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1.  Care-Seeking and Management of Common Childhood Illnesses in Tanzania – Results from the 2010 Demographic and Health Survey 
PLoS ONE  2013;8(3):e58789.
Background
Malaria, pneumonia and diarrhoea continue to kill millions of children in Africa despite the available and effective treatments. Correct diagnosis and prompt treatment with effective drugs at the first option consulted for child care is crucial for preventing severe disease and death from these illnesses. Using the 2010 Demographic and Health Survey data, the present study aims to assess care-seeking and management of suspected malaria, pneumonia and diarrhoea at various health care facilities in Tanzania.
Methods
We analyzed data for 8176 children born within a 5 years period preceding the survey.The information was collected by interviewing 5519 women aged 15–49 years in 10,300 households selected from 475 sample points throughout Tanzania.
Results
The most common first option for child care was PHC facilities (54.8%), followed by private pharmacies (23.4%). These were more commonly utilized in rural compared to urban areas: 61.2% versus 34.5% for PHC facilities, and 26.5% versus 17.7% for pharmacies. Women in urban areas and those with higher level of education more commonly utilized higher level hospitals and private facilities as their first option for child care. Only one in four children with fever had received a blood test during the illness with lowest proportion being reported among children solely attended at PHC facilities. Use of abandoned antimalarial drugs for the treatment of suspected malaria was also observed in public health facilities and antibiotics use for diarrhoea treatment was high (49.0%).
Conclusions
PHC facilities and pharmacies most commonly provided sub-optimal care. These facilities were more commonly utilized as the first option for child care in rural areas and among the poor and non-educated families. These are groups with the highest child mortality, which calls for interventions’ targeting improvement of care at these facilities to further reduce child mortality from treatable illnesses in Tanzania.
doi:10.1371/journal.pone.0058789
PMCID: PMC3595288  PMID: 23554926
2.  Community Case Management of Fever Due to Malaria and Pneumonia in Children Under Five in Zambia: A Cluster Randomized Controlled Trial 
PLoS Medicine  2010;7(9):e1000340.
In a cluster randomized trial, Kojo Yeboah-Antwi and colleagues find that integrated management of malaria and pneumonia in children under five by community health workers is both feasible and effective.
Background
Pneumonia and malaria, two of the leading causes of morbidity and mortality among children under five in Zambia, often have overlapping clinical manifestations. Zambia is piloting the use of artemether-lumefantrine (AL) by community health workers (CHWs) to treat uncomplicated malaria. Valid concerns about potential overuse of AL could be addressed by the use of malaria rapid diagnostics employed at the community level. Currently, CHWs in Zambia evaluate and treat children with suspected malaria in rural areas, but they refer children with suspected pneumonia to the nearest health facility. This study was designed to assess the effectiveness and feasibility of using CHWs to manage nonsevere pneumonia and uncomplicated malaria with the aid of rapid diagnostic tests (RDTs).
Methods and Findings
Community health posts staffed by CHWs were matched and randomly allocated to intervention and control arms. Children between the ages of 6 months and 5 years were managed according to the study protocol, as follows. Intervention CHWs performed RDTs, treated test-positive children with AL, and treated those with nonsevere pneumonia (increased respiratory rate) with amoxicillin. Control CHWs did not perform RDTs, treated all febrile children with AL, and referred those with signs of pneumonia to the health facility, as per Ministry of Health policy. The primary outcomes were the use of AL in children with fever and early and appropriate treatment with antibiotics for nonsevere pneumonia. A total of 3,125 children with fever and/or difficult/fast breathing were managed over a 12-month period. In the intervention arm, 27.5% (265/963) of children with fever received AL compared to 99.1% (2066/2084) of control children (risk ratio 0.23, 95% confidence interval 0.14–0.38). For children classified with nonsevere pneumonia, 68.2% (247/362) in the intervention arm and 13.3% (22/203) in the control arm received early and appropriate treatment (risk ratio 5.32, 95% confidence interval 2.19–8.94). There were two deaths in the intervention and one in the control arm.
Conclusions
The potential for CHWs to use RDTs, AL, and amoxicillin to manage both malaria and pneumonia at the community level is promising and might reduce overuse of AL, as well as provide early and appropriate treatment to children with nonsevere pneumonia.
Trial registration
ClinicalTrials.gov NCT00513500
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, about 11 million children die before their fifth birthday. Most of these deaths are in developing countries and most are due to a handful of causes—pneumonia (lung inflammation usually caused by an infection), malaria (a parasitic disease spread by mosquitoes), measles, diarrhea, and birth-related problems. In sub-Saharan Africa, pneumonia and malaria alone are responsible for nearly a third of deaths in young children. Both these diseases can be treated if caught early—pneumonia with antibiotics such as amoxicillin and malaria with artemisinin-based combination therapy (ACT), a treatment that contains several powerful antimalarial drugs. Unfortunately, parents in rural areas in sub-Saharan Africa rarely have easy access to health facilities and sick children are often treated at home by community health workers (CHWs, individuals with some medical training who provide basic health care to their communities), drug sellers, and traditional healers. This situation means that ongoing global efforts to reduce child mortality will require innovative community level interventions if they are to succeed.
Why Was This Study Done?
One community level intervention that the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF) recently recommended is integrated management of malaria and pneumonia in countries where these diseases are major childhood killers. One such country is Zambia. In rural areas of Zambia, CHWs treat suspected cases of uncomplicated (mild) malaria with artemether-lumefantrine (AL, an ACT) or with sulfadoxine-pyrimethamine (a non-ACT antimalarial drug combination) and refer children with suspected pneumonia to the nearest health facility. However, because uncomplicated malaria and pneumonia both cause fever, many children are treated inappropriately. This misdiagnosis is worrying because giving antimalarial drugs to children with pneumonia delays their treatment with more appropriate drugs and increases the risk of drug-resistant malaria emerging. The use of rapid diagnostic tests (RDTs) for malaria might be one way to improve the treatment of malaria and pneumonia by CHWs in Zambia. Here, the researchers investigate the feasibility and effectiveness of this approach in a cluster randomized controlled trial, a study that compares the outcomes of groups (clusters) of patients randomly allocated to different interventions.
What Did the Researchers Do and Find?
The researchers randomly allocated 31 community health posts (fixed locations where CHWs provide medical services to several villages) to the study's intervention and control arms. CHWs in the intervention arm did RDTs for malaria on all the children under 5 years old who presented with fever and/or difficult or fast breathing (symptoms of pneumonia), treated test-positive children with AL, and treated those with nonsevere pneumonia (an increased breathing rate) with amoxicillin. CHWs in the control arm did not use RDTs but treated all children with fever with AL and referred those with signs of pneumonia to the nearest health facility. About 3,000 children with fever were treated during the 12-month study. 99.1% of the children in the control arm received AL compared with 27.5% of the children in the intervention arm, a 4-fold reduction in treatment for malaria. Importantly, the CHWs in the intervention arm adhered to treatment guidelines and did not give AL to children with negative RDT results. Of the children classified with nonsevere pneumonia, 13.3% of those in the control arm received early and appropriate treatment with amoxicillin compared to 68.2% of those in the intervention arm, a 5-fold increase in the timely treatment for pneumonia.
What Do These Findings Mean?
These findings indicate that CHWs in Zambia are capable of using RDTs, AL, and amoxicillin to manage malaria and pneumonia. They show that the intervention tested in this study has the potential to reduce the overuse of AL and to provide early and appropriate treatment for nonsevere pneumonia. Although this approach needs to be tested in other settings, these findings suggest that the use of CHWs might be a feasible and effective way to provide integrated management of pneumonia and malaria at the community level in developing countries. Importantly, these results also support the evaluation of the treatment by CHWs of other major childhood diseases and raise the possibility of saving the lives of many children in sub-Saharan Africa and other developing regions of the world through community level interventions.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000340.
WHO provides information on malaria, on rapid diagnostic tests for malaria, on artemisinin-combination therapy, and on global child mortality and efforts to reduce it (in several languages); WHO also provides a country health profile for Zambia
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish)
Kidshealth, a resource maintained by the not-for-profit Nemours Foundation (a not-for-profit organization for children's health), provides information for parents on pneumonia (in English and Spanish)
MedlinePlus provides links to additional information on malaria and on pneumonia (in English and Spanish)
More information about the Zambia Integrated Management of Malaria and Pneumonia Study is available
doi:10.1371/journal.pmed.1000340
PMCID: PMC2943441  PMID: 20877714
3.  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
4.  Why caretakers bypass Primary Health Care facilities for child care - a case from rural Tanzania 
Background
Research on health care utilization in low income countries suggests that patients frequently bypass PHC facilities in favour of higher-level hospitals - despite substantial additional time and financial costs. There are limited number of studies focusing on user's experiences at such facilities and reasons for bypassing them. This study aimed to identify factors associated with bypassing PHC facilities among caretakers seeking care for their underfive children and to explore experiences at such facilities among those who utilize them.
Methods
The study employed a mixed-method approach consisting of an interviewer administered questionnaires and in-depth interviews among selected care-takers seeking care for their underfive children at Korogwe and Muheza district hospitals in north-eastern Tanzania.
Results
The questionnaire survey included 560 caretakers. Of these 30 in-depth interviews were conducted. Fifty nine percent (206/348) of caretakers had not utilized their nearer PHC facilities during the index child's sickness episode. The reasons given for bypassing PHC facilities were lack of possibilities for diagnostic facilities (42.2%), lack of drugs (15.5%), closed health facility (10.2%), poor services (9.7%) and lack of skilled health workers (3.4%). In a regression model, the frequency of bypassing a PHC facility for child care increased significantly with decreasing travel time to the district hospital, shorter duration of symptoms and low disease severity.
Findings from the in-depth interviews revealed how the lack of quality services at PHC facilities caused delays in accessing appropriate care and how the experiences of inadequate care caused users to lose trust in them.
Conclusion
The observation that people are willing to travel long distances to get better quality services calls for health policies that prioritize quality of care before quantity. In a situation with limited resources, utilizing available resources to improve quality of care at available facilities could be more appropriate for improving access to health care than increasing the number of facilities. This would also improve equity in health care access since the poor who can not afford travelling costs will then get access to quality services at their nearer PHC facilities.
doi:10.1186/1472-6963-11-315
PMCID: PMC3234197  PMID: 22094076
5.  Effect of Removing Direct Payment for Health Care on Utilisation and Health Outcomes in Ghanaian Children: A Randomised Controlled Trial 
PLoS Medicine  2009;6(1):e1000007.
Background
Delays in accessing care for malaria and other diseases can lead to disease progression, and user fees are a known barrier to accessing health care. Governments are introducing free health care to improve health outcomes. Free health care affects treatment seeking, and it is therefore assumed to lead to improved health outcomes, but there is no direct trial evidence of the impact of removing out-of-pocket payments on health outcomes in developing countries. This trial was designed to test the impact of free health care on health outcomes directly.
Methods and Findings
2,194 households containing 2,592 Ghanaian children under 5 y old were randomised into a prepayment scheme allowing free primary care including drugs, or to a control group whose families paid user fees for health care (normal practice); 165 children whose families had previously paid to enrol in the prepayment scheme formed an observational arm. The primary outcome was moderate anaemia (haemoglobin [Hb] < 8 g/dl); major secondary outcomes were health care utilisation, severe anaemia, and mortality. At baseline the randomised groups were similar. Introducing free primary health care altered the health care seeking behaviour of households; those randomised to the intervention arm used formal health care more and nonformal care less than the control group. Introducing free primary health care did not lead to any measurable difference in any health outcome. The primary outcome of moderate anaemia was detected in 37 (3.1%) children in the control and 36 children (3.2%) in the intervention arm (adjusted odds ratio 1.05, 95% confidence interval 0.66–1.67). There were four deaths in the control and five in the intervention group. Mean Hb concentration, severe anaemia, parasite prevalence, and anthropometric measurements were similar in each group. Families who previously self-enrolled in the prepayment scheme were significantly less poor, had better health measures, and used services more frequently than those in the randomised group.
