% reduction in the highest-transmission setting (baseline slide prevalence = 57.1%). Estimated percentage reductions in incidence of clinical episodes were similar. The absolute size of the public health impact, however, was greater in the highest-transmission area, with 54 clinical episodes per 100 persons per year averted compared to five per 100 persons per year in the lowest-transmission area. High coverage was important. Reducing presumptive treatment through improved diagnosis substantially reduced the number of treatment courses required per clinical episode averted in the lower-transmission settings although there was some loss of overall impact on transmission. An efficacious antimalarial regimen with no specific gametocytocidal properties but a long prophylactic time was estimated to be more effective at reducing transmission than a short-acting ACT in the highest-transmission setting.
Conclusions
Our results suggest that ACTs have the potential for transmission reductions approaching those achieved by insecticide-treated nets in lower-transmission settings. ACT partner drugs and nonartemisinin regimens with longer prophylactic times could result in a larger impact in higher-transmission settings, although their long term benefit must be evaluated in relation to the risk of development of parasite resistance.
Lucy Okell and colleagues predict the impact on transmission outcomes of ACT as first-line treatment for uncomplicated malaria in six areas of varying transmission intensity in Tanzania.
Editors' Summary
Background.
Plasmodium falciparum, a mosquito-borne parasite that causes malaria, kills nearly one million people every year. When an infected mosquito bites a person, it injects a life stage of the parasite called sporozoites, which invade human liver cells where they initially develop. The liver cells then release merozoites (another life stage of the parasite). These invade red blood cells where they multiply before bursting out and infecting more red blood cells, which can cause fever and damage vital organs. Some merozoites develop into gametocytes, which infect mosquitos when they take a blood meal. In the mosquito, the gametocytes give rise to sporozoites, thus completing the parasite's life cycle. Because malaria parasites are now resistant to many antimalarial drugs, the preferred first-line treatment for P. falciparum malaria in most countries is artemisinin combination therapy (ACT). Artemisinin derivatives are fast-acting antimalarial agents that, unlike previous first-line treatments, reduce the number of gametocytes in patients' blood, making them less infectious to mosquitos, and therefore have more potential to reduce malaria transmission. These compounds are used in combination with another antimalarial drug to reduce the chances of P. falciparum becoming resistant to either drug.
Why Was This Study Done?
Because malaria poses such a large global public-health burden, there is considerable national and international interest in eliminating it or at least minimizing its transmission. Malaria control agencies need to know how to choose between available types of ACT as well as other antimalarials so as to not only cure malaria illness but also prevent transmission as much as possible. The financial resources available to control malaria are limited, so for planning integrated transmission reduction programs it is important for policy makers to know what contribution their treatment policy could make in addition to other control strategies (for example, the provision of insecticide-treated bed nets to reduce mosquito bites) to reducing transmission. Furthermore, in areas with high levels of malaria, it is uncertain to what extent treatment can reduce transmission since many infected people are immune and do not suffer symptoms or seek health care, but continue to transmit to others. In this study, the researchers develop a mathematical model to predict the impact on malaria transmission of the introduction of ACT and alternative first-line treatments for malaria in six regions of Tanzania with different levels of malaria transmission.
What Did the Researchers Do and Find?
The researchers developed a “deterministic compartmental” model of malaria transmission in human and mosquito populations and included numerous variables likely to affect malaria transmission (variables were based on data collected in Tanzania just before the introduction of ACT). They then used the model to estimate the impact on malaria transmission of introducing ACT or other antimalarial drugs with different properties. The model predicted that the percentage reduction in the prevalence of infection (the fraction of the population with malaria) and the incidence of infection (the number of new cases in the population per year) associated with a 100% switch to ACT would be greater in areas with low initial transmission rates than in areas with high transmission rates. For example, in the area with the lowest initial transmission rates, the model predicted that the prevalence of infection would drop by 53%, but in the area with the highest initial transmission rate, the drop would be only 11%. However, because more people get malaria in high-transmission areas, the total number of malaria illness episodes prevented would be ten times higher in the area with highest transmission than in the area with lowest transmission. The model also predicted that, in areas with high transmission, long-acting treatments which protect patients from reinfection would reduce transmission more effectively than some common currently used ACT regimens which are gametocyte-killing but short-acting. Treatments which were both long-acting and gametocyte-killing were predicted to have the biggest impact across all settings.
What Do These Findings Mean?
As with all mathematical models, the accuracy of the predictions made by this model depend on the many assumptions incorporated into the model. In addition, because data from Tanzania were fed into the model, its predictions are to some extent specific to the area. Nevertheless the Tanzanian setting is typical of sub-Saharan malaria-affected areas, and the authors show that varying their assumptions and the data fed into the model within realistic ranges in most cases does not substantially change their overall conclusions. The findings in this study suggest that in low-transmission areas, provided ACT is widely used, ACT may reduce malaria transmission as effectively as the widespread use of insecticide-treated bed nets. The findings also suggest that the use of longer-acting regimens with or without artemisinin components might be a good way to reduce transmission in high-transmission areas, provided the development of parasite resistance can be avoided. More generally, these findings suggest that public-health officials need to take the properties of antimalarial drugs into account together with the levels of transmission in the area when designing policies in order to achieve the highest impact on malaria transmission.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050226.
This study is further discussed in a PLoS Medicine Perspective by Maciej Boni and colleagues
The MedlinePlus encyclopedia contains a page on malaria (in English and Spanish)
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 Roll Back Malaria Partnership on its approach to the global control of malaria, on artemisinin-based combination therapies, and on malaria in Tanzania
doi:10.1371/journal.pmed.0050226
PMCID: PMC2586356  PMID: 19067479
5.  Effect of Supplementation with Zinc and Other Micronutrients on Malaria in Tanzanian Children: A Randomised Trial 
PLoS Medicine  2011;8(11):e1001125.
Hans Verhoef and colleagues report findings from a randomized trial conducted among Tanzanian children at high risk for malaria. Children in the trial received either daily oral supplementation with either zinc alone, multi-nutrients without zinc, multi-nutrients with zinc, or placebo. The investigators did not find evidence from this study that zinc or multi-nutrients protected against malaria episodes.
Background
It is uncertain to what extent oral supplementation with zinc can reduce episodes of malaria in endemic areas. Protection may depend on other nutrients. We measured the effect of supplementation with zinc and other nutrients on malaria rates.
Methods and Findings
In a 2×2 factorial trial, 612 rural Tanzanian children aged 6–60 months in an area with intense malaria transmission and with height-for-age z-score≤−1.5 SD were randomized to receive daily oral supplementation with either zinc alone (10 mg), multi-nutrients without zinc, multi-nutrients with zinc, or placebo. Intervention group was indicated by colour code, but neither participants, researchers, nor field staff knew who received what intervention. Those with Plasmodium infection at baseline were treated with artemether-lumefantrine. The primary outcome, an episode of malaria, was assessed among children reported sick at a primary care clinic, and pre-defined as current Plasmodium infection with an inflammatory response, shown by axillary temperature ≥37.5°C or whole blood C-reactive protein concentration ≥8 mg/L. Nutritional indicators were assessed at baseline and at 251 days (median; 95% reference range: 191–296 days). In the primary intention-to-treat analysis, we adjusted for pre-specified baseline factors, using Cox regression models that accounted for multiple episodes per child. 592 children completed the study. The primary analysis included 1,572 malaria episodes during 526 child-years of observation (median follow-up: 331 days). Malaria incidence in groups receiving zinc, multi-nutrients without zinc, multi-nutrients with zinc and placebo was 2.89/child-year, 2.95/child-year, 3.26/child-year, and 2.87/child-year, respectively. There was no evidence that multi-nutrients influenced the effect of zinc (or vice versa). Neither zinc nor multi-nutrients influenced malaria rates (marginal analysis; adjusted HR, 95% CI: 1.04, 0.93–1.18 and 1.10, 0.97–1.24 respectively). The prevalence of zinc deficiency (plasma zinc concentration <9.9 µmol/L) was high at baseline (67% overall; 60% in those without inflammation) and strongly reduced by zinc supplementation.
Conclusions
We found no evidence from this trial that zinc supplementation protected against malaria.
Trial Registration
ClinicalTrials.gov NCT00623857
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Malaria is a serious global public-health problem. Half of the world's population is at risk of this parasitic disease, which kills a million people (mainly children living in sub-Saharan Africa) every year. Malaria is transmitted to people through the bites of infected night-flying mosquitoes. Soon after entering the human body, the parasite begins to replicate in red blood cells, bursting out every 2–3 days and infecting more red blood cells. The presence of the parasite in the blood stream (parasitemia) causes malaria's characteristic recurring fever and can cause life-threatening organ damage and anemia (insufficient quantity of red blood cells). Malaria transmission can be reduced by using insecticide sprays to control the mosquitoes that spread the parasite and by avoiding mosquito bites by sleeping under insecticide-treated bed nets. Effective treatment with antimalarial drugs can also reduce malaria transmission.
Why Was This Study Done?
One reason why malaria kills so many children in Africa is poverty. Many children in Africa are malnourished, and malnutrition—in particular, insufficient micronutrients in the diet—impairs the immune system, which increases the frequency and severity of many childhood diseases. Micronutrients are vitamins and minerals that everyone needs in small quantities for good health. Zinc is one of the micronutrients that helps to maintain a healthy immune system, but zinc deficiency is very common among African children. Zinc supplementation has been shown to reduce the burden of diarrhea in developing countries, so might it also reduce the burden of malaria? Unfortunately, the existing evidence is confusing—some trials show that zinc supplementation protects against malaria but others show no evidence of protection. One possibility for these conflicting results could be that zinc supplementation alone is not sufficient—supplementation with other micronutrients might be needed for zinc to have an effect. In this randomized trial (a study that compares the effects of different interventions in groups that initially are similar in all characteristics except for intervention), the researchers investigate the effect of supplementation with zinc alone and in combination with other micronutrients on the rate of uncomplicated (mild) malaria among children living in Tanzania.
What Did the Researchers Do and Find?
The researchers enrolled 612 children aged 6–60 months who were living in a rural area of Tanzania with intense malaria transmission and randomly assigned them to receive daily oral supplements containing zinc alone, multi-nutrients (including iron) without zinc, multi-nutrients with zinc, or a placebo (no micronutrients). Nutritional indicators (including zinc concentrations in blood plasma) were assessed at baseline and 6–10 months after starting the intervention. During the study period, there were 1,572 malaria episodes. The incidence of malaria in all four intervention groups was very similar (about three episodes per child-year), and there was no evidence that multi-nutrients influenced the effect of zinc (or vice versa). Moreover, none of the supplements had any effect on malaria rates when compared to the placebo, even though the occurrence of zinc deficiency was strongly reduced by zinc supplementation. In a secondary analysis in which they analyzed their data by iron status at baseline, the researchers found that multi-nutrient supplementation increased the overall number of malaria episodes in children with iron deficiency by 41%, whereas multi-nutrient supplementation had no effect on the number of malaria episodes among children who were iron-replete at baseline.
What Do These Findings Mean?