Conclusions
In the study setting, removing out-of-pocket payments for health care had an impact on health care-seeking behaviour but not on the health outcomes measured.
Trial registration: ClinicalTrials.gov (#NCT00146692).
Evelyn Ansah and colleagues report on whether removing user fees has an impact on health care-seeking behavior and health outcomes in households with children in Ghana.
Editors' Summary
Background.
Every year, about 10 million children worldwide die before their fifth birthday. About half these deaths occur in developing countries in sub-Saharan Africa. Here, 166 children out of every 1,000 die before they are five. A handful of preventable diseases—acute respiratory infections, diarrhea, malaria, measles, and HIV/AIDS—are responsible for most of these deaths. For all these diseases, delays in accessing medical care contribute to the high death rate. In the case of malaria, for example, children are rarely taken to a clinic or hospital (formal health care) when they first develop symptoms, which include fever, chills, and anemia (lack of red blood cells). Instead, they are taken to traditional healers or given home remedies (informal health care). When they are finally taken to a clinic, it is often too late to save their lives. Many factors contribute to this delay in seeking formal health care. Sometimes, health care simply isn't available. In other instances, parents may worry about the quality of the service provided or may not seek formal health care because of their sociocultural beliefs. Finally, many parents cannot afford the travel costs and loss of earnings involved in taking their child to a clinic or the cost of the treatment itself.
Why Was This Study Done?
The financial cost of seeking formal health care is often the major barrier to accessing health care in poor countries. Consequently, the governments of several developing countries have introduced free health care in an effort to improve their nation's health. Such initiatives have increased the use of formal health care in several African countries; the introduction of user fees in Ghana in the early 1980s had the opposite effect. It is generally assumed that an increase in formal health care utilization improves health—but is this true? In this study, the researchers investigate the effect of removing direct payment for health care on health service utilization and health outcomes in Ghanaian children in a randomized controlled trial (a trial in which participants are randomly assigned to an “intervention” group or “control” group and various predefined outcomes are measured).
What Did the Researchers Do and Find?
The researchers enrolled nearly 2,600 children under the age of 5 y living in a poor region of Ghana. Half were assigned to the group in which a prepayment scheme (paid for by the trial) provided free primary and basic secondary health care—this was the intervention arm. The rest were assigned to the control group in which families paid for health care. The trial's main outcome was the percentage of children with moderate anemia at the end of the malaria transmission season, an indicator of the effect of the intervention on malaria-related illness. Other outcomes included health care utilization (calculated from household diaries), severe anemia, and death. The researchers report that the children in the intervention arm attended formal health care facilities slightly more often and informal health care providers slightly less often than those in the control arm. About 3% of the children in both groups had moderate anemia at the end of the malaria transmission season. In addition, similar numbers of deaths, cases of severe anemia, fever episodes, and known infections with the malaria parasite were recorded in both groups of children.
What Do These Findings Mean?
These findings show that, in this setting, the removal of out-of-pocket payments for health care changed health care-seeking behavior but not health outcomes in children. This lack of a measured effect does not necessarily mean that the provision of free health care has no effect on children's health—it could be that the increase in health care utilization in the intervention arm compared to the control arm was too modest to produce a clear effect on health. Alternatively, in Ghana, the indirect costs of seeking health care may be more important than the direct cost of paying for treatment. Although the findings of this trial may not be generalizable to other countries, they nevertheless raise the possibility that providing free health care might not be the most cost-effective way of improving health in all developing countries. Importantly, they also suggest that changes in health care utilization should not be used in future trials as a proxy measure of improvements in health.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000007.
This research article is further discussed in a PLoS Medicine Perspective by Valéry Ridde and Slim Haddad
The World Health Organization provides information on child health and on global efforts to reduce child mortality, Millennium Development Goal 4; it also provides information about health in Ghana
The United Nations Web site provides further information on all the Millennium Development Goals, which were agreed to by the nations of the world in 2000 with the aim of ending extreme poverty by 2015 (in several languages)
The UK Department for International Development also provides information on the progress that is being made toward reducing child mortality
doi:10.1371/journal.pmed.1000007
PMCID: PMC2613422  PMID: 19127975
6.  Diagnosing Severe Falciparum Malaria in Parasitaemic African Children: A Prospective Evaluation of Plasma PfHRP2 Measurement 
PLoS Medicine  2012;9(8):e1001297.
Arjen Dondorp and colleagues investigate whether the plasma level of Plasmodium falciparum histidine-rich protein 2 can be used to distinguish between severe malaria and other severe febrile illness in African children with malaria.
Background
In African children, distinguishing severe falciparum malaria from other severe febrile illnesses with coincidental Plasmodium falciparum parasitaemia is a major challenge. P. falciparum histidine-rich protein 2 (PfHRP2) is released by mature sequestered parasites and can be used to estimate the total parasite burden. We investigated the prognostic significance of plasma PfHRP2 and used it to estimate the malaria-attributable fraction in African children diagnosed with severe malaria.
Methods and Findings
Admission plasma PfHRP2 was measured prospectively in African children (from Mozambique, The Gambia, Kenya, Tanzania, Uganda, Rwanda, and the Democratic Republic of the Congo) aged 1 month to 15 years with severe febrile illness and a positive P. falciparum lactate dehydrogenase (pLDH)-based rapid test in a clinical trial comparing parenteral artesunate versus quinine (the AQUAMAT trial, ISRCTN 50258054). In 3,826 severely ill children, Plasmadium falciparum PfHRP2 was higher in patients with coma (p = 0.0209), acidosis (p<0.0001), and severe anaemia (p<0.0001). Admission geometric mean (95%CI) plasma PfHRP2 was 1,611 (1,350–1,922) ng/mL in fatal cases (n = 381) versus 1,046 (991–1,104) ng/mL in survivors (n = 3,445, p<0.0001), without differences in parasitaemia as assessed by microscopy. There was a U-shaped association between log10 plasma PfHRP2 and risk of death. Mortality increased 20% per log10 increase in PfHRP2 above 174 ng/mL (adjusted odds ratio [AOR] 1.21, 95%CI 1.05–1.39, p = 0.009). A mechanistic model assuming a PfHRP2-independent risk of death in non-malaria illness closely fitted the observed data and showed malaria-attributable mortality less than 50% with plasma PfHRP2≤174 ng/mL. The odds ratio (OR) for death in artesunate versus quinine-treated patients was 0.61 (95%CI 0.44–0.83, p = 0.0018) in the highest PfHRP2 tertile, whereas there was no difference in the lowest tertile (OR 1.05; 95%CI 0.69–1.61; p = 0.82). A limitation of the study is that some conclusions are drawn from a mechanistic model, which is inherently dependent on certain assumptions. However, a sensitivity analysis of the model indicated that the results were robust to a plausible range of parameter estimates. Further studies are needed to validate our findings.
Conclusions
Plasma PfHRP2 has prognostic significance in African children with severe falciparum malaria and provides a tool to stratify the risk of “true” severe malaria-attributable disease as opposed to other severe illnesses in parasitaemic African children.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Malaria is a life-threatening disease caused by parasites that are transmitted to people through the bites of infected mosquitoes. In 2010, malaria caused an estimated 655,000 deaths worldwide, mostly in Africa, where according to the World Health Organization, one African child dies every minute from the disease. There are four Plasmodium parasite species that cause malaria in humans, with one species, Plasmodium falciparum, causing the most severe disease. However, diagnosing severe falciparum malaria in children living in endemic areas is problematic, as many semi-immune children may have the malaria parasites in their blood (described as being parasitaemic) but do not have clinical disease. Therefore, a positive malaria blood smear may be coincidental and not be diagnostic of severe malaria, and unfortunately, neither are the clinical symptoms of severe malaria, such as shock, acidosis, or coma, which can also be caused by other childhood infections. For these reasons, the misdiagnosis of falciparum malaria in severely ill children is an important problem in sub-Saharan Africa, and may result in unnecessary child deaths.
Why Was This Study Done?
Previous studies have suggested that a parasite protein—P. falciparum histidine-rich protein-2 (PfHRP2)—is a measure of the total number of parasites in the patient. Unlike the circulating parasites detected on a blood film, which do not represent the parasites that get stuck in vital organs, PfHRP2 is distributed equally through the total blood plasma volume, and so can be considered a measure of the total parasite burden in the previous 48 hours. So in this study, the researchers assessed the prognostic value of plasma PfHRP2 in African children with severe malaria and whether this protein could distinguish children who really do have severe malaria from those who have severe febrile illness but coincidental parasitaemia, who may have another infection.
What Did the Researchers Do and Find?
The researchers assessed levels of plasma PfHRP2 in 3,826 out of a possible 5,425 African children who participated in a large multinational trial (in Mozambique, The Gambia, Rwanda, Tanzania, Kenya, Uganda, and the Democratic Republic of Congo) that compared the anti-malarial drugs quinine and artesunate for the treatment of severe malaria. All children had a clinical diagnosis of severe malaria confirmed by a rapid diagnostic test, and the researchers used clinical signs to define the severity of malaria. The researchers assessed the relationship between plasma PfHRP2 concentrations and risk of death taking other well established predictors of death, such as coma, convulsions, hypoglycaemia, respiratory distress, and shock, into account.
The researchers found that PfHRP2 was detectable in 3,800/3,826 (99%) children with severe malaria and that the average plasma PfHRP2 levels was significantly higher in the 381 children who died from malaria than in children who survived (1,611 ng/mL versus 1,046 ng/mL). Plasma PfHRP2 was also significantly higher in children with severe malaria signs and symptoms such as coma, acidosis, and severe anaemia. Importantly, the researchers found that high death rates were associated with either very low or very high values of plasma PfHRP2: the odds (chance) of death were 20% higher per unit increase in PfHRP2 above a specific threshold (174 ng/ml), but below this concentration, the risk of death increased with decreasing levels, probably because at lower levels disease was caused by a severe febrile disease other than malaria, like septicemia. Finally, the researchers found that in children within the highest PfHRP2 tertile, the chance of death when treated with the antimalarial drug artesunate versus quinine was 0.61 but that there was no difference in death rates in the lowest tertile, which supports that patients with very low plasma PfHRP2 have a different severe febrile illness than malaria. The researchers use mathematical modeling to provide cut-off values for plasma PfHRP2 denoting the proportion of patients with a diagnosis other than severe malaria.
What Do These Findings Mean?
These findings suggest that in areas of moderate or high malaria transmission where a high proportion of children are parasitaemic, plasma PfHRP2 levels taken on admission to hospital can differentiate children at highest risk of death from severe falciparum malaria from those likely to have alternative causes of severe febrile illness. Therefore, plasma PfHRP2 could be considered a valuable additional diagnostic tool and prognostic indicator in African children with severe falciparum malaria. This finding is important for clinicians treating children with severe febrile illnesses in malaria-endemic countries: while high levels of plasma PfHRP2 is indicative of severe malaria which needs urgent antimalarial treatment, low levels suggest that another severe infective disease should be considered, warranting additional investigations and urgent treatment with antibiotics.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001297.
A previous small study in PLOS ONE explores the relationship between plasma PfHRP2 and severe malaria in Tanzanian children
The WHO website and the website of Malaria No More have comprehensive information about malaria
doi:10.1371/journal.pmed.1001297
PMCID: PMC3424256  PMID: 22927801
7.  The Impact of Retail-Sector Delivery of Artemether–Lumefantrine on Malaria Treatment of Children under Five in Kenya: A Cluster Randomized Controlled Trial 
PLoS Medicine  2011;8(5):e1000437.
In a cluster randomized trial, Beth Kangwana and colleagues find that provision of subsidized packs of the malaria therapy artemether-lumefantrine to shops more than doubled the proportion of children with fever who received drugs promptly.
Background
It has been proposed that artemisinin-based combination therapy (ACT) be subsidised in the private sector in order to improve affordability and access. This study in western Kenya aimed to evaluate the impact of providing subsidized artemether–lumefantrine (AL) through retail providers on the coverage of prompt, effective antimalarial treatment for febrile children aged 3–59 months.
Methods and Findings
We used a cluster-randomized, controlled design with nine control and nine intervention sublocations, equally distributed across three districts in western Kenya. Cross-sectional household surveys were conducted before and after the delivery of the intervention. The intervention comprised provision of subsidized packs of paediatric ACT to retail outlets, training of retail outlet staff, and community awareness activities. The primary outcome was defined as the proportion of children aged 3–59 months reporting fever in the past 2 weeks who started treatment with AL on the same day or following day of fever onset. Data were collected using structured questionnaires and analyzed based on cluster-level summaries, comparing control to intervention arms, while adjusting for other covariates. Data were collected on 2,749 children in the target age group at baseline and 2,662 at follow-up. 29% of children experienced fever within 2 weeks before the interview. At follow-up, the percentage of children receiving AL on the day of fever or the following day had risen by 14.6% points in the control arm (from 5.3% [standard deviation (SD): 3.2%] to 19.9% [SD: 10.0%]) and 40.2% points in the intervention arm (from 4.7% [SD: 3.4%] to 44.9% [SD: 11.7%]). The percentage of children receiving AL was significantly greater in the intervention arm at follow-up, with a difference between the arms of 25.0% points (95% confidence interval [CI]: 14.1%, 35.9%; unadjusted p = 0.0002, adjusted p = 0.0001). No significant differences were observed between arms in the proportion of caregivers who sought treatment for their child's fever by source, or in the child's adherence to AL.
Conclusions
Subsidizing ACT in the retail sector can significantly increase ACT coverage for reported fevers in rural areas. Further research is needed on the impact and cost-effectiveness of such subsidy programmes at a national scale.
Trial Registration
Current Controlled Trials ISRCTN59275137 and Kenya Pharmacy and Poisons Board Ethical Committee for Clinical Trials PPB/ECCT/08/07.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria is a major global public-health problem. Half the world's population is at risk of this mosquito-borne parasitic disease, which kills a million people (mainly children living in sub-Saharan Africa) every year. Although several parasites cause malaria, Plasmodium falciparum is responsible for most of these deaths. For the past 50 years, the main treatments for malaria have been drugs such as sulfadoxine–pyrimethamine and chloroquine. Unfortunately, parasitic resistance to these inexpensive "monotherapies" is now widespread and there has been an upsurge in the illness and death caused by P. falciparum. To combat this increase, the World Health Organization (WHO) now recommends artemisinin-based combination therapy (ACT) for first-line treatment of 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?
Despite WHO's recommendation, ACT use in many developing countries remains low partly because of its high retail price. To increase the affordability of and access to ACT, the Global Fund to Fight AIDS, Tuberculosis and Malaria is planning to run an ACT subsidy mechanism called the “Affordable Medicines Facility – malaria” (AMF-m). Using money provided by various donors, the Global Fund aims to reduce the private sector retail costs of ACT to those of monotherapies by making "copayments" directly to ACT manufacturers. Phase I of the AMF-m is already being implemented in pilots in several countries, but there are few data on the likely impact of private sector ACT subsidies on the coverage of prompt, effective treatment at the community level. In this cluster randomized controlled trial, the researchers investigate the impact of an intervention package that includes ACT subsidies on malaria treatment of young children in a high malaria transmission area of western Kenya. In a cluster randomized controlled trial, groups of patients rather than individual patients are randomly assigned to receive a test or control intervention, and the outcomes in different clusters are compared.
What Did the Researchers Do and Find?
The researchers randomly assigned 18 rural sublocations (the lowest administrative level in Kenya) to receive the intervention—the provision of subsidized packs of the ACT artemether-lumefantrine (AL) to retail outlets, retail staff training, and community awareness activities—or to act as controls. The researchers collected data about recent fever (a symptom of malaria) in children aged 3–59 months and its treatment with AL from randomly selected households in the intervention and control sublocations 4 months before and 8 months after roll-out of the intervention. At follow-up, 19.9% of children in the control arm received AL within 24 hours of fever developing compared to 5.3% of children at baseline (a 14.5% point rise). In the intervention arm, the percentage of children receiving AL within 24 hours of fever developing increased from 4.7% at baseline to 44.9% at follow-up (a 40.2% point rise). Moreover, the proportion of children receiving AL in the intervention arm was significantly greater than in the control arm (that is, unlikely to have happened by chance). Put another way, the intervention more than doubled the proportion of children with fever who received AL promptly.
What Do These Findings Mean?
These findings show that in the rural areas of Kenya included in this study, the provision of subsidized ACT in the private retail sector can significantly increase the coverage of prompt and effective treatment of fever in children with ACT; the increase in ACT coverage in the control arm probably reflects improved availability of AL in public-health facilities. However, these findings may not be generalizable to other settings and, because the design of this trial and that of the planned AMF-m roll-out are somewhat different (through AMF-m, subsidized drugs will be available to all age groups, for example), these results must be used with caution when trying to predict the outcome of AMF-m. Most importantly, the tested intervention only achieved prompt ACT uptake in 44.9% of children with fever, somewhat lower than the target of 80% set by the Roll Back Malaria Partnership. Thus, although the provision of subsidized ACTs is likely to improve ACT coverage, additional strategies to increase the prompt use of ACT need to be identified.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000437.
Information is available from the World Health Organization on malaria (in several languages); 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)
Information is available from the Roll Back Malaria Partnership on the global control of malaria including fact sheets about ACT and about malaria in Kenya, and information on AMF-m
The Global Fund to Fight AIDS, Tuberculosis and Malaria, an international financing institution that invests the world's money to save lives, also has information on fighting malaria and on the AMF-m (in several languages)
MedlinePlus provides links to additional information on malaria (in English and Spanish)
doi:10.1371/journal.pmed.1000437
PMCID: PMC3104978  PMID: 21655317
8.  A Multifaceted Intervention to Implement Guidelines and Improve Admission Paediatric Care in Kenyan District Hospitals: A Cluster Randomised Trial 
PLoS Medicine  2011;8(4):e1001018.
Philip Ayieko and colleagues report the outcomes of a cluster-randomized trial carried out in eight Kenyan district hospitals evaluating the effects of a complex intervention involving improved training and supervision for clinicians. They found a higher performance of hospitals assigned to the complex intervention on a variety of process of care measures, as compared to those receiving the control intervention.
Background
In developing countries referral of severely ill children from primary care to district hospitals is common, but hospital care is often of poor quality. However, strategies to change multiple paediatric care practices in rural hospitals have rarely been evaluated.
Methods and Findings
This cluster randomized trial was conducted in eight rural Kenyan district hospitals, four of which were randomly assigned to a full intervention aimed at improving quality of clinical care (evidence-based guidelines, training, job aides, local facilitation, supervision, and face-to-face feedback; n = 4) and the remaining four to control intervention (guidelines, didactic training, job aides, and written feedback; n = 4). Prespecified structure, process, and outcome indicators were measured at baseline and during three and five 6-monthly surveys in control and intervention hospitals, respectively. Primary outcomes were process of care measures, assessed at 18 months postbaseline.
In both groups performance improved from baseline. Completion of admission assessment tasks was higher in intervention sites at 18 months (mean = 0.94 versus 0.65, adjusted difference 0.54 [95% confidence interval 0.05–0.29]). Uptake of guideline recommended therapeutic practices was also higher within intervention hospitals: adoption of once daily gentamicin (89.2% versus 74.4%; 17.1% [8.04%–26.1%]); loading dose quinine (91.9% versus 66.7%, 26.3% [−3.66% to 56.3%]); and adequate prescriptions of intravenous fluids for severe dehydration (67.2% versus 40.6%; 29.9% [10.9%–48.9%]). The proportion of children receiving inappropriate doses of drugs in intervention hospitals was lower (quinine dose >40 mg/kg/day; 1.0% versus 7.5%; −6.5% [−12.9% to 0.20%]), and inadequate gentamicin dose (2.2% versus 9.0%; −6.8% [−11.9% to −1.6%]).
Conclusions
Specific efforts are needed to improve hospital care in developing countries. A full, multifaceted intervention was associated with greater changes in practice spanning multiple, high mortality conditions in rural Kenyan hospitals than a partial intervention, providing one model for bridging the evidence to practice gap and improving admission care in similar settings.
Trial registration
Current Controlled Trials ISRCTN42996612
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 2008, nearly 10 million children died in early childhood. Nearly all these deaths were in low- and middle-income countries—half were in Africa. In Kenya, for example, 74 out every 1,000 children born died before they reached their fifth birthday. About half of all childhood (pediatric) deaths in developing countries are caused by pneumonia, diarrhea, and malaria. Deaths from these common diseases could be prevented if all sick children had access to quality health care in the community (“primary” health care provided by health centers, pharmacists, family doctors, and traditional healers) and in district hospitals (“secondary” health care). Unfortunately, primary health care facilities in developing countries often lack essential diagnostic capabilities and drugs, and pediatric hospital care is frequently inadequate with many deaths occurring soon after admission. Consequently, in 1996, as part of global efforts to reduce childhood illnesses and deaths, the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF) introduced the Integrated Management of Childhood Illnesses (IMCI) strategy. This approach to child health focuses on the well-being of the whole child and aims to improve the case management skills of health care staff at all levels, health systems, and family and community health practices.
Why Was This Study Done?
The implementation of IMCI has been evaluated at the primary health care level, but its implementation in district hospitals has not been evaluated. So, for example, interventions designed to encourage the routine use of WHO disease-specific guidelines in rural pediatric hospitals have not been tested. In this cluster randomized trial, the researchers develop and test a multifaceted intervention designed to improve the implementation of treatment guidelines and admission pediatric care in district hospitals in Kenya. In a cluster randomized trial, groups of patients rather than individual patients are randomly assigned to receive alternative interventions and the outcomes in different “clusters” of patients are compared. In this trial, each cluster is a district hospital.
What Did the Researchers Do and Find?
The researchers randomly assigned eight Kenyan district hospitals to the “full” or “control” intervention, interventions that differed in intensity but that both included more strategies to promote implementation of best practice than are usually applied in Kenyan rural hospitals. The full intervention included provision of clinical practice guidelines and training in their use, six-monthly survey-based hospital assessments followed by face-to-face feedback of survey findings, 5.5 days training for health care workers, provision of job aids such as structured pediatric admission records, external supervision, and the identification of a local facilitator to promote guideline use and to provide on-site problem solving. The control intervention included the provision of clinical practice guidelines (without training in their use) and job aids, six-monthly surveys with written feedback, and a 1.5-day lecture-based seminar to explain the guidelines. The researchers compared the implementation of various processes of care (activities of patients and doctors undertaken to ensure delivery of care) in the intervention and control hospitals at baseline and 18 months later. The performance of both groups of hospitals improved during the trial but more markedly in the intervention hospitals than in the control hospitals. At 18 months, the completion of admission assessment tasks and the uptake of guideline-recommended clinical practices were both higher in the intervention hospitals than in the control hospitals. Moreover, a lower proportion of children received inappropriate doses of drugs such as quinine for malaria in the intervention hospitals than in the control hospitals.
What Do These Findings Mean?
These findings show that specific efforts are needed to improve pediatric care in rural Kenya and suggest that interventions that include more approaches to changing clinical practice may be more effective than interventions that include fewer approaches. These findings are limited by certain aspects of the trial design, such as the small number of participating hospitals, and may not be generalizable to other hospitals in Kenya or to hospitals in other developing countries. Thus, although these findings seem to suggest that efforts to implement and scale up improved secondary pediatric health care will need to include more than the production and dissemination of printed materials, further research including trials or evaluation of test programs are necessary before widespread adoption of any multifaceted approach (which will need to be tailored to local conditions and available resources) can be contemplated.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001018.