In this study, the researchers found no evidence that zinc supplementation protected against malaria among young children living in Tanzania when given alone or in combination with other multi-nutrients. However, the researchers did find some evidence that multi-nutrient supplementation may increase the risk of malaria in children with iron deficiency. Because this finding came out of a secondary analysis of the data, it needs to be confirmed in a trial specifically designed to assess the effect of multi-nutrient supplements on malaria risk in iron-deficient children. Nevertheless, it is a potentially worrying result because, on the basis of evidence from a single study, the World Health Organization currently recommends that regular iron supplements be given to iron-deficient children in settings where there is adequate access to anti-malarial treatment. This recommendation should be reconsidered, suggest the researchers, and the safety of multi-nutrient mixes that contain iron and that are dispensed in countries affected by malaria should also be carefully evaluated.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001125.
Information is available from the World Health Organization on malaria (in several languages), on micronutrients, and on zinc deficiency; the 2010 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 a selection of personal stories about malaria
Information is available from the Roll Back Malaria Partnership on the global control of malaria and on malaria in Africa
The Malaria Centre at the UK London School of Hygiene & Tropical Medicine develops tools, techniques, and knowledge about malaria, and has a strong emphasis on teaching, training, and translating research outcomes into practice
The Micronutrient Initiative, the Global Alliance for Improved Nutrition, and the Flour Fortification Initiative are not-for-profit organizations dedicated to ensuring that people in developing countries get the minerals and vitamins they need to survive and thrive
The International Zinc Nutrition Consultative Group (iZiNCG) is a non-profit organization that aims to promote and assist efforts to reduce zinc deficiency worldwide, through advocacy efforts, education, and technical assistance
MedlinePlus provides links to additional information on malaria (in English and Spanish)
doi:10.1371/journal.pmed.1001125
PMCID: PMC3222646  PMID: 22131908
6.  Intermittent Preventive Treatment of Malaria Provides Substantial Protection against Malaria in Children Already Protected by an Insecticide-Treated Bednet in Burkina Faso: A Randomised, Double-Blind, Placebo-Controlled Trial 
PLoS Medicine  2011;8(2):e1000408.
A randomized trial reported by Diadier Diallo and colleagues shows that intermittent preventive treatment for malaria in children who are protected from mosquitoes using insecticide-treated bednets provides substantial protection from malaria.
Background
Intermittent preventive treatment of malaria in children (IPTc) is a promising new approach to the control of malaria in areas of seasonal malaria transmission but it is not known if IPTc adds to the protection provided by an insecticide-treated net (ITN).
Methods and Findings
An individually randomised, double-blind, placebo-controlled trial of seasonal IPTc was conducted in Burkina Faso in children aged 3 to 59 months who were provided with a long-lasting insecticide-treated bednet (LLIN). Three rounds of treatment with sulphadoxine pyrimethamine plus amodiaquine or placebos were given at monthly intervals during the malaria transmission season. Passive surveillance for malaria episodes was established, a cross-sectional survey was conducted at the end of the malaria transmission season, and use of ITNs was monitored during the intervention period. Incidence rates of malaria were compared using a Cox regression model and generalized linear models were fitted to examine the effect of IPTc on the prevalence of malaria infection, anaemia, and on anthropometric indicators. 3,052 children were screened and 3,014 were enrolled in the trial; 1,505 in the control arm and 1,509 in the intervention arm. Similar proportions of children in the two treatment arms were reported to sleep under an LLIN during the intervention period (93%). The incidence of malaria, defined as fever or history of fever with parasitaemia ≥5,000/µl, was 2.88 (95% confidence interval [CI] 2.70–3.06) per child during the intervention period in the control arm versus 0.87 (95% CI 0.78–0.97) in the intervention arm, a protective efficacy (PE) of 70% (95% CI 66%–74%) (p<0.001). There was a 69% (95% CI 6%–90%) reduction in incidence of severe malaria (p = 0.04) and a 46% (95% CI 7%–69%) (p = 0.03) reduction in the incidence of all-cause hospital admissions. IPTc reduced the prevalence of malaria infection at the end of the malaria transmission season by 73% (95% CI 68%–77%) (p<0.001) and that of moderately severe anaemia by 56% (95% CI 36%–70%) (p<0.001). IPTc reduced the risks of wasting (risk ratio [RR] = 0.79; 95% CI 0.65–1.00) (p = 0.05) and of being underweight (RR = 0.84; 95% CI 0.72–0.99) (p = 0.03). Children who received IPTc were 2.8 (95% CI 2.3–3.5) (p<0.001) times more likely to vomit than children who received placebo but no drug-related serious adverse event was recorded.
Conclusions
IPT of malaria provides substantial protection against malaria in children who sleep under an ITN. There is now strong evidence to support the integration of IPTc into malaria control strategies in areas of seasonal malaria transmission.
Trial Registration
ClinicalTrials.gov NCT00738946
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria accounts for one in five of all childhood deaths in Africa and of the one million annual malarial deaths world-wide, over 75% occur in African children under 5 years old. Malaria also causes severe morbidity in children, such as anemia, low birth weight, and neurological problems, which compromise the health and development of millions of children living in malaria endemic areas. As much of the impact of malaria on African children can be effectively prevented, significant efforts have been made in recent years to improve malaria control, such as the implementation of intermittent preventive treatment of malaria.
Intermittent preventive treatment (IPT) involves administration of antimalarial drugs at defined time intervals to individuals, regardless of whether they are known to be infected with malaria, to prevent morbidity and mortality. IPT was initially recommended for pregnant women and recently this strategy was extended to include infants (IPTi). Now, there is also IPT of malaria in children (IPTc), which is designed to protect against malaria during the high malaria transmission season.
Why Was This Study Done?
Large clinical trials have shown that IPTc involving the administration of two to three doses of an antimalarial drug (sulphadoxine pyrimethamine [SP] and artesunate [AS] or amodiaquine [AQ]) during the high malaria transmission season effectively reduces the incidence of malaria. However, these studies were conducted in countries where the use of insecticide-treated bednets—an intervention that provides at least 50% protection against morbidity from malaria and is the main tool used for malaria control in most of sub-Saharan Africa—was relatively low. Therefore, it is unclear whether IPTc will be as effective in children who sleep under insecticide-treated bednets as has been previously shown in communities where insecticide-treated bednet usage is low. So to determine the answer to this important question, the researchers conducted a randomized, placebo-controlled trial of IPTc with SP + AQ (chosen because of the effectiveness of this combination in a pilot study) in children who slept under an insecticide-treated bednet in an area of seasonal malaria transmission in Burkina Faso.
What Did the Researchers Do and Find?
The researchers enrolled 3,014 eligible children aged 3–59 months into a randomized double-blind, placebo-controlled trial during the 2008 malaria transmission season in Burkina Faso. All children were given a long-lasting insecticide-treated bednet at the start of the study with instructions to their family on the correct use of the net. Children were then randomized into two arms—1,509 were allocated to the intervention group and 1,505 to the control group—to receive three courses of IPTc with SP plus AQ or placebos given at monthly intervals during the peak malaria transmission season. The researchers monitored the incidence of malaria throughout the malaria season and also monitored the use of long-lasting insecticide-treated bednets throughout the study period. In addition, researchers conducted a cross-sectional survey in 150 randomly selected children every week and in every child enrolled in the trial 6 weeks after the last course of IPTc, to measure their temperature, height and weight, and blood hemoglobin and parasite count levels.
The number of children who slept under their long-lasting insecticide-treated bednet was similar in both arms. During the intervention period, the researchers found that the incidence of clinical malaria (defined as fever or a history of fever and the presence of at least 5,000 asexual forms of P. falciparum per microliter) was 2.88 in the control arm versus 0.87 in the intervention arm—giving a protective efficacy of 70%. There were 13 cases of severe malaria in the control arm and four in the IPTc arm—a 69% reduction in incidence. Additionally, all-cause hospital admission rate was reduced by 46%. At the end of the malaria transmission period, IPTc reduced the proportion of children infected with malaria parasites by 73% and reduced anemia by 33%. In addition, IPTc appeared to reduce the risk of wasting (risk ratio  = 0.79) and of being underweight (risk ratio  = 0.84). However, children who received IPTc were almost three times more likely to vomit than children who received placebo but there were no drug-related serious adverse events.
What Do These Findings Mean?
The results of this study show that in peak malarial transmission season in Burkina Faso, IPTc provides substantial additional protection against episodes of clinical malaria, severe malaria, and all-cause hospital admissions in children sleeping under long-lasting insecticide-treated bednets. In addition, intermittent preventive treatment of malaria with SP plus AQ appears to be safe for use in children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000408.
This topic is further discussed in two PLoS Medicine research articles: Dicko et al. and Bojang et al., and in a PLoS Medicine Perspective by Beeson
Roll Back Malaria has information about malaria in children, including intervention strategies
UNICEF also provides comprehensive information about malaria in children
The Intermittent Preventive Treatment in Infants Consortium (ipti) provides information on intermittent preventive treatment in infants
Roll Back Malaria has an information sheet on insecticide-treated bednets
doi:10.1371/journal.pmed.1000408
PMCID: PMC3032552  PMID: 21304925
7.  HIV, HBV, HCV and T. pallidum infections among blood donors and Transfusion-related complications among recipients at the Laquintinie hospital in Douala, Cameroon 
BMC Hematology  2014;14:5.
Background
Transfusion-transmissible infections (TTIs) pose a major health risk in Cameroon given the high prevalence of such pathogens and increased demands for blood donations in the local communities. This study aims at establishing the prevalence of commonly encountered TTIs among blood donors and transfusion-related complications among recipients in an urban center of Cameroon.
Methods
A total of 477 blood donors and 83 blood recipients were recruited by consecutive sampling at the Laquintinie Hospital in Douala (LHD), Cameroon. Serum samples from blood donors were tested by quantitative enzyme-linked immunosorbent assays (ELISA) and/or using various Rapid diagnostic test (RDT) for presence of Hepatits B (HBV) viral antigens, and antibodies to human immunodeficiency (HIV-1/2), Hepatits B (HCV) and Treponema pallidum. Recipient’s medical records were also analyzed for possible transfusion-associated complications.
Results
The male/female sex ratio of the blood donors was 4/1 with a mean age of 30.2 (Sd = 8.3) years. Of all blood donors, 64/467 (13.7%) were infected by at least one of the four TTIs. Infected volunteer donors represented 8.3% while infected family donors comprised 14.3% of the donor population. The prevalence of HCV, HIV, HBV and T. pallidum were 1.3%, 1.8%, 3.5%, and 8.1%, respectively. More than half of the blood recipients were female (78.3%) and the mean age was 20.6 (SD = 16.1) years. The causes of severe anemia indicative of transfusion in recipients varied with wards (postpartum hemorrhage, caesarean section, uterine or cervical lacerations, abortions, urinary tract infections, severe malaria, vaso-occlusive attacks, wounds and gastrointestinal bleeding). The most frequent complications were chills and hematuria, which represented 46.1% of all observed complications. Other complications such as nausea, vomiting, jaundice, sudden diarrhea, anxiety, tachycardia, or hyperthermia were also found in recipients. Three cases of deaths occurred during the study, including a girl of less than one year.