WHO provides information on efforts to reduce global child mortality and on Integrated Management of Childhood Illness (IMCI); the WHO pocket book “Hospital care for children contains guidelines for the management of common illnesses with limited resources (available in several languages)
UNICEF also provides information on efforts to reduce child mortality and detailed statistics on child mortality
The iDOC Africa Web site, which is dedicated to improving the delivery of hospital care for children and newborns in Africa, provides links to the clinical guidelines and other resources used in this study
doi:10.1371/journal.pmed.1001018
PMCID: PMC3071366  PMID: 21483712
9.  Risk Factors for Death among Children Less than 5 Years Old Hospitalized with Diarrhea in Rural Western Kenya, 2005–2007: A Cohort Study 
PLoS Medicine  2012;9(7):e1001256.
A hospital-based surveillance study conducted by Ciara O'Reilly and colleagues describes the risk factors for death amongst children who have been hospitalized with diarrhea in rural Kenya.
Background
Diarrhea is a leading cause of childhood morbidity and mortality in sub-Saharan Africa. Data on risk factors for mortality are limited. We conducted hospital-based surveillance to characterize the etiology of diarrhea and identify risk factors for death among children hospitalized with diarrhea in rural western Kenya.
Methods and Findings
We enrolled all children <5 years old, hospitalized with diarrhea (≥3 loose stools in 24 hours) at two district hospitals in Nyanza Province, western Kenya. Clinical and demographic information was collected. Stool specimens were tested for bacterial and viral pathogens. Bivariate and multivariable logistic regression analyses were carried out to identify risk factors for death. From May 23, 2005 to May 22, 2007, 1,146 children <5 years old were enrolled; 107 (9%) children died during hospitalization. Nontyphoidal Salmonella were identified in 10% (118), Campylobacter in 5% (57), and Shigella in 4% (42) of 1,137 stool samples; rotavirus was detected in 19% (196) of 1,021 stool samples. Among stools from children who died, nontyphoidal Salmonella were detected in 22%, Shigella in 11%, rotavirus in 9%, Campylobacter in 5%, and S. Typhi in <1%. In multivariable analysis, infants who died were more likely to have nontyphoidal Salmonella (adjusted odds ratio [aOR] = 6·8; 95% CI 3·1–14·9), and children <5 years to have Shigella (aOR = 5·5; 95% CI 2·2–14·0) identified than children who survived. Children who died were less likely to be infected with rotavirus (OR = 0·4; 95% CI 0·2–0·8). Further risk factors for death included being malnourished (aOR = 4·2; 95% CI 2·1–8·7); having oral thrush on physical exam (aOR = 2·3; 95% CI 1·4–3·8); having previously sought care at a hospital for the illness (aOR = 2·2; 95% CI 1·2–3·8); and being dehydrated as diagnosed at discharge/death (aOR = 2·5; 95% CI 1·5–4·1). A clinical diagnosis of malaria, and malaria parasites seen on blood smear, were not associated with increased risk of death. This study only captured in-hospital childhood deaths, and likely missed a substantial number of additional deaths that occurred at home.
Conclusion
Nontyphoidal Salmonella and Shigella are associated with mortality among rural Kenyan children with diarrhea who access a hospital. Improved prevention and treatment of diarrheal disease is necessary. Enhanced surveillance and simplified laboratory diagnostics in Africa may assist clinicians in appropriately treating potentially fatal diarrheal illness.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Diarrhea—passing three or more loose or liquid stools per day—kills about 1.5 million young children every year, mainly in low- and middle-income countries. Globally, it is the second leading cause of death in under-5-year olds, causing nearly one in five child deaths. Diarrhea, which can lead to life-threatening dehydration, is a common symptom of gastrointestinal infections. The pathogens (viruses, bacteria, and parasites) that cause diarrhea spread through contaminated food or drinking water, and from person to person through poor hygiene and inadequate sanitation (unsafe disposal of human excreta). Interventions that prevent diarrhea include improvements in water supplies, sanitation and hygiene, the promotion of breast feeding, and vaccination against rotavirus (a major viral cause of diarrhea). Treatments for diarrhea include oral rehydration salts, which prevent and treat dehydration, zinc supplementation, which decreases the severity and duration of diarrhea, and the use of appropriate antibiotics when indicated for severe bacterial diarrhea.
Why Was This Study Done?
Nearly half of deaths from diarrhea among young children occur in Africa where diarrhea is the single largest cause of death among under 5-year-olds and a major cause of childhood illness. Unfortunately, although some of the risk factors for death from diarrhea in children in sub-Saharan Africa have been identified (for example, having other illnesses, poor nutrition, and not being breastfed), little is known about the relative contributions of different diarrhea-causing pathogens to diarrheal deaths. Clinicians need to know which of these pathogens are most likely to cause death in children so that they can manage their patients appropriately. In this cohort study, the researchers characterize the causes and risk factors associated with death among young children hospitalized for diarrhea in Nyanza Province, western Kenya, an area where most households have no access to safe drinking water and a quarter lack latrines. In a cohort study, a group of people with a specific condition is observed to identify which factors lead to different outcomes.
What Did the Researchers Do and Find?
The researchers enrolled all the children under 5 years old who were hospitalized over a two-year period for diarrhea at two district hospitals in Nyanza Province, tested their stool samples for diarrhea-causing viral and bacterial pathogens, and recorded which patients died in-hospital. They then used multivariable regression analysis (a statistical method) to determine which risk factors and diarrheal pathogens were associated with death among the children. During the study, 1,146 children were hospitalized, 107 of whom died in the hospital. 10% of all the stool samples contained nontyphoidal Salmonella, 4% contained Shigella (two types of diarrhea-causing bacteria), and 19% contained rotavirus. By contrast, 22% of the samples taken from children who died contained nontyphoidal Salmonella, 11% contained Shigella, 9% contained rotavirus, and 5% contained Campylobacter (another bacterial pathogen that causes diarrhea). Compared to survivors, infants (children under 1 year of age) who died were nearly seven times more likely to have nontyphoidal Salmonella in their stools and children under 5 years old who died were five and half times more likely to have Shigella in their stools but less likely to have rotavirus in their stools. Other factors associated with death included being malnourished, having oral thrush (a fungal infection of the mouth), having previously sought hospital care for diarrhea, and being dehydrated.
What Do These Findings Mean?
These findings indicate that, among young children admitted to the hospital in western Kenya with diarrhea, infections with nontyphoidal Salmonella and with Shigella (but not with rotavirus) were associated with an increased risk of death. Because this study only captured deaths in hospital and most diarrheal deaths in developing countries occur at home, these results may not accurately reflect the pathogens associated with overall childhood diarrheal deaths. In addition, they may not be generalizable to other geographical regions. Nevertheless, given that that there are currently no vaccines available for most bacterial diarrheal diseases, these findings highlight the importance of Kenya and other developing countries implementing effective strategies for the prevention and management of diarrheal diseases in children such as increasing access to improved water, sanitation, and hygiene, and community-level promotion of the use of oral rehydration solution and zinc supplements. They also suggest that enhanced surveillance and simplified laboratory diagnostics for diarrheal pathogens could help clinicians identify those children presenting to hospital with diarrhea who are at high risk of death and prioritize their treatment.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001256.
The World Health Organization provides information on diarrhea (in several languages); its 2009 report with UNICEF Diarrhea: why children are still dying and what can be done, which includes the WHO/UNICEF recommendations for the treatment and prevention of diarrhea in children, can be downloaded from the Internet
The children's charity UNICEF, which protects the rights of children and young people around the world, provides information on diarrhea (in several languages)
doi:10.1371/journal.pmed.1001256
PMCID: PMC3389023  PMID: 22802736
10.  Estimating the Number of Paediatric Fevers Associated with Malaria Infection Presenting to Africa's Public Health Sector in 2007 
PLoS Medicine  2010;7(7):e1000301.
Peter Gething and colleagues compute the number of fevers likely to present to public health facilities in Africa and the estimated number of these fevers likely to be infected with Plasmodium falciparum malaria parasites.
Background
As international efforts to increase the coverage of artemisinin-based combination therapy in public health sectors gather pace, concerns have been raised regarding their continued indiscriminate presumptive use for treating all childhood fevers. The availability of rapid-diagnostic tests to support practical and reliable parasitological diagnosis provides an opportunity to improve the rational treatment of febrile children across Africa. However, the cost effectiveness of diagnosis-based treatment polices will depend on the presumed numbers of fevers harbouring infection. Here we compute the number of fevers likely to present to public health facilities in Africa and the estimated number of these fevers likely to be infected with Plasmodium falciparum malaria parasites.
Methods and Findings
We assembled first administrative-unit level data on paediatric fever prevalence, treatment-seeking rates, and child populations. These data were combined in a geographical information system model that also incorporated an adjustment procedure for urban versus rural areas to produce spatially distributed estimates of fever burden amongst African children and the subset likely to present to public sector clinics. A second data assembly was used to estimate plausible ranges for the proportion of paediatric fevers seen at clinics positive for P. falciparum in different endemicity settings. We estimated that, of the 656 million fevers in African 0–4 y olds in 2007, 182 million (28%) were likely to have sought treatment in a public sector clinic of which 78 million (43%) were likely to have been infected with P. falciparum (range 60–103 million).
Conclusions
Spatial estimates of childhood fevers and care-seeking rates can be combined with a relational risk model of infection prevalence in the community to estimate the degree of parasitemia in those fevers reaching public health facilities. This quantification provides an important baseline comparison of malarial and nonmalarial fevers in different endemicity settings that can contribute to ongoing scientific and policy debates about optimum clinical and financial strategies for the introduction of new diagnostics. These models are made publicly available with the publication of this paper.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria —an infectious parasitic disease transmitted to people through the bite of an infected mosquito —kills about one million people (mainly children living in sub-Saharan Africa) every year. Although several parasites cause malaria, Plasmodium falciparum is responsible for most of these deaths. For the past 50 years, the main treatments for P. falciparum malaria have been chloroquine and sulfadoxine/pyrimethamine. Unfortunately, parasitic resistance to these “monotherapies” is now widespread and there has been a global upsurge in the illness and deaths caused by P. falciparum. To combat this increase, the World Health Organization 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?
All African countries at risk of P. falciparum have now adopted ACT as first-line therapy for malaria in their public clinics. However, experts are concerned that ACT is often given to children who don't actually have malaria because, in many parts of Africa, health care workers assume that all childhood fevers are malaria. This practice, which became established when diagnostic facilities for malaria were very limited, increases the chances of P. falciparum becoming resistant to ACT, wastes limited drug stocks, and means that many ill children are treated inappropriately. Recently, however, rapid diagnostic tests for malaria have been developed and there have been calls to expand their use to improve the rational treatment of African children with fever. Before such an expansion is initiated, it is important to know how many African children develop fever each year, how many of these ill children attend public clinics, and what proportion of them is likely to have malaria. Unfortunately, this type of information is incompletely or unreliably collected in many parts of Africa. In this study, therefore, the researchers use a mathematical model to estimate the number of childhood fevers associated with malaria infection that presented to Africa's public clinics in 2007 from survey data.
What Did the Researchers Do and Find?
The researchers used survey data on the prevalence (the proportion of a population with a specific disease) of childhood fever and on treatment-seeking behavior and data on child populations to map the distribution of fever among African children and the likelihood of these children attending public clinics for treatment. They then used a recent map of the distribution of P. falciparum infection risk to estimate what proportion of children with fever who attended clinics were likely to have had malaria in different parts of Africa. In 2007, the researchers estimate, 656 million cases of fever occurred in 0–4-year-old African children, 182 million were likely to have sought treatment in a public clinic, and 78 million (just under half of the cases that attended a clinic with fever) were likely to have been infected with P. falciparum. Importantly, there were marked geographical differences in the likelihood of children with fever presenting at public clinics being infected with P. falciparum. So, for example, whereas nearly 60% of the children attending public clinics with fever in Burkino Faso were likely to have had malaria, only 15% of similar children in Kenya were likely to have had this disease.
What Do These Findings Mean?
As with all mathematical models, the accuracy of these findings depends on the assumptions included in the model and on the data fed into it. Nevertheless, these findings provide a map of the prevalence of malarial and nonmalarial childhood fevers across sub-Saharan Africa and an indication of how many of the children with fever reaching public clinics are likely to have malaria and would therefore benefit from ACT. The finding that in some countries more than 80% of children attending public clinics with fever probably don't have malaria highlights the potential benefits of introducing rapid diagnostic testing for malaria. Furthermore, these findings can now be used to quantify the resources needed for and the potential clinical benefits of different policies for the introduction of rapid diagnostic testing for malaria across Africa.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000301.
Information is available from the World Health Organization on malaria (in several languages) and on rapid diagnostic tests for malaria
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish)
MedlinePlus provides links to additional information on malaria (in English and Spanish)
Information on the global mapping of malaria is available at the Malaria Atlas Project
Information is available from the Roll Back Malaria Partnership on the global control of malaria (in English and French) and on artemisinin combination therapy
doi:10.1371/journal.pmed.1000301
PMCID: PMC2897768  PMID: 20625548
11.  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
12.  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
13.  A Multifaceted Intervention to Improve the Quality of Care of Children in District Hospitals in Kenya: A Cost-Effectiveness Analysis 
PLoS Medicine  2012;9(6):e1001238.
A cost-effective analysis conducted by Edwine Barasa and colleagues estimates that a complex intervention aimed at improving quality of pediatric care would be affordable and cost-effective in Kenya.
Background
To improve care for children in district hospitals in Kenya, a multifaceted approach employing guidelines, training, supervision, feedback, and facilitation was developed, for brevity called the Emergency Triage and Treatment Plus (ETAT+) strategy. We assessed the cost effectiveness of the ETAT+ strategy, in Kenyan hospitals. Further, we estimate the costs of scaling up the intervention to Kenya nationally and potential cost effectiveness at scale.
Methods and Findings
Our cost-effectiveness analysis from the provider's perspective used data from a previously reported cluster randomized trial comparing the full ETAT+ strategy (n = 4 hospitals) with a partial intervention (n = 4 hospitals). Effectiveness was measured using 14 process measures that capture improvements in quality of care; their average was used as a summary measure of quality. Economic costs of the development and implementation of the intervention were determined (2009 US$). Incremental cost-effectiveness ratios were defined as the incremental cost per percentage improvement in (average) quality of care. Probabilistic sensitivity analysis was used to assess uncertainty. The cost per child admission was US$50.74 (95% CI 49.26–67.06) in intervention hospitals compared to US$31.1 (95% CI 30.67–47.18) in control hospitals. Each percentage improvement in average quality of care cost an additional US$0.79 (95% CI 0.19–2.31) per admitted child. The estimated annual cost of nationally scaling up the full intervention was US$3.6 million, approximately 0.6% of the annual child health budget in Kenya. A “what-if” analysis assuming conservative reductions in mortality suggests the incremental cost per disability adjusted life year (DALY) averted by scaling up would vary between US$39.8 and US$398.3.
Conclusion
Improving quality of care at scale nationally with the full ETAT+ strategy may be affordable for low income countries such as Kenya. Resultant plausible reductions in hospital mortality suggest the intervention could be cost-effective when compared to incremental cost-effectiveness ratios of other priority child health interventions.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
According to latest global estimates from UNICEF, 7.6 million children currently die every year before they reach five years of age. Half of these deaths occur in children in sub-Saharan Africa and tragically, most of these deaths are due to a few treatable and preventable diseases, such as pneumonia, malaria, and diarrhea, for which effective interventions are already available. In order to meet the target of the 4th Millennium Development Goal—which aims to reduce the under-five child mortality rate by two-thirds from 1990 levels by 2015—delivering these interventions is essential.
In Kenya, the under-five child mortality rate must be reduced by half from its 2008 level in order to meet the Millennium Development Goal (MDG) target and so improving the management of serious child illness might help achieve this goal. A study published last year in PLoS Medicine described such an approach and included the development and implementation of evidence-based clinical practice guidelines linked to health worker training, follow-up supervision, performance feedback, and facilitation in eight district hospitals in Kenya.
Why Was This Study Done?
In the study mentioned above, the researchers compared the implementation of various processes of care in intervention and control hospitals at baseline and 18 months later and found that performance improved more in the intervention hospitals than in the control hospitals. However, while this strategy was effective at improving the quality of health care, it is unclear whether scaling up the approach would be a good use of limited resources. So in this study, the same researchers performed a cost-effectiveness analysis (which they conducted alongside the original trial) of their quality improvement intervention and estimated the costs and effects of scaling up this approach to cover the entire population of Kenya.
What Did the Researchers Do and Find?
In order to perform the cost part of the analysis, the researchers collected the relevant information on costs by using clinical and accounting record reviews and interviews with those involved in developing and implementing the intervention. The researchers evaluated the effectiveness part of the analysis by comparing the implementation of their improved quality of care strategy as delivered in the intervention hospitals with the partial intervention as delivered in the control hospitals by calculating the mean percentage improvement in the 14 process of care indicators at 18 months. Finally, the researchers calculated the costs of scaling up the intervention by applying their results to the whole of Kenya—121 hospital facilities with an estimated annual child admission rate of 2,000 per facility.
The researchers found that the quality of care (as measured by the process of care indicators) was 25% higher in intervention hospitals than in control hospitals, while the cost per child admission was US$50.74 in intervention hospitals compared to US$31.1 in control hospitals. The researchers calculated that each percentage improvement in the average quality of care was achieved at an additional cost of US$0.79 per admitted child. Extrapolating these results to all of Kenya, the estimated annual cost of scaling up the intervention nationally was US$3.6 million, about 0.6% of the annual child health budget in Kenya.
What Do These Findings Mean?
The findings of this cost-effectiveness analysis suggests that a comprehensive quality improvement intervention is effective at improving standards of care but at an additional cost, which may be relatively cost effective compared with basic care if the improvements observed are associated with decreases in child inpatient mortality. The absolute costs for scaling up are comparable to, or even lower than, costs of other, major child health interventions. As the international community is giving an increasing focus to strengthening health systems, these findings provide a strong case for scaling up this intervention, which improves quality of care and service provision for the major causes of child mortality, in rural hospitals throughout Kenya and other district hospitals in sub-Saharan Africa.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001238.
The researchers' original article appeared in PLoS Medicine in 2011: Ayieko P, Ntoburi S, Wagai J, Opondo C, Opiyo N, et al. (2011) A Multifaceted Intervention to Implement Guidelines and Improve Admission Paediatric Care in Kenyan District Hospitals: A Cluster Randomised Trial. PLoS Med 8(4): e1001018. doi:10.1371/journal.pmed.1001018
The IDOC Africa provides further information on the ETAT+ strategy
The World Health Organization (WHO) provides information on MDG 4, including strategies to reduce global child mortality) and the WHO pocket-book “Hospital care for children” includes guidelines for the management of common but serious childhood illnesses in resource-limited settings
UNICEF www.unicef.org also publishes information on global child mortality rates and the Countdown to 2015 website tracks coverage levels for health interventions proven to reduce child mortality
doi:10.1371/journal.pmed.1001238
PMCID: PMC3373608  PMID: 22719233
14.  Use of drugs, perceived drug efficacy and preferred providers for febrile children: implications for home management of fever 
Malaria Journal  2009;8:131.
Background
Community distribution of anti-malarials and antibiotics has been recommended as a strategy to reduce the under-five mortality due to febrile illnesses in sub-Saharan Africa. However, drugs distributed in these interventions have been considered weak by some caretakers and utilization of community medicine distributors has been low. The aim of the study was to explore caretakers' use of drugs, perceptions of drug efficacy and preferred providers for febrile children in order to make suggestions for community management of pneumonia and malaria.
Methods
The study was conducted in eastern Uganda using four focus group discussions with fathers and mothers of children under five; and eight key informant interviews with health workers in government and non-governmental organization facilities, community medicine distributors, and attendants in drug shops and private clinics. Caretakers were asked the drugs they use for treatment of fever, why they considered them efficacious, and the providers they go to and why they go there. Health providers were interviewed on their opinions of caretakers' perceptions of drugs and providers. Analysis was done using content analysis.
Results
Drugs that have been phased out as first-line treatment for malaria, such as chloroquine and sulphadoxine/pyrimethamine, are still perceived as efficacious. Use of drugs depended on perception of the disease, cost and drug availability. There were divergent views about drug efficacy concerning drug combinations, side effects, packaging, or using drugs over time. Bitter taste and high cost signified high efficacy for anti-malarials. Government facilities were preferred for conducting diagnostic investigations and attending to serious illnesses, but often lacked drugs and did not treat people fast. Drug shops were preferred for having a variety of drugs, attending to clients promptly and offering treatment on credit. However, drug shops were considered disadvantageous since they lacked diagnostic capability and had unqualified providers.
Conclusion
Community views about drug efficacy are divergent and some may divert caretakers from obtaining efficacious drugs for febrile illness. Interventions should address these perceptions, equip community medicine distributors with capacity to do diagnostic investigations and provide a constant supply of drugs. Subsidized efficacious drugs could be made available in the private sector.
doi:10.1186/1475-2875-8-131
PMCID: PMC2702349  PMID: 19523220
15.  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
16.  Malaria treatment in the retail sector: Knowledge and practices of drug sellers in rural Tanzania 
BMC Public Health  2008;8:157.
Background
Throughout Africa, the private retail sector has been recognised as an important source of antimalarial treatment, complementing formal health services. However, the quality of advice and treatment at private outlets is a widespread concern, especially with the introduction of artemisinin-based combination therapies (ACTs). As a result, ACTs are often deployed exclusively through public health facilities, potentially leading to poorer access among parts of the population. This research aimed at assessing the performance of the retail sector in rural Tanzania. Such information is urgently required to improve and broaden delivery channels for life-saving drugs.
Methods
During a comprehensive shop census in the districts of Kilombero and Ulanga, Tanzania, we interviewed 489 shopkeepers about their knowledge of malaria and malaria treatment. A complementary mystery shoppers study was conducted in 118 retail outlets in order to assess the vendors' drug selling practices. Both studies included drug stores as well as general shops.
Results
Shopkeepers in drug stores were able to name more malaria symptoms and were more knowledgeable about malaria treatment than their peers in general shops. In drug stores, 52% mentioned the correct child-dosage of sulphadoxine-pyrimethamine (SP) compared to only 3% in general shops. In drug stores, mystery shoppers were more likely to receive an appropriate treatment (OR = 9.6), but at an approximately seven times higher price. Overall, adults were more often sold an antimalarial than children (OR = 11.3). On the other hand, general shopkeepers were often ready to refer especially children to a higher level if they felt unable to manage the case.
Conclusion
The quality of malaria case-management in the retail sector is not satisfactory. Drug stores should be supported and empowered to provide correct malaria-treatment with drugs they are allowed to dispense. At the same time, the role of general shops as first contact points for malaria patients needs to be re-considered. Interventions to improve availability of ACTs in the retail sector are urgently required within the given legal framework.
doi:10.1186/1471-2458-8-157
PMCID: PMC2405791  PMID: 18471299
17.  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
18.  Age Interactions in the Development of Naturally Acquired Immunity to Plasmodium falciparum and Its Clinical Presentation 
PLoS Medicine  2007;4(7):e242.