Conclusion
This study confirms the presence of blood-borne infectious diseases in blood donors at the LHD, identifying T. pallidum as the greatest threat to blood safety in the region, and hematuria as the most common immunological complications in blood recipients.
doi:10.1186/2052-1839-14-5
PMCID: PMC3944961  PMID: 24517107
Blood transfusion; HIV; HBV; HCV; T. pallidum; Complications
8.  Is a Plasmodium lactate dehydrogenase (pLDH) enzyme-linked immunosorbent (ELISA)-based assay a valid tool for detecting risky malaria blood donations in Africa? 
Malaria Journal  2013;12:279.
Background
Malaria is a leading cause of mortality in southern Benin. The main causative agent, Plasmodium falciparum, poses a threat on critical transfusions in pregnant women and children. This study’s objective was to compare the performance of different malaria screening methods in blood donors in southern Benin, a malaria-endemic country.
Methods
Blood from 2,515 voluntary blood donors in Benin was collected over a period of 10 months in ethylenediaminetetraacetic acid (EDTA) tubes, which were then classified according to extraction time: long rainy season, short dry season, short rainy season, and long dry season. Microscopic examination was used to count parasites. Parasite density (PD) was expressed as the number of parasites per μL of blood. Pan Plasmodium pLDH detection was assessed by an ELISA-malaria antigen test. Using crude soluble P. falciparum antigens, an ELISA-malaria antibody test detected anti-Plasmodium antibodies.
Results
Among the 2,515 blood donors (2,025 males and 488 females) screened, the rate of asymptomatic Plasmodium carriage was 295/2,515 (11.72%, 95% CI: 10.5-13.1%). Males had a higher infection rate (12.4%) than did females (8.8%). Parasite density was very low: between seven and100 parasites per μL of blood was reported in 80% of donors with parasitaemia. Three Plasmodium species were diagnosed: P. falciparum in 280/295 patients (95.0%), Plasmodium malariae in 14/295 (5.0%), and Plasmodium ovale in 1/295 (0.34%). Malaria prevalence in donors was higher during the rainy seasons (13.7%) compared with the dry seasons (9.9%). The use of a highly sensitive assay enabled pan Plasmodium pLDH detection in 966/2,515 (38.4%, 95% CI: 36.5%-40.3%). Malaria antibody prevalence was 1,859/2,515 (73.9%, 95% CI: 72.16-75.6%). Donors’ antigenaemia and antibody levels varied significantly (P <0.05) over the course of the four seasons. The highest antigenaemia rate 323/630 (51.3%), was observed during the short rainy season, while the highest antibody prevalence, 751/886 (84.7%), was recorded during the long dry season.
Conclusion
Blood donations infected with Plasmodium can transmit malaria to donation recipients. Malaria diagnostic methods are currently available, but the feasibility criteria for mass screening in endemic areas become preponderant. Detection of the pLDH antigen seems to be an adequate screening tool in endemic areas, for this antigen indicates parasite presence. Routine screening of all donated blood would prevent infected blood donations and reduce P. falciparum transmission in critical patients, such as children and pregnant women. This tool would also decrease medical prophylaxis in donation recipients and contribute to lower Plasmodium resistance.
doi:10.1186/1475-2875-12-279
PMCID: PMC3750723  PMID: 23927596
Malaria; Transfusion; Plasmodium falciparum; pLDH; Antibodies
9.  Worldwide Incidence of Malaria in 2009: Estimates, Time Trends, and a Critique of Methods 
PLoS Medicine  2011;8(12):e1001142.
Richard Cibulskis and colleagues present estimates of the worldwide incidence of malaria in 2009, together with a critique of different estimation methods, including those based on risk maps constructed from surveys of parasite prevalence, and those based on routine case reports compiled by health ministries.
Background
Measuring progress towards Millennium Development Goal 6, including estimates of, and time trends in, the number of malaria cases, has relied on risk maps constructed from surveys of parasite prevalence, and on routine case reports compiled by health ministries. Here we present a critique of both methods, illustrated with national incidence estimates for 2009.
Methods and Findings
We compiled information on the number of cases reported by National Malaria Control Programs in 99 countries with ongoing malaria transmission. For 71 countries we estimated the total incidence of Plasmodium falciparum and P. vivax by adjusting the number of reported cases using data on reporting completeness, the proportion of suspects that are parasite-positive, the proportion of confirmed cases due to each Plasmodium species, and the extent to which patients use public sector health facilities. All four factors varied markedly among countries and regions. For 28 African countries with less reliable routine surveillance data, we estimated the number of cases from model-based methods that link measures of malaria transmission with case incidence. In 2009, 98% of cases were due to P. falciparum in Africa and 65% in other regions. There were an estimated 225 million malaria cases (5th–95th centiles, 146–316 million) worldwide, 176 (110–248) million in the African region, and 49 (36–68) million elsewhere. Our estimates are lower than other published figures, especially survey-based estimates for non-African countries.
Conclusions
Estimates of malaria incidence derived from routine surveillance data were typically lower than those derived from surveys of parasite prevalence. Carefully interpreted surveillance data can be used to monitor malaria trends in response to control efforts, and to highlight areas where malaria programs and health information systems need to be strengthened. As malaria incidence declines around the world, evaluation of control efforts will increasingly rely on robust systems of routine surveillance.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria is a life-threatening disease caused by the Plasmodium parasite, which is transmitted to people through the bites of infected mosquitoes. According to latest estimates from the World Health Organization (WHO), in 2009, there were 225 million cases of malaria and an estimated 781,000 deaths worldwide—most deaths occurring among children living in the WHO African Region (mainly sub-Saharan Africa). Knowing the burden of malaria in any country is an essential component of public health planning and accurately estimating the global burden is essential to monitor progress towards the United Nations' Millennium Development Goals.
Currently, there are generally two approaches used to estimate malaria incidence:
One method uses routine surveillance reports of malaria cases compiled by national health ministries, which are analyzed to take into account some deficincies in data collection, such as incomplete reporting by health facilities, the potential for overdiagnosis of malaria among patients with fever, and the use of private health facilities or none at all. The second method uses population-based surveys of Plasmodium prevalence and case incidence from selected locations in malaria endemic areas and then uses this information to generate risk maps and to estimate the case incidence of malaria per 1,000 population, for all of the world's malaria endemic regions. The Malaria Atlas Project—a database of malaria epidemiology based on medical intelligence and satellite-derived climate data—uses this second method.
Why Was This Study Done?
In order for malaria epidemiology to be as accurate as possible, an evaluation of the strengths and weaknesses of both methods is necessary. In this study, the researchers analyzed the merits of the estimates calculated by using the different approaches, to highlight areas in which both methods need to be improved to provide better assessments of malaria control.
What Did the Researchers Do and Find?
The researchers estimated the number of malaria cases in 2009, for each of the 99 countries with ongoing malaria transmission using a combination of the two methods. The researchers used the first method for 56 malaria endemic countries outside the WHO African Region, and for nine African countries which had the quality of data necessary to calculate estimates using the researchers statistical model—which the researchers devised to take the upper and lower limits of case detection into account. The researchers used the second method for 34 countries in the African Region to classify malaria risk into low-transmission and high-transmission categories, and then to derive incidence rates for populations from observational studies conducted in populations in which there were no malaria control activities. For both methods, the researchers conducted a statistical analysis to determine the range of uncertainty.
The researchers found that using a combination of methods there was a combined total of 225 million malaria cases, in the 99 countries malaria endemic countries—the majority of cases (78%) were in the WHO African region, followed by the Southeast Asian (15%) and Eastern Mediterranean regions. In Africa, there were 214 cases per 1,000 population, compared with 23 per 1,000 in the Eastern Mediterranean region, and 19 per 1,000 in the Southeast Asia region. Sixteen countries accounted for 80% of all estimated cases globally—all but two countries were in the African region. The researchers found that despite the differences between methods 1 and 2, the ratio of the upper and lower limit for country estimates was approximately the same.
What Do These Findings Mean?
Using the combined methods, the incidence of malaria was estimated to be lower than previous estimates, particularly outside of Africa. Nevertheless the methods suggest that malaria surveillance systems currently miss the majority of cases, detecting less than 10% of those estimated to occur globally. Although the best assessment of malaria burden and trends should rely on a combination of surveillance and survey data, accurate surveillance is the ultimate goal for malaria control programs, especially as routine surveillance has advantages for estimating case incidence, spatially and through time. However, as the researchers have identified in this study, strengthening surveillance requires a critical evaluation of inherent errors and these errors must be adequately addressed in order to have confidence in estimates of malaria burden and trends, and therefore, the return on investments for malaria control programs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001142.
This study is further discussed in a PLoS Medicine Perspective by Ivo Mueller and colleagues
The WHO provides information on malaria and produces the World Malaria Report each year, summarizing global progress in malaria control
More information is available on The Malaria Atlas Project
doi:10.1371/journal.pmed.1001142
PMCID: PMC3243721  PMID: 22205883
10.  Impact of Artemisinin-Based Combination Therapy and Insecticide-Treated Nets on Malaria Burden in Zanzibar 
PLoS Medicine  2007;4(11):e309.
Background
The Roll Back Malaria strategy recommends a combination of interventions for malaria control. Zanzibar implemented artemisinin-based combination therapy (ACT) for uncomplicated malaria in late 2003 and long-lasting insecticidal nets (LLINs) from early 2006. ACT is provided free of charge to all malaria patients, while LLINs are distributed free to children under age 5 y (“under five”) and pregnant women. We investigated temporal trends in Plasmodium falciparum prevalence and malaria-related health parameters following the implementation of these two malaria control interventions in Zanzibar.
Methods and Findings
Cross-sectional clinical and parasitological surveys in children under the age of 14 y were conducted in North A District in May 2003, 2005, and 2006. Survey data were analyzed in a logistic regression model and adjusted for complex sampling design and potential confounders. Records from all 13 public health facilities in North A District were analyzed for malaria-related outpatient visits and admissions. Mortality and demographic data were obtained from District Commissioner's Office. P. falciparum prevalence decreased in children under five between 2003 and 2006; using 2003 as the reference year, odds ratios (ORs) and 95% confidence intervals (CIs) were, for 2005, 0.55 (0.28–1.08), and for 2006, 0.03 (0.00–0.27); p for trend < 0.001. Between 2002 and 2005 crude under-five, infant (under age 1 y), and child (aged 1–4 y) mortality decreased by 52%, 33%, and 71%, respectively. Similarly, malaria-related admissions, blood transfusions, and malaria-attributed mortality decreased significantly by 77%, 67% and 75%, respectively, between 2002 and 2005 in children under five. Climatic conditions favorable for malaria transmission persisted throughout the observational period.
Conclusions
Following deployment of ACT in Zanzibar 2003, malaria-associated morbidity and mortality decreased dramatically within two years. Additional distribution of LLINs in early 2006 resulted in a 10-fold reduction of malaria parasite prevalence. The results indicate that the Millennium Development Goals of reducing mortality in children under five and alleviating the burden of malaria are achievable in tropical Africa with high coverage of combined malaria control interventions.
Zanzibar has implemented artemisinin-based combination therapy for uncomplicated malaria, plus long-lasting insecticidal nets. Achuyt Bhattarai and colleagues found malaria morbidity and mortality decreased dramatically within two years.
Editors' Summary
Background.
Malaria kills about one million people every year, many of them young children living in sub-Saharan Africa. The parasite responsible for these deaths—Plasmodium falciparum—is transmitted to people when they are bitten (usually at night) by an infected mosquito. In the human body, the parasites reproduce in the liver before invading red blood cells. Here, they multiply again before bursting out and infecting more red blood cells as well as causing a high fever and sometimes damaging vital organs. The transmission cycle is completed when a mosquito bites an infected person and ingests parasites with its blood meal. To reduce the global burden of malaria, this cycle needs to be broken. This can be done in several ways. First, mosquitoes can be controlled with insecticides. Second, individuals can avoid mosquito bites by sleeping under insecticide-treated nets. Finally, antimalaria drugs can reduce the illness and death caused by the malaria parasite and can lessen the likelihood that a mosquito will pick up the parasite when it bites a person. The World Health Organization (WHO) currently recommends artemisinin-based combination therapies (ACTs) for malaria control. These contain a natural antimalarial compound from sweet wormwood and a synthetic drug. The use of insecticide-treated nets is also now being strongly promoted.
Why Was This Study Done?
The Roll Back Malaria Partnership—a coordinated global approach to fighting malaria—recommends that the strategies described above be combined to control malaria. But, although the public-health impact of insecticidal nets (ITNs) has been investigated, the large-scale effect of ACT use and the combined ACT/ITN effect in a malaria-endemic area has not been studied. This information is needed to allow governments and international agencies to use their resources as effectively as possible to control malaria. In this study, the researchers have asked how the introduction of ACT, first alone and later combined with distribution of long-lasting insecticidal nets (LLINs), affected the malaria burden in Zanzibar, a malaria-endemic country. People with malaria have had free access to ACT in Zanzibar since late 2003; children under the age of 5 y and pregnant women have been given free LLINs since early 2006.
What Did the Researchers Do and Find?
The researchers counted the parasites in the blood of a group of children under the age of 14 years in the North A District of Zanzibar in May 2003, 2005, and 2006 (the seasonal peaks for malaria in Zanzibar occur in March–May and October–December). They also looked in local health records for malaria-related outpatient visits and admissions between 2000 and 2005 and analyzed the overall death records for the region over the same period. Between 2003 (before the introduction of ACT) and 2005, the proportion of children under five with P. falciparum in their blood halved (a 2-fold decrease). It decreased another 10-fold between 2005 and 2006 after the distribution of LLINs to this age group. Deaths from all causes in children under five halved between 2002 and 2005, and malaria-related admissions and death attributed to malaria in 2005 in these children were one-fourth of those recorded in 2002. The climate in Zanzibar remained favorable for malaria transmission throughout this period.
What Do These Findings Mean?
These findings show that malaria-associated illness (outpatient malaria diagnosis) decreased by 77% and overall deaths in children decreased to about half in Zanzibar within two years of the introduction of ACT. Free distribution of LLINs from early 2006 to children under five produced a further significant reduction in parasite prevalence in this age group and a smaller but also important reduction in parasite prevalence in older children. Because these results only show short-term trends in the malaria burden associated with the introduction of these control strategies, they need confirmation in longer studies. They also need confirmation in other countries because the malaria burden in Zanzibar could have fallen for reasons unrelated to ACT or LLINs, such as other changes in medical practice. Nevertheless, these results strongly suggest that ACTs together with the widespread use of LLINs could help achieve the goal of eliminating malaria as a public-health problem in sub-Saharan Africa, provided the poor countries in this region can sustain these control strategies over the long term.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040309.
The MedlinePlus encyclopedia contains a page on malaria (in English and Spanish)
Information is available from the World Health Organization on malaria (in English, Spanish, French, Russian, Arabic and Chinese)
The US Centers for Disease Control and Prevention provide information on malaria and on insecticide-treated nets (in English and Spanish)
Information is available from the Roll Back Malaria Partnership on its approach to global control of malaria, on malaria in Zanzibar, part of the United Republic of Tanzania, on artemisinin-based combination therapy, and on the use of insecticide-treated nets
doi:10.1371/journal.pmed.0040309
PMCID: PMC2062481  PMID: 17988171
11.  Impact of Intermittent Screening and Treatment for Malaria among School Children in Kenya: A Cluster Randomised Trial 
PLoS Medicine  2014;11(1):e1001594.
Katherine Halliday and colleagues conducted a cluster randomized controlled trial in Kenyan school children in an area of low to moderate malaria transmission to investigate the effect of intermittent screening and treatment of malaria on health and education.
Please see later in the article for the Editors' Summary
Background
Improving the health of school-aged children can yield substantial benefits for cognitive development and educational achievement. However, there is limited experimental evidence of the benefits of alternative school-based malaria interventions or how the impacts of interventions vary according to intensity of malaria transmission. We investigated the effect of intermittent screening and treatment (IST) for malaria on the health and education of school children in an area of low to moderate malaria transmission.
Methods and Findings
A cluster randomised trial was implemented with 5,233 children in 101 government primary schools on the south coast of Kenya in 2010–2012. The intervention was delivered to children randomly selected from classes 1 and 5 who were followed up for 24 months. Once a school term, children were screened by public health workers using malaria rapid diagnostic tests (RDTs), and children (with or without malaria symptoms) found to be RDT-positive were treated with a six dose regimen of artemether-lumefantrine (AL). Given the nature of the intervention, the trial was not blinded. The primary outcomes were anaemia and sustained attention. Secondary outcomes were malaria parasitaemia and educational achievement. Data were analysed on an intention-to-treat basis.
During the intervention period, an average of 88.3% children in intervention schools were screened at each round, of whom 17.5% were RDT-positive. 80.3% of children in the control and 80.2% in the intervention group were followed-up at 24 months. No impact of the malaria IST intervention was observed for prevalence of anaemia at either 12 or 24 months (adjusted risk ratio [Adj.RR]: 1.03, 95% CI 0.93–1.13, p = 0.621 and Adj.RR: 1.00, 95% CI 0.90–1.11, p = 0.953) respectively, or on prevalence of P. falciparum infection or scores of classroom attention. No effect of IST was observed on educational achievement in the older class, but an apparent negative effect was seen on spelling scores in the younger class at 9 and 24 months and on arithmetic scores at 24 months.
Conclusion
In this setting in Kenya, IST as implemented in this study is not effective in improving the health or education of school children. Possible reasons for the absence of an impact are the marked geographical heterogeneity in transmission, the rapid rate of reinfection following AL treatment, the variable reliability of RDTs, and the relative contribution of malaria to the aetiology of anaemia in this setting.
Trial registration
www.ClinicalTrials.gov NCT00878007
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, more than 200 million cases of malaria occur worldwide and more than 600,000 people, mostly children living in sub-Saharan Africa, die from this mosquito-borne parasitic infection. Malaria can be prevented by controlling the night-biting mosquitoes that transmit Plasmodium parasites and by sleeping under insecticide-treated nets to avoid mosquito bites. Infection with malaria parasites causes recurring flu-like symptoms and needs to be treated promptly with antimalarial drugs to prevent the development of anaemia (a reduction in red blood cell numbers) and potentially fatal damage to the brain and other organs. Treatment also reduces malaria transmission. In 1998, the World Health Organization and several other international bodies established the Roll Back Malaria Partnership to provide a coordinated global approach to fighting malaria. In 2008, the Partnership launched its Global Malaria Action Plan, which aims to control malaria to reduce the current burden, to eliminate malaria over time country by country, and, ultimately, to eradicate malaria.
Why Was This Study Done?
In recent years, many malaria-endemic countries (countries where malaria is always present) have implemented successful malaria control programs and reduced malaria transmission levels. In these countries, immunity to malaria is now acquired more slowly than in the past, the burden of clinical malaria is shifting from very young children to older children, and infection rates with malaria parasites are now highest among school-aged children. Chronic untreated Plasmodium infection, even when it does not cause symptoms, can negatively affect children's health, cognitive development (the acquisition of thinking skills), and educational achievement. However, little is known about how school-based malaria interventions affect the health of children or their educational outcomes. In this cluster randomized trial, the researchers investigate the effect of intermittent screening and treatment (IST) of malaria on the health and education of school children in a rural area of southern Kenya with low-to-moderate malaria transmission. Cluster randomized trials compare the outcomes of groups (“clusters”) of people randomly assigned to receive alternative interventions. IST of malaria involves periodical screening of individuals for Plasmodium infection followed by treatment of everyone who is infected, including people without symptoms, with antimalarial drugs.
What Did the Researchers Do and Find?
The researchers enrolled more than 5,000 children aged between 5 and 20 years from 101 government primary schools in Kenya into their 24-month study. Half the schools were randomly selected to receive the IST intervention (screening once a school term for infection with a malaria parasite with a rapid diagnostic test [RDT] and treatment of all RDT-positive children, with or without malaria symptoms, with six doses of artemether-lumefantrine), which was delivered to randomly selected children from classes 1 and 5 (which contained younger and older children, respectively). During the study, 17.5% of the children in the intervention schools were RDT-positive at screening on average. The prevalences of anaemia and parasitemia (the proportion of children with anaemia and the proportion who were RDT-positive, respectively) were similar in the intervention and control groups at the 12-month and 24-month follow-up and there was no difference between the two groups in classroom attention scores at the 9-month and 24-month follow-up. The IST intervention also had no effect on educational achievement in the older class but, unexpectedly, appeared to have a negative effect on spelling and arithmetic scores in the younger class.
What Do These Findings Mean?
These findings indicate that, in this setting in Kenya, IST as implemented in this study provided no health or education benefits to school children. The finding that the educational achievement of younger children was lower in the intervention group than in the control group may be a chance finding or may indicate that apprehension about the finger prick needed to take blood for the RDT had a negative effect on the performance of younger children during educational tests. The researchers suggest that their failure to demonstrate that the school-based IST intervention they tested had any long-lasting health or education benefits may be because, in a low-to-moderate malaria transmission setting, most of the children screened did not require treatment and those who did lived in focal high transmission regions, where rapid re-infection occurred between screening rounds. Importantly, however, these findings suggest that school screening using RDT could be an efficient way to identify transmission hotspots in communities that should be targeted for malaria control interventions.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001594.
This study is further discussed in a PLOS Medicine Perspective by Lorenz von Seidlein
Information is available fro m 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 a selection of personal stories about children with malaria
Information is available from the Roll Back Malaria Partnership on the global control of malaria and on the Global Malaria Action Plan (in English and French); its website includes a fact sheet about malaria in Kenya
MedlinePlus provides links to additional information on malaria (in English and Spanish)
More information about this trial is available
More information about malaria control in schools is provided in the toolkit
doi:10.1371/journal.pmed.1001594
PMCID: PMC3904819  PMID: 24492859
12.  RISK FOR MALARIA IN UNITED STATES DONORS DEFERRED FOR TRAVEL TO MALARIA-ENDEMIC AREAS 
Transfusion  2009;49(11):2335-2345.
BACKGROUND
Deferral for travel to malaria-endemic areas excludes many blood donors in the United States. Most transfusion-transmitted malaria is associated with lengthy residence in malaria-endemic areas rather than routine travel. This study compares the impact of existing deferral requirements to the risk that a presenting donor with malaria travel history harbors malaria parasites under current and hypothetical alternate regulations.