Background
Naturally acquired malaria immunity has many determinants and, in the absence of immunological markers of protection, studies assessing malaria incidence through clinical endpoints remain an approach to defining immunity acquisition. We investigated the role of age in disease incidence and the effects of chemoprophylaxis on clinical immunity development to Plasmodium falciparum during a randomised controlled trial.
Methods and Findings
A total of 415 Tanzanian infants were randomly assigned to receive weekly malaria prophylaxis with Deltaprim (3.125 mg of pyrimethamine plus 25 mg of dapsone) or placebo between the ages of 2 and 12 mo. Children were followed up until 4 y of age. Uncomplicated febrile malaria, severe malaria, and anaemia morbidity were assessed through hospital-based passive surveillance. Compared with the group of control participants, there was a marked reduction in the incidence of clinical malaria, severe malaria, and anaemia in the group of children who had received chemoprophylaxis during the first year of life. After discontinuing the intervention, there was a significant increase in the incidence of clinical malaria for 2 y. The cumulative rates of clinical malaria, by age 4 y, were slightly higher in the group of children who had previously received chemoprophylaxis: 3.22 episodes versus 3.02 episodes in the group of control participants; rate difference 0.20 (95% confidence interval [CI]: −0.21 to 0.59). By age 4 y, the cumulative rates of severe malaria, however, were slightly lower in chemosuppressed children (0.47 versus 0.59) (rate difference −0.12 [95% CI: −0.27 to 0.03]). The number of episodes of anaemia was also slightly lower in chemosuppressed children by age 4y: 0.93 episodes (95% CI: 0.79 to 0.97) versus 1.12 episodes in the group of control participants (95% CI: 0.97 to 1.28) (rate difference −0.19 [95% CI: −0.40 to 0.01]), respectively.
Conclusions
Reducing exposure to P. falciparum antigens through chemoprophylaxis early in life can delay immunity acquisition. Infants appear to acquire immunity faster than older children, but have a higher risk of developing severe forms of malaria and anaemia. These findings provide insight on the interplay between immunity and exposure-reduction interventions.
John Aponte and colleagues report that reducing exposure to parasite antigens early in life through chemoprophylaxis, while reducing the incidence of severe malaria, can delay the development of immunity.
Editors' Summary
Background.
Malaria is a life-threatening disease caused by Plasmodium falciparum, a parasite that is transmitted from person to person by infected mosquitoes. People living in areas where malaria is common (malaria-endemic regions) gradually acquire immunity to this parasite through repeated exposure to it, but the development of this immunity is complex. As with other infectious diseases, the immune system has to learn how to recognize and attack the parasite so that parasitaemia (the number of parasites in the blood) is kept to a minimum. In addition, because several symptoms of clinical malaria (for example, the characteristic fever) are side effects of the immune system's response to the parasite, it also has to learn not to overreact to this foreign invader. Consequently, in malaria-endemic areas, where individuals first become infected with P. falciparum as infants, many children develop severe malaria and anemia (parasite-induced killing of red blood cells) during their first 5 y of life. Later, as their immunity to P. falciparum develops, they experience less severe disease and reduced parasitaemia.
Why Was This Study Done?
Little is known about how quickly immunity to P. falciparum is acquired or how age affects this process. This study was done to document the long-term effects of malaria prophylaxis given to young Tanzanian infants. More specifically, the researchers examined whether and how prophylaxis affects the rate of acquisition of malaria immunity, and whether a possible delay in immunity would be associated with more severe forms of malaria in children.
What Did the Researchers Do and Find?
Infants in Ifakara, a town in Tanzania, received either antimalarial tablets or placebo (inactive) tablets every week between the ages of 2 and 12 mo. Cases of clinical malaria (parasitaemia and fever), severe malaria (parasitaemia plus dehydration, breathing problems, impaired consciousness, or low blood sugar), and anemia among the children were recorded until they were 4 y old. During their first year, the children receiving antimalarial drugs had fewer episodes of malaria, severe malaria, and anemia than the children receiving the placebo. After the antimalarial drugs were stopped, cases of clinical malaria, severe malaria, and anemia were more frequent among the treated children than among the control children for the next 2 y. By the time they were 4 y old, the treated children had had slightly more episodes of clinical malaria in total than the control children, but slightly fewer episodes of severe malaria and anemia.
What Do These Findings Mean?
These findings show that reducing exposure to P. falciparum in early life with continuous malaria prophylaxis delays the acquisition of immunity to the parasite. They also show that infants acquire this immunity slightly faster than do older children, but that this speedier acquisition of immunity is accompanied by a slightly increased risk of severe malaria and anemia. Because these findings may, in part, reflect a local decrease in malaria transmission that occurred during the study, they need confirming in other settings and with many more children. Nevertheless, they suggest that although age at first exposure to P. falciparum helps to determine both the rate at which immunity is acquired and the severity of disease caused by the parasite, delaying the acquisition of immunity through early prophylaxis is unlikely to have long-term negative health effects. This information will help public-health experts to plan prophylactic interventions designed to control malaria transmission in endemic regions.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040242.
US Centers for Disease Control and Prevention information on malaria and on immune responses to malaria (in English and Spanish)
MedlinePlus encyclopedia page on malaria (in English and Spanish)
Information from the World Health Organization on malaria (in English, Spanish, French, Russian, Arabic, and Chinese)
Short articles from the Wellcome Trust on immunity to malaria and on malaria and the human immune system
doi:10.1371/journal.pmed.0040242
PMCID: PMC1950208  PMID: 17676985
19.  Defining Childhood Severe Falciparum Malaria for Intervention Studies 
PLoS Medicine  2007;4(8):e251.
Background
Clinical trials of interventions designed to prevent severe falciparum malaria in children require a clear endpoint. The internationally accepted definition of severe malaria is sensitive, and appropriate for clinical purposes. However, this definition includes individuals with severe nonmalarial disease and coincident parasitaemia, so may lack specificity in vaccine trials. Although there is no “gold standard” individual test for severe malaria, malaria-attributable fractions (MAFs) can be estimated among groups of children using a logistic model, which we use to test the suitability of various case definitions as trial endpoints.
Methods and Findings
A total of 4,583 blood samples were taken from well children in cross-sectional surveys and from 1,361 children admitted to a Kenyan District hospital with severe disease. Among children under 2 y old with severe disease and over 2,500 parasites per microliter of blood, the MAFs were above 85% in moderate- and low-transmission areas, but only 61% in a high-transmission area. HIV and malnutrition were not associated with reduced MAFs, but gastroenteritis with severe dehydration (defined by reduced skin turgor), lower respiratory tract infection (clinician's final diagnosis), meningitis (on cerebrospinal fluid [CSF] examination), and bacteraemia were associated with reduced MAFs. The overall MAF was 85% (95% confidence interval [CI] 83.8%–86.1%) without excluding these conditions, 89% (95% CI 88.4%–90.2%) after exclusions, and 95% (95% CI 94.0%–95.5%) when a threshold of 2,500 parasites/μl was also applied. Applying a threshold and exclusion criteria reduced sensitivity to 80% (95% CI 77%–83%).
Conclusions
The specificity of a case definition for severe malaria is improved by applying a parasite density threshold and by excluding children with meningitis, lower respiratory tract infection (clinician's diagnosis), bacteraemia, and gastroenteritis with severe dehydration, but not by excluding children with HIV or malnutrition.
The accepted definition of severe malaria is appropriate for clinical purposes, but Philip Bejon and colleagues show its specificity in clinical trials may be improved by a parasite density threshold and by excluding children with certain conditions.
Editors' Summary
Background.
Malaria is responsible for over a million deaths every year, and most of those who die are children in Africa. Until a few years ago, not enough research was being done on malaria, but now many researchers are active in this field. Doctors describe some cases of malaria as being “severe.” Severe malaria in children is very hard to diagnose precisely. Current protocols for diagnosing severe malaria are very sensitive: that is, virtually all children who do have severe malaria will be correctly diagnosed as such. However, the protocols are not very specific: many children who do not have severe malaria, but whose symptoms are instead caused by other diseases, will be defined as suffering from severe malaria. This definition is acceptable for the clinical care of sick children, because it ensures that antimalarial drugs are given to all who might benefit from them, plus some additional children for whom those drugs are not required. However, this definition is not particularly useful for research purposes. When conducting a clinical trial aimed at preventing cases of malaria, it is important to evaluate whether the intervention being tested actually works. Therefore, a more specific method of calculating the number of malaria cases within a population is needed for this type of research.
Why Was This Study Done?
The current definition for diagnosing severe malaria includes a set of signs and symptoms that may be observed at the bedside or as a result of laboratory investigation, along with the detection of malaria parasites in the patient's blood. However, in many malarious areas, a large proportion of the population carries malaria parasites without signs of disease; at the same time, the signs and symptoms of malaria are shared with other diseases. The investigators here wanted to find out whether they could develop an accurate “case definition” of severe malaria that can be used in research.
What Did the Researchers Do and Find?
In this study, two groups of children were studied: first, 1,422 children admitted to the children's wards of the Kilifi District Hospital in Kenya, and second, 4,583 children from the surrounding community. Blood samples were taken in order to find out how common malaria parasites were in the children's blood, and standard clinical and laboratory data were also collected from the children admitted to the hospital. The researchers then compared these data using a computer and tried to find out whether, by excluding certain children who had particular signs, symptoms, or observations, from the diagnosis of severe malaria, they were able to improve the accuracy of their definition. Essentially, for each patient group, the authors calculated “malaria-attributable fractions,” i.e., the proportion of individuals studied whose disease was likely caused by malaria.
The researchers found that in areas with low and moderate transmission of malaria, the proportion of individuals whose disease could be attributed to malaria was high—nearly 85%. In areas with a high transmission rate of malaria, this fraction was much lower, but could be improved by including only children with a high proportion of parasites in their blood. Importantly, the researchers were also able to increase the recognition of children with disease likely caused by malaria by excluding individuals who had also been diagnosed with gastroenteritis, lower respiratory tract infections, meningitis, and bacterial infection in the blood. If all of these individuals were excluded—so only individuals with more than 2,500 parasites per microliter in their blood were regarded as having severe malaria—the “malaria-attributable fraction” rose to 95%.
What Do These Findings Mean?
These findings should not be directly used to change the clinical care of children with the signs and symptoms of severe malaria, but rather can be used within a clinical trial to create a “case definition” of malaria particular to that trial. This ability will help researchers more accurately find out whether the intervention being tested in their trial really does help to prevent cases of malaria or not.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040251.
The World Health Organization Global Malaria Programme details the organization's activities in fighting malaria, and provides a number of helpful resources; a factsheet on children and malaria is also available
The US Centers for Disease Control and Prevention provides many malaria resources
General information about malaria, including illustrations, is available from the“Medline Plus” encyclopedia
doi:10.1371/journal.pmed.0040251
PMCID: PMC1949845  PMID: 17713980
20.  Unfulfilled expectations to services offered at primary health care facilities: Experiences of caretakers of underfive children in rural Tanzania 
Background
There is growing evidence that patients frequently bypass primary health care (PHC) facilities in favour of higher level hospitals regardless of substantial additional time and costs. Among the reasons given for bypassing are poor services (including lack of drugs and diagnostic facilities) and lack of trust in health workers. The World Health Report 2008 “PHC now more than ever” pointed to the importance of organizing health services around people’s needs and expectations as one of the four main issues of PHC reforms. There is limited documentation of user’s expectations to services offered at PHC facilities. The current study is a community extension of a hospital-based survey that showed a high bypassing frequency of PHC facilities among caretakers seeking care for their underfive children at two district hospitals. We aimed to explore caretakers’ perceptions and expectations to services offered at PHC facilities in their area with reference to their experiences seeking care at such facilities.
Methods
We conducted four community-based focus group discussions (FGD’s) with 47 caretakers of underfive children in Muheza district of Tanga region, Tanzania in October 2009.