STUDY DESIGN AND METHODS
Deferred donors from six blood centers were sampled to estimate a national cohort of donors deferred annually for malaria travel to different geographic regions. Risk for malaria infection following travel to each region, and distribution of incubation periods for each malaria species were estimated for U.S. travelers. Region-specific travel risks were used to estimate the risk that a presenting blood donor with malaria travel might asymptomatically harbor malaria parasites at different intervals following return to the United States.
RESULTS
Travel to Africa presents risk for malaria infection >1000 times that of travel to malaria-endemic parts of Mexico, yet Mexico accounts for >10 times as many deferred donors. Shortening the deferral period from 12 to 3 months for travelers to Mexico increases the risk of collecting a contaminated unit by only 1 unit per 57 years (sensitivity analysis, 1 every 29 - 114 years), at annual gain of >56,000 donations.
CONCLUSION
This study provides the first systematic appraisal of the U.S. requirements for donor qualification regarding travel to malarial areas. Consideration should be given to relaxing the guidelines for travel to very low-risk areas such as Mexico.
doi:10.1111/j.1537-2995.2009.02290.x
PMCID: PMC2777701  PMID: 19903290
Plasmodium; malaria; blood donor; deferral; malaria travel; transfusion transmitted disease
13.  What is the best strategy for the prevention of transfusion-transmitted malaria in sub-Saharan African countries where malaria is endemic? 
Malaria Journal  2013;12:465.
The transmission of malaria by blood transfusion was one of the first recorded incidents of transfusion-transmitted infections (TTIs). Although the World Health Organization (WHO) recommends that blood for transfusion should be screened for TTIs, malaria screening is not performed in most malaria-endemic countries in sub-Saharan Africa (SSA). The transfusion of infected red blood cells may lead to severe post-transfusion clinical manifestations of malaria, which could be rapidly fatal. Ensuring that blood supply in endemic countries is free from malaria is highly problematical, as most of the donors may potentially harbour low levels of malaria parasites. Pre-transfusion screening within endemic settings has been identified as a cost-effective option for prevention of transfusion-transmitted malaria (TTM). But currently, there is no screening method that is practical, affordable and suitably sensitive for use by blood banks in SSA. Even if this method was available, rejection of malaria-positive donors would considerably jeopardize the blood supply and increase morbidity and mortality, especially among pregnant women and children who top the scale of blood transfusion users in SSA. In this context, the systematic prophylaxis of recipients with anti-malarials could constitute a good alternative, as it prevents any deferral of donor units as well as the occurrence of TTM. With the on-going programme, namely the Affordable Medicine Facility - Malaria, there is an increase in the availability of low-priced artemisinin-based combination therapy that can be used for systematic prophylaxis. It appears nonetheless an urgent need to conduct cost-benefit studies in order to evaluate each of the TTM preventive methods. This approach could permit the design and implementation of an evidence-based measure of TTM prevention in SSA, advocating thereby its widespread use in the region.
doi:10.1186/1475-2875-12-465
PMCID: PMC3877868  PMID: 24373501
Malaria; Blood transfusion; Transfusion-transmitted malaria; Sub-Saharan Africa
14.  Intermittent Preventive Treatment of Malaria Provides Substantial Protection against Malaria in Children Already Protected by an Insecticide-Treated Bednet in Mali: A Randomised, Double-Blind, Placebo-Controlled Trial 
PLoS Medicine  2011;8(2):e1000407.
A randomized trial reported by Alassane Dicko and colleagues shows that intermittent preventive treatment for malaria in children who are protected from mosquitoes by insecticide-treated bednets provides substantial protection from malaria.
Background
Previous studies have shown that in areas of seasonal malaria transmission, intermittent preventive treatment of malaria in children (IPTc), targeting the transmission season, reduces the incidence of clinical malaria. However, these studies were conducted in communities with low coverage with insecticide-treated nets (ITNs). Whether IPTc provides additional protection to children sleeping under an ITN has not been established.
Methods and Findings
To assess whether IPTc provides additional protection to children sleeping under an ITN, we conducted a randomised, double-blind, placebo-controlled trial of IPTc with sulphadoxine pyrimethamine (SP) plus amodiaquine (AQ) in three localities in Kati, Mali. After screening, eligible children aged 3–59 mo were given a long-lasting insecticide-treated net (LLIN) and randomised to receive three rounds of active drugs or placebos. Treatments were administered under observation at monthly intervals during the high malaria transmission season in August, September, and October 2008. Adverse events were monitored immediately after the administration of each course of IPTc and throughout the follow-up period. The primary endpoint was clinical episodes of malaria recorded through passive surveillance by study clinicians available at all times during the follow-up. Cross-sectional surveys were conducted in 150 randomly selected children weekly and in all children at the end of the malaria transmission season to assess usage of ITNs and the impact of IPTc on the prevalence of malaria, anaemia, and malnutrition. Cox regression was used to compare incidence rates between intervention and control arms. The effects of IPTc on the prevalence of malaria infection and anaemia were estimated using logistic regression. 3,065 children were screened and 3,017 (1,508 in the control and 1,509 in the intervention arm) were enrolled in the study. 1,485 children (98.5%) in the control arm and 1,481 (98.1%) in the intervention arm completed follow-up. During the intervention period, the proportion of children reported to have slept under an ITN was 99.7% in the control and 99.3% in intervention arm (p = 0.45). A total of 672 episodes of clinical malaria defined as fever or a history of fever and the presence of at least 5,000 asexual forms of Plasmodium falciparum per microlitre (incidence rate of 1.90; 95% confidence interval [CI] 1.76–2.05 episodes per person year) were observed in the control arm versus 126 (incidence rate of 0.34; 95% CI 0.29–0.41 episodes per person year) in the intervention arm, indicating a protective effect (PE) of 82% (95% CI 78%–85%) (p<0.001) on the primary endpoint. There were 15 episodes of severe malaria in children in the control arm compared to two in children in the intervention group giving a PE of 87% (95% CI 42%–99%) (p = 0.001). IPTc reduced the prevalence of malaria infection by 85% (95% CI 73%–92%) (p<0.001) during the intervention period and by 46% (95% CI 31%–68%) (p<0.001) at the end of the intervention period. The prevalence of moderate anaemia (haemoglobin [Hb] <8 g/dl) was reduced by 47% (95% CI 15%–67%) (p<0.007) at the end of intervention period. The frequencies of adverse events were similar between the two arms. There was no drug-related serious adverse event.
Conclusions
IPTc given during the malaria transmission season provided substantial protection against clinical episodes of malaria, malaria infection, and anaemia in children using an LLIN. SP+AQ was safe and well tolerated. These findings indicate that IPTc could make a valuable contribution to malaria control in areas of seasonal malaria transmission alongside other interventions.
Trial Registration
ClinicalTrials.gov NCT00738946
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria accounts for one in five of all childhood deaths in Africa and of the one million annual malarial deaths world-wide, over 75% occur in African children <5 years old infected with Plasmodium falciparum. Malaria also causes severe morbidity in children, such as anemia, low birth-weight, epilepsy, and neurological problems, which compromise the health and development of millions of children living in malaria endemic areas. As much of the impact of malaria on African children can be effectively prevented, significant efforts have been made in recent years to improve malaria control, such as the implementation of intermittent preventive treatment (IPT) of malaria.
IPT involves administration of antimalarial drugs at defined time intervals to individuals, regardless of whether they are known to be infected with malaria, to prevent morbidity and mortality. IPT was initially recommended for pregnant women and recently this strategy was extended to include infants (IPTi). Now, there is also intermittent preventive treatment of malaria in children (IPTc), which is designed to protect against seasonal malaria transmission including those above one year of age.
Why Was This Study Done?
Large clinical trials have shown that IPTc involving the administration of two to three doses of an antimalarial drug (sulphadoxine pyrimethamine [SP] and artesunate [AS] or amodiaquine [AQ]) during the high malaria transmission season effectively reduces the incidence of malaria. However, these studies were conducted in countries where the use of insecticide-treated bednets—an intervention that provides at least 50% protection against morbidity from malaria and is the main tool used for malaria control in most of sub-Saharan Africa—was relatively low. Therefore, it is unclear whether IPTc will be as effective in children who sleep under insecticide-treated bednets as has been previously shown in communities where insecticide-treated bednet usage is low. So to determine the answer to this important question, the researchers conducted a randomized, placebo controlled trial of IPTc with SP+AQ (chosen because of the effectiveness of this combination in a pilot study) in children who slept under an insecticide-treated bednet in an area of seasonal malaria transmission in Mali.
What Did the Researchers Do and Find?
The researchers enrolled 3,017 eligible children aged 3–59 months into a randomized double-blind, placebo-controlled trial during the 2008 malaria transmission season in Mali. All children were given a long-lasting insecticide-treated bednet at the start of the study with instructions to their family on the correct use of the net. Children were then randomized into two arms—1,509 were allocated to the intervention group and 1,508 to the control group—to receive three courses of IPTc with SP plus AQ or placebos given at monthly intervals during the peak malaria transmission season. The researchers monitored the incidence of malaria throughout the malaria season and also monitored the use of long-lasting insecticide-treated bednets throughout the study period. In addition, researchers conducted a cross-sectional survey in 150 randomly selected children every week and in every child enrolled in the trial 6 weeks after the last course of IPTc, to measure their temperature, height and weight, and blood hemoglobin and parasite level.
The number of children who slept under their long-lasting insecticide-treated bednet was similar in both arms. During the intervention period, the researchers observed a total of 672 episodes of clinical malaria (defined as fever or a history of fever and the presence of at least 5,000 asexual forms of Plasmodium falciparum per microliter) in the control arm versus 126 episodes in the intervention arm, which is an incidence rate of 1.90 episodes per person year in the control arm versus 0.34 in the interventions arm—giving a protective efficacy of 87%. IPTc reduced the prevalence of malaria infection during the intervention period by 85% and by 46% at the end of the intervention period. The prevalence of moderate anemia was also reduced (by 47%) at the end of intervention period. The frequencies of adverse events were similar between the two arms and there were no drug-related serious adverse events.
What Do These Findings Mean?
The results of this study show that in peak malarial transmission season in Mali, IPTc provides substantial additional protection against episodes of clinical malaria and severe malaria in children sleeping under long-lasting insecticide-treated bednets. In addition, intermittent preventive treatment of malaria with SP plus AQ appears to be safe and well tolerated for use in children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000407.
This topic is further discussed in two PLoS Medicine research articles by Konat et al. and Bojang et al., and a PLoS Medicine Perspective by Beeson
Roll Back Malaria has information about malaria in children, including intervention strategies and an information sheet on insecticide-treated bednets
UNICEF also provides comprehensive information about malaria in children
The Intermittent Preventive Treatment in Infants Consortium (ipti) provides information on intermittent preventive treatment in infants
doi:10.1371/journal.pmed.1000407
PMCID: PMC3032550  PMID: 21304923
15.  Trends of Transfusion Transmissible Diseases Among Blood Donors at Uttarakhand, India 
Context:
Blood can save lives; however, it can be a source of transfusion transmitted diseases if proper screening of donated blood is not done. It is now mandatory to screen all donated blood units, whether replacement or voluntary for five transfusion transmitted diseases-namely human immunodeficiency virus (HIV), hepatitis B and C, syphilis, and malaria.
Aims:
The present study was done to study the prevalence of infectious disease markers among donors at the blood bank of a tertiary care center.
Settings and Design:
A total of 53,069 donors donated blood over 11 years. The number of replacement and voluntary donors was 41,710 and 11,359, respectively.
Materials and Methods:
Screening of blood units was done by enzyme-linked immunosorbent assay (ELISA) method for HIV and hepatitis B and C. HIV testing was done using fourth generation ELISA kits. Syphilis was tested by latex agglutination assay and malaria was tested using slide method up to the year 2008-2009 and by rapid immunochromatographic assay after that.
Results:
The mean percentage of these infections per year was found to be 0.2, 1.2, 0.9, 0.3, and 0.002% for HIV, hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), syphilis, and malarial parasite (MP), respectively.
Conclusions:
The risk of transfusion transmissible infection (TTI) today is low but supply of safe blood depends on proper donor selection and sensitive screening tests.
doi:10.4103/0970-0218.137161
PMCID: PMC4134536  PMID: 25136161
Blood donors; transfusion; transmissible infections
16.  G6PD Deficiency Prevalence and Estimates of Affected Populations in Malaria Endemic Countries: A Geostatistical Model-Based Map 
PLoS Medicine  2012;9(11):e1001339.
Rosalind Howes and colleagues present a map of glucose-6-phosphate dehydrogenase deficiency prevalence and severity. Individuals with the deficiency are at risk of mild to severe hemolysis when taking the antimalarial primaquine.
Background
Primaquine is a key drug for malaria elimination. In addition to being the only drug active against the dormant relapsing forms of Plasmodium vivax, primaquine is the sole effective treatment of infectious P. falciparum gametocytes, and may interrupt transmission and help contain the spread of artemisinin resistance. However, primaquine can trigger haemolysis in patients with a deficiency in glucose-6-phosphate dehydrogenase (G6PDd). Poor information is available about the distribution of individuals at risk of primaquine-induced haemolysis. We present a continuous evidence-based prevalence map of G6PDd and estimates of affected populations, together with a national index of relative haemolytic risk.
Methods and Findings
Representative community surveys of phenotypic G6PDd prevalence were identified for 1,734 spatially unique sites. These surveys formed the evidence-base for a Bayesian geostatistical model adapted to the gene's X-linked inheritance, which predicted a G6PDd allele frequency map across malaria endemic countries (MECs) and generated population-weighted estimates of affected populations. Highest median prevalence (peaking at 32.5%) was predicted across sub-Saharan Africa and the Arabian Peninsula. Although G6PDd prevalence was generally lower across central and southeast Asia, rarely exceeding 20%, the majority of G6PDd individuals (67.5% median estimate) were from Asian countries. We estimated a G6PDd allele frequency of 8.0% (interquartile range: 7.4–8.8) across MECs, and 5.3% (4.4–6.7) within malaria-eliminating countries. The reliability of the map is contingent on the underlying data informing the model; population heterogeneity can only be represented by the available surveys, and important weaknesses exist in the map across data-sparse regions. Uncertainty metrics are used to quantify some aspects of these limitations in the map. Finally, we assembled a database of G6PDd variant occurrences to inform a national-level index of relative G6PDd haemolytic risk. Asian countries, where variants were most severe, had the highest relative risks from G6PDd.
Conclusions
G6PDd is widespread and spatially heterogeneous across most MECs where primaquine would be valuable for malaria control and elimination. The maps and population estimates presented here reflect potential risk of primaquine-associated harm. In the absence of non-toxic alternatives to primaquine, these results represent additional evidence to help inform safe use of this valuable, yet dangerous, component of the malaria-elimination toolkit.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria is a parasitic infection that is transmitted to people through the bites of infected mosquitoes. Of the four parasites that cause malaria, Plasmodium falciparum is the most deadly and P. vivax is the commonest and most widely distributed. Malaria parasites have a complex life cycle. Infected mosquitoes inject “sporozoites” into people, a form of the parasite that replicates inside human liver cells. After a few days, the liver cells release “merozoites,” which invade red blood cells where they replicate rapidly before bursting out and infecting other red blood cells. This increase in the parasitic burden causes malaria's characteristic fever and can cause organ damage and death. Infected red blood cells also release “gametocytes,” which infect mosquitoes when they take a blood meal. In the mosquito, gametocytes multiply and develop into sporozoites, thus completing the parasite's life cycle. Malaria can be prevented by controlling the mosquitoes that spread the parasite and by avoiding mosquito bites by sleeping under insecticide-treated bed nets. Treatment with effective antimalarial drugs also decreases malaria transmission.
Why Was This Study Done?
The Global Malaria Action Plan aims to reduce malaria deaths to zero by 2015 and to eradicate malaria in the long-term through its progressive elimination in malaria-endemic countries (countries where malaria is always present). Primaquine is a key drug for malaria elimination. It is the only treatment effective against the gametocytes that transmit malaria between people and mosquitoes and against P. vivax “hypnozoites,” which hibernate in the liver and cause malaria relapses. Unfortunately, primaquine induces mild to severe destruction of red blood cells (hemolysis) in people who have a deficiency in the enzyme glucose-6-phosphate dehydrogenase (G6PD). G6PD deficiency (G6PDd) is common in some ethnic groups but the global distribution of individuals at risk of primaquine-induced hemolysis is unknown and there is no practical field test for G6PDd. Consequently, it is hard to design and implement primaquine treatment practices that balance the benefits of malaria transmission reduction and relapse prevention against the risk of hemolysis. Here, the researchers use a geostatistical model to map the prevalence (frequency in a population) of G6PDd in malaria-endemic countries and to estimate how many people are affected in these countries. They also develop a national index of relative hemolytic risk.
What Did the Researchers Do and Find?
The researchers fed data from community surveys of the prevalence of phenotypic G6PDd (reduced enzyme activity) for 1,734 sites (including 1,289 sites in malaria-endemic countries) into a geostatistical model originally developed to map global malaria endemicity. The model predicted that G6PDd is widespread across malaria-endemic regions, with the lowest prevalences in the Americas and the highest in tropical Africa and the Arabian Peninsula, but that most G6PDd individuals live in Asian countries. The predicted prevalence of G6PDd varied considerably over relatively short distances in many areas but, averaged across malaria-endemic countries it was 8%, which corresponds to about 350 million affected individuals; averaged across countries that are currently planning for malaria elimination, the prevalence was 5.3% (nearly 100 million affected individuals). Finally, the researchers used data on the geographical occurrence of G6PD variants classified according to their enzyme activity levels as mild or severe to derive an index of hemolytic risk from G6PDd for each malaria-endemic country. The greatest risk was in the Arabian Peninsula and west Asia where the predicted prevalence of G6PDd and the occurrence of severe G6PD variants were both high.
What Do These Findings Mean?
These findings suggest that G6PDd is widespread and spatially heterogeneous across most of the malaria-endemic countries where primaquine would be valuable for malaria control and elimination. The accuracy of these findings is limited, however, by the assumptions made in the geostatistical model, by the accuracy of the data fed into the model, and by the lack of data for some malaria-endemic countries. Moreover, there is considerable uncertainty associated with the proposed index of hemolysis risk because it is based on phenotypic G6PDd enzyme activity classifications, which is presumed, but not widely demonstrated, to be a surrogate marker for hemolysis. Nevertheless, these findings pave the way for further data collection and for the refinement of G6PDd maps that, in the absence of non-toxic alternatives to primaquine, will guide the design of safe primaquine regimens for the elimination of malaria.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001339.
Information is available from the World Health Organization on malaria; its 2011 World Malaria Report provides details of the current global malaria situation (some information is available in several languages)
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 and on the Global Malaria Action Plan
Information on the global mapping of malaria is available at the Malaria Atlas Project website where G6PD deficiency prevalence maps, population estimates and the data used in this study can also be accessed
Information about G6PD deficiency for affected families can be found on KidsHealth from the Nemous Children's Health System and the G6PD Deficiency Association website
MedlinePlus provides links to additional information on malaria; the MedlinePlus Encyclopedia provides information about G6PD deficiency (in English and Spanish)
doi:10.1371/journal.pmed.1001339
PMCID: PMC3496665  PMID: 23152723
17.  Real-time PCR diagnosis of Plasmodium vivax among blood donors 
Malaria Journal  2012;11:345.
Background
When selecting blood donors in transfusion centres, one important problem is to identify, during screening, individuals with infectious diseases that can be transmitted by blood, such as malaria, especially when the parasite densities are very low. This problem is particularly severe in endemic areas, such as the Brazilian Amazon. In the present study, molecular diagnostic (real-time PCR) of Plasmodium vivax was used to identify blood donors infected with malaria parasites.
Methods
Samples from 595 blood donors were collected in seven haemotherapy centres in northern Brazil located in areas at risk for malaria transmission, and the analyses were performed by real-time PCR with TaqMan probes on 7500 Real-Time PCR Systems, to genotype the mitochondrial DNA region specific to P. vivax. The experiment was designed for hybridization of the cytochrome c oxidase genes of the mitochondrial genome (GenBank GI63022502). The serological data were obtained using enzyme-linked immunosorbent assay - ELISA (Anti-HIV, Anti-HTLV I-II; Anti-HVC, HBsAg, Anti-HBc, Chagas disease) and VDRL (Syphilis) from the Blood Bank System of the Haematology and Haemotherapy Centre of Pará.
Results
The assay identified eight individuals in the sample (1.34%) infected with P. vivax at the time of blood donation. This percentage was higher than the altered serological results (reactive or inconclusive) of the prevalence of anti-HIV (0.67%), anti-hepatitis C virus (0.34%), anti-hepatitis B surface antigen (0.67%), anti-human T-lymphotropic virus I/II (1.18%), anti-Chagas disease (0.17%) and syphilis (VDRL) (0.50%), but not higher than anti-hepatitis B core antigen antibodies (4.37%). This result indicates the need to use more sensitive methods of diagnosing malaria in blood banks.
Conclusion
The real-time PCR with TaqMan probes enabled the identification of P. vivax in a high proportion of clinically healthy donors, highlighting the potential risk for transfusion-transmitted malaria. Additionally, this molecular diagnostic tool can be adopted as a new laboratory screening method in haemotherapy centres, especially in malaria-endemic areas.
doi:10.1186/1475-2875-11-345
PMCID: PMC3523982  PMID: 23062229
Malaria; Molecular diagnostic; Plasmodium vivax; Blood donors
18.  Prevalence of HLA antibodies in remotely transfused or alloexposed volunteer blood donors 
Transfusion  2010;50(6):1328-1334.
Background
HLA antibody testing of previously transfused or pregnant donors may help reduce the risk of transfusion-related acute lung injury (TRALI). However, the prevalence of HLA antibodies in transfused donors has not been well characterized.
Methods
Transfusion and pregnancy history was obtained from consenting donors. HLA Class I & II antibody testing was performed by multi-antigen bead Luminex platform. Cut off values for class I & II antibodies used normalized background ratio of 10.8 and 6.9 respectively. Linear probability models were used to evaluate potential associations between HLA alloimmunization and donor characteristics.