Results
Lack of clinical examinations and laboratory tests, combined with shortage of drugs and health workers, were common experiences. Across all the focus group discussions, unpleasant health workers’ behaviors, lack of urgency and unnecessary delays were major complaints. In some places, unauthorized fees reduced access to services.
Conclusion
The study revealed significant disappointments among caretakers with regard to the quality of services offered at PHC facilities in their areas, with implications for their utilization and proper functioning of the referral system. Practices regarding partial drugs administrations, skipping of injections, unofficial payments and consultations by unskilled health care providers need urgent action. There is also a need for proper accountability mechanisms to govern appropriate allocation and monitoring of health care resources and services in Tanzania.
doi:10.1186/1472-6963-12-158
PMCID: PMC3420314  PMID: 22697458
21.  Population Pharmacokinetics of Artesunate and Dihydroartemisinin following Intra-Rectal Dosing of Artesunate in Malaria Patients 
PLoS Medicine  2006;3(11):e444.
Background
Intra-rectal artesunate has been developed as a potentially life-saving treatment of severe malaria in rural village settings where administration of parenteral antimalarial drugs is not possible. We studied the population pharmacokinetics of intra-rectal artesunate and the relationship with parasitological responses in patients with moderately severe falciparum malaria.
Methods and Findings
Adults and children in Africa and Southeast Asia with moderately severe malaria were recruited in two Phase II studies (12 adults from Southeast Asia and 11 children from Africa) with intensive sampling protocols, and three Phase III studies (44 children from Southeast Asia, and 86 children and 26 adults from Africa) with sparse sampling. All patients received 10 mg/kg artesunate as a single intra-rectal dose of suppositories. Venous blood samples were taken during a period of 24 h following dosing. Plasma artesunate and dihydroartemisinin (DHA, the main biologically active metabolite) concentrations were measured by high-performance liquid chromatography with electrochemical detection. The pharmacokinetic properties of DHA were determined using nonlinear mixed-effects modelling. Artesunate is rapidly hydrolysed in vivo to DHA, and this contributes the majority of antimalarial activity. For DHA, a one-compartment model assuming complete conversion from artesunate and first-order appearance and elimination kinetics gave the best fit to the data. The mean population estimate of apparent clearance (CL/F) was 2.64 (l/kg/h) with 66% inter-individual variability. The apparent volume of distribution (V/F) was 2.75 (l/kg) with 96% inter-individual variability. The estimated DHA population mean elimination half-life was 43 min. Gender was associated with increased mean CL/F by 1.14 (95% CI: 0.36–1.92) (l/kg/h) for a male compared with a female, and weight was positively associated with V/F. Larger V/Fs were observed for the patients requiring early rescue treatment compared with the remainder, independent of any confounders. No associations between the parasitological responses and the posterior individual estimates of V/F, CL/F, and AUC0–6h were observed.
Conclusions
The pharmacokinetic properties of DHA were affected only by gender and body weight. Patients with the lowest area under the DHA concentration curve did not have slower parasite clearance, suggesting that rectal artesunate is well absorbed in most patients with moderately severe malaria. However, a number of modelling assumptions were required due to the large intra- and inter-individual variability of the DHA concentrations.
A study of the population pharmacokinetics of intra-rectal artesunate in patients with moderately severe falciparum malaria found the pharmacokinetic properties of dihydroartemisinin were affected only by gender and body weight.
Editors' Summary
Background.
More than 40% of the world's population is at risk of malaria, a tropical parasitic disease that is transmitted between people by infected mosquitoes. Malaria parasites cause a 'flu-like illness that includes chills, fevers, headaches, and sometimes nausea and vomiting. If untreated, people with malaria can rapidly become anemic—the parasite destroys their red blood cells—or can develop complications that damage the brain and other organs. Severe malaria can be fatal and must be treated quickly. It has become a matter of great concern that the parasite has developed resistance to most of the drugs used to treat or prevent malaria. In the past few years, artemisinin derivatives have been shown to be an effective new form of treatment. Artemisinin derivatives are effective, rapid-acting antimalarial drugs—wormwood, the plant source of artemisinin, is an ancient Chinese cure for malaria. Artesunate, a water-soluble derivative of artemisinin, can be given as tablets or as injections. However, people with severe malaria often cannot take oral medicines, and in rural settings in the developing world, artesunate injections are usually impracticable. Consequently, rectal artesunate suppositories have been developed to provide first-line treatment of severe malaria in these settings. This simple dosing method can “buy” patients valuable time during which they can be moved to a hospital for further treatment.
Why Was This Study Done?
When treating severe malaria, it is important that every patient absorbs the antimalarial drug rapidly and efficiently into their blood. If even a small proportion of patients malabsorb the drug, many people could die. How the body processes a drug is known as pharmacokinetics, and although some pharmacokinetic studies have investigated how the body processes artesunate given in rectal suppositories, relatively little is know about the population pharmacokinetics of artesunate given this way. That is, the patient characteristics that affect the processing of intra-rectal artesunate are not known, and it is unclear whether a small proportion of the population might fail to absorb the drug given via this route. In this study, the researchers have developed and tested a population pharmacokinetic model for artesunate given rectally to children and adults with moderately severe malaria.
What Did the Researchers Do and Find?
The researchers took serial blood samples from nearly 200 patients with moderately severe malaria in Africa and Southeast Asia for the first 24 hours after they received a rectal artesunate suppository. They measured the levels of artesunate and dihydroartemisinin (DHA; the body rapidly converts artesunate to DHA, which kills the malaria parasites) in these samples and used these data to build a pharmacokinetic model for how the body processes. Averaged out across the patients, they calculated, for example, that half of the drug present absorbed was eliminated within 43 minutes. To find out whether any patient characteristics affected the pharmacokinetics of intra-rectal artesunate, the researchers used their model to estimate the clearance of DHA from the body and the ability of DHA to spread through the body (so-called apparent volume of distribution) for the study patients. This analysis showed that only gender and weight affected DHA pharmacokinetics. Finally, the researchers showed that how well the parasite was cleared from the patients was not related to these pharmacokinetic parameters, although the need for earlier rescue treatment was associated with a larger volume of distribution for DHA. Importantly, the parasitological response was not affected by the estimated cumulative amount of DHA absorbed into the blood during the first six hours after treatment.
What Do These Findings Mean?
The data presented in this study indicate that individual patients processed artesunate very differently in terms of how they absorbed the drug and how it spread around the body. Even so, the maximal effects of artesunate on the malaria parasite were achieved rapidly in nearly all the patients. This and other pharmacokinetic findings must be interpreted with caution, warn the researchers, because their model included many assumptions to allow, for example, for the variability of DHA concentrations both within individual patients and between patients. Nevertheless, the findings provide important clues about which patient characteristics might cause early treatment failure, and indicate that artesunate is sufficiently well absorbed via the rectal route in most patients to make artesunate suppositories a promising first-line treatment for moderately severe malaria.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030444.
• World Health Organization links to general information on malaria plus specific information on rectal artesunate
• MedlinePlus encyclopedia entry on malaria
• US Centers for Disease Control and Prevention information on malaria for patients and professionals
• Wikipedia pages on malaria and artemisinin (note that Wikipedia is a free online encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0030444
PMCID: PMC1664603  PMID: 17132053
22.  Who Gets Prompt Access to Artemisinin-Based Combination Therapy? A Prospective Community-Based Study in Children from Rural Kilosa, Tanzania 
PLoS ONE  2010;5(8):e12104.
Background
Effective and timely case management remains one of the fundamental pillars for control of malaria. Tanzania introduced artemisinin-combination therapy [ACT] for uncomplicated malaria; however, the policy change is challenged by limited availability of ACTs due to high cost. This study aimed to determine factors influencing prompt access to ACTs among febrile children in rural Kilosa, Tanzania.
Methods and Findings
In a community-based study, 1,235 randomly selected children under five were followed up weekly for six months, in 2008. Using a structured questionnaire, children's caretakers were asked about the child's febrile history in the last seven days, and treatment actions including timing, medicines used and source of care. Caretakers' knowledge about malaria and socioeconomic and demographic data were also obtained. About half of followed-up children had at least one episode of fever. Less than half (44.8%) of febrile children were taken to government facilities. Almost one-third (37.6%; 95% CI 33.1–42.1) of febrile children had prompt access to ACT. Care-seeking from a government facility was the overriding factor, increasing the likelihood of prompt access to an ACT 18 times (OR 17.7; 95% CI 10.55–29.54; adjusted OR 16.9; 95% CI 10.06–28.28). Caretakers from the better-off household (3rd–5th quintiles) were more likely to seek care from government facilities (OR 3.66; 95% CI 2.56–5.24; adjusted OR 1.80; 95% CI 1.18–2.76). The majority of antimalarials accessed by the poor were ineffective [86.0%; 295/343], however, they paid more for them (median Tsh 500) compared to the better-offs (median Tsh 0).
Conclusions
Prompt access to ACT among febrile children was unacceptably low, due mainly to limited availability of subsidised ACT at the location where most caretakers sought care. There is urgent need to accelerate implementation of strategies that will ensure availability of ACT at an affordable price in remote rural areas, where the burden of malaria is highest.
doi:10.1371/journal.pone.0012104
PMCID: PMC2938374  PMID: 20856897
23.  Two Strategies for the Delivery of IPTc in an Area of Seasonal Malaria Transmission in The Gambia: A Randomised Controlled Trial 
PLoS Medicine  2011;8(2):e1000409.
Bojang and colleagues report a randomized trial showing that delivery of intermittent preventive treatment for malaria in children by village health workers is more effective than delivery by reproductive and child health trekking clinics.
Background
The Expanded Programme on Immunisation (EPI) provides an effective way of delivering intermittent preventive treatment for malaria (IPT) to infants. However, it is uncertain how IPT can be delivered most effectively to older children. Therefore, we have compared two approaches to the delivery of IPT to Gambian children: distribution by village health workers (VHWs) or through reproductive and child health (RCH) trekking teams. In rural areas, RCH trekking teams provide most of the health care to children under the age of 5 years in the Infant Welfare Clinic, and provide antenatal care for pregnant women.
Methods and Findings
During the 2006 malaria transmission season, the catchment populations of 26 RCH trekking clinics in The Gambia, each with 400–500 children 6 years of age and under, were randomly allocated to receive IPT from an RCH trekking team or from a VHW. Treatment with a single dose of sulfadoxine pyrimethamine (SP) plus three doses of amodiaquine (AQ) were given at monthly intervals during the malaria transmission season. Morbidity from malaria was monitored passively throughout the malaria transmission season in all children, and a random sample of study children from each cluster was examined at the end of the malaria transmission season. The primary study endpoint was the incidence of malaria. Secondary endpoints included coverage of IPTc, mean haemoglobin (Hb) concentration, and the prevalence of asexual malaria parasitaemia at the end of malaria transmission period. Financial and economic costs associated with the two delivery strategies were collected and incremental cost and effects were compared. A nested case-control study was used to estimate efficacy of IPT treatment courses.
Treatment with SP plus AQ was safe and well tolerated. There were 49 cases of malaria with parasitaemia above 5,000/µl in the areas where IPT was delivered through RCH clinics and 21 cases in the areas where IPT was delivered by VHWs, (incidence rates 2.8 and 1.2 per 1,000 child months, respectively, rate difference 1.6 [95% confidence interval (CI) −0.24 to 3.5]). Delivery through VHWs achieved a substantially higher coverage level of three courses of IPT than delivery by RCH trekking teams (74% versus 48%, a difference of 27% [95% CI 16%–38%]). For both methods of delivery, coverage was unrelated to indices of wealth, with similar coverage being achieved in the poorest and wealthiest groups. The prevalence of anaemia was low in both arms of the trial at the end of the transmission season. Efficacy of IPTc against malaria during the month after each treatment course was 87% (95% CI 54%–96%). Delivery of IPTc by VHWs was less costly in both economic and financial terms than delivery through RCH trekking teams, resulting in incremental savings of US$872 and US$1,244 respectively. The annual economic cost of delivering at least the first dose of each course of IPTc was US$3.47 and US$1.63 per child using trekking team and VHWs respectively.
Conclusions
In this setting in The Gambia, delivery of IPTc to children 6 years of age and under by VHWs is more effective and less costly than delivery through RCH trekking clinics.
Trial Registration
ClinicalTrials.gov NCT00376155
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In sub-Saharan Africa, malaria kills 800,000 people, the majority of whom are children, every year. Intermittent preventive treatment (IPT) of malaria is an effective malaria control strategy. 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 from the infection. IPT was initially recommended for pregnant women (IPTp) who are given at least two doses of suphadoxine pyrimethamine (SP) during antenatal visits after the first trimester of pregnancy. IPT is also effective in infants (IPTi) and recently IPTi has been rolled out with the administration of three doses of an antimalarial drug during the expanded program of immunization visits. Clinical studies have also shown that IPT is effective at reducing malaria incidence in children (IPTc) by administering SP alone, or in combination with artesunate (AS) or amodiaquine (AQ,) over three intervals during the peak malarial season.
Why Was This Study Done?
The inclusion of IPTp in antenatal visits and IPTi in the expanded program of immunization has effectively scaled up these interventions to the population level. So far, IPTc has only been administered to children within the confines of clinical trials—there is currently no established system for delivery of IPTc. For the scale-up of IPTc to be successful, there needs to be an appropriate point of entry and the roll out of a delivery system that can be generalized to most settings in sub-Saharan Africa. In order to address this issue, the researchers conducted a randomized trial to compare the effectiveness of IPTc delivery to children up to 6 y of age by village health workers (VHW) or by reproductive and child health (RCH) trekking teams (run by the Ministry of Health) in rural areas of The Gambia.
What Did the Researchers Do and Find?
During the 2006 malaria transmission season, the researchers randomly allocated the catchment populations of 26 RCH clinics, each with 400–500 children 6 y of age and under, to receive IPT from an RCH trekking team or from a VHW. Before the trial started, the researchers, accompanied by the district health team, visited all villages in the study area to explain the purpose and methods of the study and to obtain consent from the elders of all participating villages. Eligible children were treated with a single dose of SP plus three doses of AQ given at monthly intervals during the malaria transmission season. The researchers passively monitored malaria incidence throughout the transmission season and at the end of the malaria season, examined a random sample of 40 children from each cluster to measure their temperature, height, and weight and to take a finger-prick blood sample to measure blood hemoglobin and parasite levels (by microscopy of thick blood smears). The researchers recorded the financial costs associated with each delivery strategy (mostly on the basis of staff pay and the financial incentives given to VHWs).
There were 49 cases of clinical malaria in the areas where IPT was delivered through RCH clinics and 21 cases in the areas where IPT was delivered by VHWs. In addition, VHW delivery of IPTc achieved a higher coverage level of three courses of IPT than delivery by RCH trekking teams (74% versus 48%). The prevalence of anemia was low in both arms at the end of the transmission season. Delivery of IPTc by VHWs was cheaper than delivery through RCH trekking teams, resulting in incremental savings of US$872 and US$1,244, respectively. The annual economic cost of delivering at least the first dose of each course of IPTc using the RCH trekking team was US$3.47 per child and with VHWs was US$1.63 per child.
What Do These Findings Mean?
The results of this study show that in rural areas of The Gambia, delivery of IPTc by VHWs is more effective and less costly than delivery by RCH trekking teams through RCH clinics. Delivering IPTc through community-based VHWs versus monthly visits by the RCH team has several advantages: VHWs are resident in the community, making drug administration easy and flexible (as children were able to receive their medication on any day of the month), and they can remind mothers/guardians to attend for treatment. Therefore, operationally, VHW delivery is less restrictive and more convenient for parents and guardians.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000409.
This topic is further discussed in two PLoS Medicine research articles by Dicko et al. and Konat et al., and a PLoS Medicine Perspective by Beeson
WHO provides information about The Gambia
WHO also provides information about the health workforce, including the role of village health workers
Roll Back Malaria has information about malaria in children, including intervention strategies
Unicef also provides comprehensive information about malaria in children
doi:10.1371/journal.pmed.1000409
PMCID: PMC3032548  PMID: 21304921
24.  Understanding caretakers' dilemma in deciding whether or not to adhere with referral advice after pre-referral treatment with rectal artesunate 
Malaria Journal  2010;9:123.
Background
Malaria kills. A single rectal dose of artesunate before referral can reduce mortality and prevent permanent disability. However, the success of this intervention depends on caretakers' adherence to referral advice for follow-up care. This paper explores the dilemma facing caretakers when they are in the process of deciding whether or not to transit their child to a health facility after pre-referral treatment with rectal artesunate.
Methods
Four focus group discussions were held in each of three purposively selected villages in Mtwara rural district of Tanzania. Data were analysed manually using latent qualitative content analysis.
Results
The theme "Caretakers dilemma in deciding whether or not to adhere with referral advice after pre-referral treatment with rectal artesunate" depicts the challenge they face. Caretakers' understanding of the rationale for going to hospital after treatment - when and why they should adhere - influenced adherence. Caretakers, whose children did not improve, usually adhered to referral advice. If a child had noticeably improved with pre-referral treatment however, caretakers weighed whether they should proceed to the facility, balancing the child's improved condition against other competing priorities, difficulties in reaching the health facilities, and the perceived quality of care at the health facility. Some misinterpretation were found regarding the urgency and rationale for adherence among some caretakers of children who improved which were attributed to be possibly due to their prior understanding.
Conclusion
Some caretakers did not adhere when their children improved and some who adhered did so without understanding why they should proceed to the facility. Successful implementation of the rectal artesunate strategy depends upon effective communication regarding referral to clinic.
doi:10.1186/1475-2875-9-123
PMCID: PMC2877062  PMID: 20459853
25.  Impact Monitoring of the National Scale Up of Zinc Treatment for Childhood Diarrhea in Bangladesh: Repeat Ecologic Surveys 
PLoS Medicine  2009;6(11):e1000175.
Charles Larson and colleagues find that 23 months into a national campaign to scale up zinc treatment for diarrhea in children under age 5 years, only 10% of children with diarrhea in rural areas and 20%–25% in urban/municipal areas were getting the treatment.
Background
Zinc treatment of childhood diarrhea has the potential to save 400,000 under-five lives per year in lesser developed countries. In 2004 the World Health Organization (WHO)/UNICEF revised their clinical management of childhood diarrhea guidelines to include zinc. The aim of this study was to monitor the impact of the first national campaign to scale up zinc treatment of childhood diarrhea in Bangladesh.
Methods/Findings
Between September 2006 to October 2008 seven repeated ecologic surveys were carried out in four representative population strata: mega-city urban slum and urban nonslum, municipal, and rural. Households of approximately 3,200 children with an active or recent case of diarrhea were enrolled in each survey round. Caretaker awareness of zinc as a treatment for childhood diarrhea by 10 mo following the mass media launch was attained in 90%, 74%, 66%, and 50% of urban nonslum, municipal, urban slum, and rural populations, respectively. By 23 mo into the campaign, approximately 25% of urban nonslum, 20% of municipal and urban slum, and 10% of rural under-five children were receiving zinc for the treatment of diarrhea. The scale-up campaign had no adverse effect on the use of oral rehydration salt (ORS).
Conclusions
Long-term monitoring of scale-up programs identifies important gaps in coverage and provides the information necessary to document that intended outcomes are being attained and unintended consequences avoided. The scale-up of zinc treatment of childhood diarrhea rapidly attained widespread awareness, but actual use has lagged behind. Disparities in zinc coverage favoring higher income, urban households were identified, but these were gradually diminished over the two years of follow-up monitoring. The scale up campaign has not had any adverse effect on the use of ORS.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Diarrheal disease is a significant global health problem with approximately 4 billion cases and 2.5 million deaths annually. The overwhelming majority of cases are in developing countries where there is a particularly high death rate among children under five years of age. Diarrhea is caused by bacterial, parasitic, or viral pathogens, which often spread in contaminated water. Poor hygiene and sanitation, malnutrition, and lack of medical care all contribute to the burden of this disease. Replacing lost fluids and salts is a cheap and effective method to rehydrate people following dehydration caused by diarrhea. Clinical trials show that zinc, as part of a treatment for childhood diarrhea, not only helps to reduce the severity and duration of diarrhea but also reduces the likelihood of a repeat episode in the future. Zinc is now included in the guidelines by the World Health Organization (WHO)/UNICEF for treatment of childhood diarrhea.
Why Was This Study Done?
Zinc treatment together with traditional oral rehydration salts therapy following episodes of diarrhea could potentially benefit millions of children in areas where diarrheal disease is prevalent. The “Scaling Up of Zinc for Young Children” (SUZY) project was established in 2003 to provide zinc treatment for diarrhea in all children under five years of age in Bangladesh. The project was supported by a partnership of public, private, nongovernmental organization, and multinational sector agencies during its scale up to a national campaign across Bangladesh. The partners helped to develop the scale-up campaign, produce and distribute zinc tablets, train health professionals to provide zinc treatment, and create media campaigns (such as advertisements in TV, radio, and newspapers) to raise awareness and promote the use of zinc for diarrhea. The researchers wanted to monitor how effective and successful the national campaign was at promoting zinc treatment for childhood diarrhea. Also, they wanted to highlight any potential problems during the implementation of health care initiatives in areas with deprived health systems.
What Did the Researchers Do and Find?
The researchers set up survey sites to monitor results from the first two years of the SUZY campaign. Four areas, each representing different segments of the population across Bangladesh were surveyed; urban slums, urban nonslums, municipal (small city), and rural. There are approximately 1.5 million children under the age of five across these sites. Households in each survey site were selected at random, and seven surveys were conducted at each site between September 2006 and October 2008—about 3,200 children with diarrhea for each survey. Over 90% of parents used private sector providers of drug treatment so the campaign focused on distribution of zinc tablets in the private sector. They were also available free of charge in the public health sector. TV and radio campaigns for zinc treatment rapidly raised awareness across Bangladesh. Awareness was less than 10% in all communities prelaunch and peaked 10 months later at 90%, 74%, 66%, and 50% in urban nonslum, municipal, urban slum, and rural sites, respectively. However, after 23 months only 25% of urban nonslum, 20% of municipal and urban slum, and 10% of rural children under five years of age were actually using zinc for childhood diarrhea. Use of zinc was shown to be safe, with few side-effects, and did not affect the use of traditional treatments for diarrhea. Researchers also found that many children were not given the correct ten-day course of treatment; 50% of parents were sold seven or fewer zinc tablets.
What Do These Findings Mean?
These findings show that the first national campaign promoting zinc treatment for childhood diarrhea in Bangladesh has had some success. Addition of zinc tablets for diarrhea treatment did not interfere with existing therapies. Mass media campaigns, using TV and radio, were useful for promoting health care initiatives nationwide alongside the education of health care providers and care-givers. The study also identified areas where more work is needed. Surveys in more remote, hard to reach sites in Bangladesh would provide better representation of the country as a whole. High awareness of zinc did not translate into high use. Repeated surveying in the same subdistricts may have overestimated actual awareness levels. Furthermore, mass media messages must link with messages from health care providers to help to reinforce and promote understanding of the use of zinc. A change in focus of media messages from awareness to promoting household decision-making may aid the adoption of zinc treatment for childhood diarrhea and improve adherence.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000175
The International Centre for Diarrhoeal Disease Research, Bangladesh Web site has information about the study
The World Health Organisation provides information on diarrhea
The study was sponsored by the Bill & Melinda Gates Foundation
doi:10.1371/journal.pmed.1000175
PMCID: PMC2765636  PMID: 19888335

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