Results
7,920 donors (2,086 males and 5,834 females) were tested. HLA antibody prevalence did not significantly differ between 895 transfused (1.7%) and 1138 non-transfused males (1.0%), [odds ratio (OR) 1.75; 95% CI 0.80, 3.82]. Prevalence in 45 transfused nulliparous females (4.4%, 95% CI 0.1%, 11.8%) was not statistically different from the 1.6% prevalence in 1732 non-transfused nulliparous females (odds ratio 2.94, 95% CI 0.68, 12.74). Transfused parous females had higher prevalence than non-transfused counterparts (p=0.004), odds ratio 1.39 (95% CI 1.07, 1.80). In a linear probability model, the estimated additive risk of transfusion-induced alloimmunization was only 0.8% (95% CI -0.2%, 1.8%), (p=0.10). Donor transfusion history showed that 58% of transfusions occurred >10 years previously.
Conclusion
Transfused volunteer blood donors do not appear to have a significantly higher prevalence of HLA antibodies than their non-transfused counterparts. Thus, in an effort to reduce TRALI risk, ascertaining past history of transfusion and testing these donors for HLA antibodies is not necessary.
doi:10.1111/j.1537-2995.2009.02556.x
PMCID: PMC2891258  PMID: 20070615
19.  Estimating the Global Clinical Burden of Plasmodium falciparum Malaria in 2007 
PLoS Medicine  2010;7(6):e1000290.
Simon Hay and colleagues derive contemporary estimates of the global clinical burden of Plasmodium falciparum malaria (the deadliest form of malaria) using cartography-based techniques.
Background
The epidemiology of malaria makes surveillance-based methods of estimating its disease burden problematic. Cartographic approaches have provided alternative malaria burden estimates, but there remains widespread misunderstanding about their derivation and fidelity. The aims of this study are to present a new cartographic technique and its application for deriving global clinical burden estimates of Plasmodium falciparum malaria for 2007, and to compare these estimates and their likely precision with those derived under existing surveillance-based approaches.
Methods and Findings
In seven of the 87 countries endemic for P. falciparum malaria, the health reporting infrastructure was deemed sufficiently rigorous for case reports to be used verbatim. In the remaining countries, the mapped extent of unstable and stable P. falciparum malaria transmission was first determined. Estimates of the plausible incidence range of clinical cases were then calculated within the spatial limits of unstable transmission. A modelled relationship between clinical incidence and prevalence was used, together with new maps of P. falciparum malaria endemicity, to estimate incidence in areas of stable transmission, and geostatistical joint simulation was used to quantify uncertainty in these estimates at national, regional, and global scales.
Combining these estimates for all areas of transmission risk resulted in 451 million (95% credible interval 349–552 million) clinical cases of P. falciparum malaria in 2007. Almost all of this burden of morbidity occurred in areas of stable transmission. More than half of all estimated P. falciparum clinical cases and associated uncertainty occurred in India, Nigeria, the Democratic Republic of the Congo (DRC), and Myanmar (Burma), where 1.405 billion people are at risk.
Recent surveillance-based methods of burden estimation were then reviewed and discrepancies in national estimates explored. When these cartographically derived national estimates were ranked according to their relative uncertainty and replaced by surveillance-based estimates in the least certain half, 98% of the global clinical burden continued to be estimated by cartographic techniques.
Conclusions and Significance
Cartographic approaches to burden estimation provide a globally consistent measure of malaria morbidity of known fidelity, and they represent the only plausible method in those malaria-endemic countries with nonfunctional national surveillance. Unacceptable uncertainty in the clinical burden of malaria in only four countries confounds our ability to evaluate needs and monitor progress toward international targets for malaria control at the global scale. National prevalence surveys in each nation would reduce this uncertainty profoundly. Opportunities for further reducing uncertainty in clinical burden estimates by hybridizing alternative burden estimation procedures are also evaluated.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria is a major global public-health problem. Nearly half the world's population is at risk of malaria, and Plasmodium falciparum malaria—the deadliest form of the disease—causes about one million deaths each year. Malaria is a parasitic disease that is transmitted to people through the bite of an infected mosquito. These insects inject a parasitic form known as sporozoites into people, where they replicate briefly inside liver cells. The liver cells then release merozoites (another parasitic form), which invade red blood cells. Here, the merozoites 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 fevers and chills. Infected red blood cells also release gametocytes, which infect mosquitoes when they take a blood meal. In the mosquito, the gametocytes multiply and develop into sporozoites, thus completing the parasite's life cycle. Malaria can be prevented by controlling the mosquitoes that spread the parasite and by avoiding mosquito bites. Effective treatment with antimalarial drugs also helps to reduce malaria transmission.
Why Was This Study Done?
In 1998, the World Health Organization (WHO) and several other international agencies launched Roll Back Malaria, a global partnership that aims to provide a coordinated, global approach to fighting malaria. For this or any other malaria control initiative to be effective, however, an accurate picture of the global clinical burden of malaria (how many people become ill because of malaria and where they live) is needed so that resources can be concentrated where they will have the most impact. Estimates of the global burden of many infectious diseases are obtained using data collected by national surveillance systems. Unfortunately, this approach does not work very well for malaria because in places where malaria is endemic (always present), diagnosis is often inaccurate and national reporting is incomplete. In this study, therefore, the researchers use an alternative, “cartographic” method for estimating the global clinical burden of P. falciparum malaria.
What Did the Researchers Do and Find?
The researchers identified seven P. falciparum malaria-endemic countries that had sufficiently reliable health information systems to determine the national clinical malaria burden in 2007 directly. They divided the other 80 malaria endemic countries into countries with a low risk of transmission (unstable transmission) and countries with a moderate or high risk of transmission (stable transmission). In countries with unstable transmission, the researchers assumed a uniform annual clinical incidence rate of 0.1 cases per 1,000 people and multiplied this by population sizes to get disease burden estimates. In countries with stable transmission, they used a modeled relationship between clinical incidence (number of new cases in a population per year) and prevalence (the proportion of a population infected with malaria parasites) and a global malaria endemicity map (a map that indicates the risk of malaria infection in different countries) to estimate malaria incidences. Finally, they used a technique called “joint simulation” to quantify the uncertainty in these estimates. Together, these disease burden estimates gave an estimated global burden of 451 million clinical cases of P. falciparum in 2007. Most of these cases occurred in areas of stable transmission and more than half occurred in India, Nigeria, the Democratic Republic of the Congo, and Myanmar. Importantly, these four nations alone contributed nearly half of the uncertainty in the global incidence estimates.
What Do These Findings Mean?
These findings are extremely valuable because they provide a global map of malaria cases that should facilitate the implementation and evaluation of malaria control programs. However, the estimate of the global clinical burden of P. falciparum malaria reported here is higher than the WHO estimate of 247 million cases each year that was obtained using surveillance-based methods. The discrepancy between the estimates obtained using the cartographic and the surveillance-based approach is particularly marked for India. The researchers discuss possible reasons for these discrepancies and suggest improvements that could be made to both methods to increase the validity and precision of estimates. Finally, they note that improvements in the national prevalence surveys in India, Nigeria, the Democratic Republic of the Congo, and Myanmar would greatly reduce the uncertainty associated with their estimate of the global clinical burden of malaria, an observation that should encourage efforts to improve malaria surveillance in these countries.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000261.
A PLoS Medicine Health in Action article by Hay and colleagues, a Research Article by Guerra and colleagues, and a Research Article by Hay and colleagues provide further details about the global mapping of malaria risk
Additional national and regional level maps and more information on the global mapping of malaria are available at the Malaria Atlas Project
Information is available from the World Health Organization on malaria (in several languages)
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish)
Information is available from the Roll Back Malaria Partnership on its approach to the global control of malaria (in English and French)
MedlinePlus provides links to additional information on malaria (in English and Spanish)
doi:10.1371/journal.pmed.1000290
PMCID: PMC2885984  PMID: 20563310
20.  The Effect of Previous Pregnancy and Transfusion on HLA Alloimmunization in Blood Donors: Implications for a Transfusion Related Acute Lung Injury (TRALI) Risk Reduction Strategy 
Transfusion  2009;49(9):1825-1835.
Background
Antibodies to human leukocyte antigens (HLA) in donated blood have been implicated as a cause of transfusion related acute lung injury (TRALI). A potential measure to reduce the risk of TRALI includes screening platelet apheresis donors for HLA antibodies. The prevalence of HLA antibodies and their relationship to previous transfusion or pregnancy in blood donors was determined.
Study design and methods
8171 volunteer blood donors were prospectively recruited by 6 U.S. blood centers from December 2006 to May 2007. Donors provided a detailed history of pregnancy and transfusion, and a sample for HLA class I and II antibody testing by multi-antigen bead flow analysis.
Results
8171 donors were enrolled, 7920 (96.9%) had valid HLA antibody test results and 7841(99%) of those had complete pregnancy and transfusion information. The prevalence of any HLA antibody was similar in non-transfused (n=1138) and transfused (n=895) men, 1.0 vs. 1.7% (p=0.16). HLA antibodies were detected in 17.3% of all female donors (n=5834) and in 24.4 % of those with a history of previous pregnancy (n=3992). The prevalence of HLA antibodies increased in women with greater numbers of pregnancy: 1.7%(zero), 11.2%(one), 22.5%(two), 27.5%(three) and 32.2%(four or more pregnancies), p<0.0001.
Conclusion
HLA class I and class II antibodies are detectable at low prevalence in male donors regardless of transfusion and in female donors without known immunizing events. The prevalence of HLA antibodies increases significantly with more pregnancies. These data will allow blood centers to estimate the impact of HLA antibody testing as a potential TRALI risk-reduction measure.
doi:10.1111/j.1537-2995.2009.02206.x
PMCID: PMC2841001  PMID: 19453983
HLA antibody; pregnancy; transfusion; transfusion related acute lung injury
21.  Impact of Inconsistent Policies for Transfusion-Transmitted Malaria on Clinical Practice in Ghana 
PLoS ONE  2012;7(3):e34201.
Background
Policies concerning the prevention of transfusion transmitted malaria (TTM) are the responsibility of blood transfusion services and malaria control programmes. To prevent spreading drug resistance due to over-use of malaria drugs, recent malaria treatment guidelines recommend prompt parasitological confirmation before treatment is started. In contrast, blood safety policies from the World Health Organisation (WHO) recommend presumptive malaria treatment for recipients of blood in endemic countries but evidence supporting this approach is lacking. Our study documented how these conflicting policies relating to malaria transmission through blood transfusion impact on clinical practice in a teaching hospital in West Africa.
Methods/Principal Findings
We randomly selected and reviewed case notes of 151 patients within 24 hours of their receiving a blood transfusion. Transfusion practices including the confirmation of diagnosis and anti-malarial treatment given were compared across three departments; Obstetrics and Gynaecology (O&G), Paediatrics and Medicine. Overall, 66 (44%) of patients received malaria treatment within 24 hrs of their blood transfusion; of which only 2 (3%) received anti-malarials based on a laboratory confirmation of malaria. Paediatric patients (87%) received the most anti-malarials and only 7% and 24% of recipients in medicine and O&G respectively received anti malarials. In 51 patients (78%), the anti-malarials were prescribed at the same time as the blood transfusion and anti-malarials prescriptions exceeded the number of patients with a presumptive diagnosis of malaria.
Conclusions
It is common practice in paediatrics to prescribe anti-malarials routinely with blood transfusions. This contravenes the malaria treatment guidelines of laboratory confirmation before treatment but is in accordance with the less-well evidenced blood safety guidelines. There is an urgent need for more evidence about the clinical impact of transfusion transmitted malaria to enable malaria and blood transfusion programmes to harmonize their policies and give clear guidance to clinicians who prescribe blood transfusions in malaria-endemic areas
doi:10.1371/journal.pone.0034201
PMCID: PMC3313967  PMID: 22479564
22.  Stable and Unstable Malaria Hotspots in Longitudinal Cohort Studies in Kenya 
PLoS Medicine  2010;7(7):e1000304.
Philip Bejon and colleagues document the clustering of malaria episodes and malarial parasite infection. These patterns may enable future prediction of hotspots of malaria infection and targeting of treatment or preventive interventions.
Background
Infectious diseases often demonstrate heterogeneity of transmission among host populations. This heterogeneity reduces the efficacy of control strategies, but also implies that focusing control strategies on “hotspots” of transmission could be highly effective.
Methods and Findings
In order to identify hotspots of malaria transmission, we analysed longitudinal data on febrile malaria episodes, asymptomatic parasitaemia, and antibody titres over 12 y from 256 homesteads in three study areas in Kilifi District on the Kenyan coast. We examined heterogeneity by homestead, and identified groups of homesteads that formed hotspots using a spatial scan statistic. Two types of statistically significant hotspots were detected; stable hotspots of asymptomatic parasitaemia and unstable hotspots of febrile malaria. The stable hotspots were associated with higher average AMA-1 antibody titres than the unstable clusters (optical density [OD] = 1.24, 95% confidence interval [CI] 1.02–1.47 versus OD = 1.1, 95% CI 0.88–1.33) and lower mean ages of febrile malaria episodes (5.8 y, 95% CI 5.6–6.0 versus 5.91 y, 95% CI 5.7–6.1). A falling gradient of febrile malaria incidence was identified in the penumbrae of both hotspots. Hotspots were associated with AMA-1 titres, but not seroconversion rates. In order to target control measures, homesteads at risk of febrile malaria could be predicted by identifying the 20% of homesteads that experienced an episode of febrile malaria during one month in the dry season. That 20% subsequently experienced 65% of all febrile malaria episodes during the following year. A definition based on remote sensing data was 81% sensitive and 63% specific for the stable hotspots of asymptomatic malaria.
Conclusions
Hotspots of asymptomatic parasitaemia are stable over time, but hotspots of febrile malaria are unstable. This finding may be because immunity offsets the high rate of febrile malaria that might otherwise result in stable hotspots, whereas unstable hotspots necessarily affect a population with less prior exposure to malaria.
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 the world's population is at risk of malaria and about one million people (mainly children living in sub-Saharan Africa) die each year from the disease. Malaria is transmitted to people through the bite of an infected mosquito. Initially, the parasite replicates inside human liver cells but, about a week after infection, these cells release “merozoites” (one of the life-stages of the parasite), which invade red blood cells. Here, the merozoites replicate rapidly before bursting out after 2–3 days and infecting more red blood cells. The cyclical and massive increase in parasitemia (parasites in the bloodstream) that results from this pattern of replication is responsible for malaria's recurring fevers and can cause life-threatening organ damage and anemia (a lack of red blood cells). Malaria can be prevented by controlling the mosquitoes that spread the parasite and by avoiding mosquito bites. Effective treatment with antimalarial drugs can also reduce malaria transmission.
Why Was This Study Done?
Like many other infectious diseases, the transmission of malaria is heterogeneous. That is, even in places where malaria is always present, there are “hotspots” of transmission, areas where the risk of catching malaria is particularly high. The existence of these hotspots, which are caused by a combination of genetic factors (for example, host susceptibility to infection) and environmental factors (for example, distance from mosquito breeding sites), reduces the efficacy of control strategies. However, mathematical models suggest that focusing control strategies on transmission hotspots might be an effective way to reduce overall malaria transmission. Efforts have been made to identify such hotspots using environmental data collected by satellites but with limited success. In this study, therefore, the researchers investigate the heterogeneity of malaria transmission in the Kilifi District of Kenya over time by analyzing data collected over up to 12 years (“longitudinal” data) on malaria episodes and parasitemia in three groups (cohorts) of children living in 256 homesteads.
What Did the Researchers Do and Find?
The researchers identified febrile malaria episodes in the homesteads by taking blood from children with fever (febrile children) to analyze for parasitemia. They took blood once a year from all the study participants just before the rainy season (when malaria peaks) to look for symptom-free parasitemia and they also looked for antibodies (proteins made by the immune system that fight disease) against malaria parasites in the blood of the participants. They then used a “spatial scan statistic” to look for heterogeneity of transmission and to identify transmission hotspots (groups of homesteads where the observed incidence of malaria or parasitemia was higher than would be expected if cases were evenly distributed). The researchers identified two types of hotspots—stable hotspots of symptom-free parasitemia that were still hotspots several years later and unstable hotspots of febrile malaria that rarely stayed in the same place for more than a year or two. Children living in the stable hotspots had slightly higher average amounts of antimalaria antibodies and developed malaria at a slightly lower average age than children living in the unstable hotspots.
What Do These Findings Mean?
These findings show that in Kilifi District, Kenya, hotspots of symptom-free parasitemia are stable over time but hotspots of febrile malaria are unstable. The researchers suggest that rapid acquisition of immunity in the stable hotspots reduces the occurrence of febrile malaria whereas in the unstable hotspots there is a high incidence of febrile malaria because lack of previous exposure to the parasite means there is a low level of immunity. Targeted strategies for malaria control should target both types of hotspots, suggest the researchers. Stable hotspots of symptom-free parasitemia (which can be identified by parasite or antibody surveys or by remote environmental sensing) should be targeted because mosquito dispersion probably increases malaria transmission rates near these hotspots. Unstable hotspots of febrile disease should be targeted to reduce both the burden of disease and transmission in the wider community. Unstable hotspots of febrile malaria, the researchers suggest, could be efficiently identified in Kilifi District (and maybe elsewhere) by determining which homesteads had malaria outbreaks during September (part of the dry season) one year and then focusing control interventions on these homesteads the next year.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000304.
Information is available from the World Health Organization on malaria (in several languages)
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish)
MedlinePlus provides links to additional information on malaria (in English and Spanish)
Information is available from the Roll Back Malaria Partnership on the global control of malaria (in English and French) and on malaria in Kenya
doi:10.1371/journal.pmed.1000304
PMCID: PMC2897769  PMID: 20625549
23.  Increased use of malaria rapid diagnostic tests improves targeting of anti-malarial treatment in rural Tanzania: implications for nationwide rollout of malaria rapid diagnostic tests 
Malaria Journal  2012;11:221.
Background
The World Health Organization recommends parasitological confirmation of all malaria cases. Tanzania is implementing a phased rollout of malaria rapid diagnostic tests (RDTs) for routine use in all levels of care as one strategy to increase parasitological confirmation of malaria diagnosis. This study was carried out to evaluated artemisinin combination therapy (ACT) prescribing patterns in febrile patients with and without uncomplicated malaria in one pre-RDT implementation and one post-RDT implementation area.
Methods
A cross-sectional health facility surveys was conducted during high and low malaria transmission seasons in 2010 in both areas. Clinical information and a reference blood film on all patients presenting for an initial illness consultation were collected. Malaria was defined as a history of fever in the past 48 h and microscopically confirmed parasitaemia. Routine diagnostic testing was defined as RDT or microscopy ordered by the health worker and performed at the health facility as part of the health worker-patient consultation. Correct diagnostic testing was defined as febrile patient tested with RDT or microscopy. Over-testing was defined as a non-febrile patient tested with RDT or microscopy. Correct treatment was defined as patient with malaria prescribed ACT. Over-treatment was defined as patient without malaria prescribed ACT.
Results
A total of 1,247 febrile patients (627 from pre-implementation area and 620 from post-implementation area) were included in the analysis. In the post-RDT implementation area, 80.9% (95% CI, 68.2-89.3) of patients with malaria received recommended treatment with ACT compared to 70.3% (95% CI, 54.7-82.2) of patients in the pre-RDT implementation area. Correct treatment was significantly higher in the post-implementation area during high transmission season (85.9% (95%CI, 72.0-93.6) compared to 58.3% (95%CI, 39.4-75.1) in pre-implementation area (p = 0.01). Over-treatment with ACT of patients without malaria was less common in the post-RDT implementation area (20.9%; 95% CI, 14.7-28.8) compared to the pre-RDT implementation area (45.8%; 95% CI, 37.2-54.6) (p < 0.01) in high transmission. The odds of overtreatment was significantly lower in post- RDT area (adjusted Odds Ratio (OR: 95%CI) 0.57(0.36-0.89); and much higher with clinical diagnosis adjusted OR (95%CI) 2.24(1.37-3.67)
Conclusion
Implementation of RDTs increased use of RDTs for parasitological confirmation and reduced over-treatment with ACT during high malaria transmission season in one area in Tanzania. Continued monitoring of the national RDT rollout will be needed to assess whether these changes in case management practices will be replicated in other areas and sustained over time. Additional measures (such as refresher trainings, closer supervisions, etc.) may be needed to improve ACT targeting during low transmission seasons.
doi:10.1186/1475-2875-11-221
PMCID: PMC3471012  PMID: 22747655
Malaria rapid diagnostic tests; ACT; HDSS; INDEPTH network; Tanzania
24.  Seroprevalence of human T lymphotropic virus antibodies among healthy blood donors at a tertiary centre in Lagos, Nigeria 
Introduction
Transmission of human T-lymphotropic viruses (HTLV) occurs from mother to child, by sexual contact and blood transfusion. Presently, in most centres in Nigeria, there is no routine pre-transfusion screening for HTLV. The study aims to determine the prevalence of HTLV-1 and HTLV-2 among healthy blood donors at a tertiary centre in Lagos.
Methods
A cross-sectional study was carried out at the blood donor clinic of the Lagos State University Teaching Hospital (LASUTH), Ikeja. About 5mls of venous blood was collected from each subject into a sterile plain bottle after obtaining subject's consent. The serum separated and stored at -200C. Sera were assayed for HTLV by an enzyme-linked immunoassay (ELISA) for the determination of antibodies to HTLV 1 and HTLV -2. Western blot confirmatory testing was done on reactive samples. All donors were also screened for HIV, HBsAg and HCV by rapid kits.
Results
The seroprevalence of HTLV -1 by ELISA was 1.0% and 0.5% by Western Blot among blood donors. A total of 210 healthy blood donors were enrolled. Only 2 (1.0%) blood donors were repeatedly reactive with ELISA test. On confirmatory testing with Western Blot, 1 (0.5%) blood donor was positive for HTLV. All the healthy blood donors were negative for HIV, HbsAg and HCV. None of the 210 blood donors had been previously transfused; as such no association could be established between transfusion history and HTLV positivity among the blood donors.
Conclusion
The seroprevalence of HTLV in this environment is low among healthy blood donors.
doi:10.11604/pamj.2014.17.301.4075
PMCID: PMC4198262  PMID: 25328597
Seroprevalence; HTLV; healthy blood donors; Nigeria
25.  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

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