Introduction

Equitable access to health care is a key health systems goal, and is a particular concern in low-income countries. In Kenya, public facilities are an important resource for the poor, but little is known on the equity of service provision. This paper assesses whether poorer areas have poorer health services by investigating associations between public facility characteristics and the poverty level of the area in which the facility is located.

Methods

Data on facility characteristics were collected from a nationally representative sample of public health centers and dispensaries across all 8 provinces in Kenya. A two-stage cluster randomized sampling process was used to select facilities. Univariate associations between facility characteristics and socioeconomic status (SES) of the area in which the facility was located were assessed using chi-squared tests, equity ratios and concentration indices. Indirectly standardized concentration indices were used to assess the influence of SES on facility inputs and service availability while controlling for facility type, province, and remoteness.

Results

For most indicators, we found no indication of variation by SES. The clear exceptions were electricity and laboratory services which showed evidence of pro-rich inequalities, with equity ratios of 3.16 and 3.43, concentration indices of 0.09 (p<0.01) and 0.05 (p=0.01), and indirectly standardized concentration ratios of 0.07 (p<0.01) and 0.05 (p=0.01). There were also some indications of pro-rich inequalities for availability of drugs and qualified staff. The lack of evidence of inequality for other indicators does not imply that availability of inputs and services was invariably high; for example, while availability was close to 90% for water supply and family planning services, under half of facilities offered delivery services or outreach.

Conclusions

The paper shows how local area poverty data can be combined with national health facility surveys, providing a tool for policy makers to assess the equity of input and service availability. There was little evidence of inequalities for most inputs and services, with the clear exceptions of electricity and laboratory services. However, efforts are required to improve the availability of key inputs and services across public facilities in all areas, regardless of SES.

Summary

Background

Many people with epilepsy in low-income countries do not receive appropriate biomedical treatment. This epilepsy treatment gap might be caused by patients not seeking biomedical treatment or not adhering to prescribed antiepileptic drugs (AEDs). We measured the prevalence of and investigated risk factors for the epilepsy treatment gap in rural Kenya.

Methods

All people with active convulsive epilepsy identified during a cross-sectional survey of 232 176 people in Kilifi were approached. The epilepsy treatment gap was defined as the percentage of people with active epilepsy who had not accessed biomedical services or who were not on treatment or were on inadequate treatment. Information about risk factors was obtained through a questionnaire-based interview of sociodemographic characteristics, socioeconomic status, access to health facilities, seizures, stigma, and beliefs and attitudes about epilepsy. The factors associated with people not seeking biomedical treatment and not adhering to AEDs were investigated separately, adjusted for age.

Findings

673 people with epilepsy were interviewed, of whom 499 (74%) reported seeking treatment from a health facility. Blood samples were taken from 502 (75%) people, of whom 132 (26%) reported taking AEDs, but 189 (38%) had AEDs detectable in the blood. The sensitivity and specificity of self-reported adherence compared with AEDs detected in blood were 38·1% (95% CI 31·1–45·4) and 80·8% (76·0–85·0). The epilepsy treatment gap was 62·4% (58·1–66·6). In multivariable analysis, failure to seek biomedical treatment was associated with a patient holding traditional animistic religious beliefs (adjusted odds ratio 1·85, 95% CI 1·11–2·71), reporting negative attitudes about biomedical treatment (0·86, 0·78–0·95), living more than 30 km from health facilities (3·89, 1·77–8·51), paying for AEDs (2·99, 1·82–4·92), having learning difficulties (2·30, 1·29–4·11), having had epilepsy for longer than 10 years (4·60, 2·07–10·23), and having focal seizures (2·28, 1·50–3·47). Reduced adherence was associated with negative attitudes about epilepsy (1·10, 1·03–1·18) and taking of AEDs for longer than 5 years (3·78, 1·79–7·98).

Interpretation

The sensitivity and specificity of self-reported adherence is poor, but on the basis of AED detection in blood almost two-thirds of patients with epilepsy were not on treatment. Education about epilepsy and making AEDs freely available in health facilities near people with epilepsy should be investigated as potential ways to reduce the epilepsy treatment gap.

Funding

Wellcome Trust.

Background

The emergence of artemisinin-resistant P. falciparum malaria in South-East Asia highlights the need for continued global surveillance of the efficacy of artemisinin-based combination therapies.

Methods

On the Kenyan coast we studied the treatment responses in 474 children 6–59 months old with uncomplicated P. falciparum malaria in a randomized controlled trial of dihydroartemisinin-piperaquine vs. artemether-lumefantrine from 2005 to 2008. (ISRCTN88705995)

Results

The proportion of patients with residual parasitemia on day 1 rose from 55% in 2005–2006 to 87% in 2007–2008 (odds ratio, 5.4, 95%CI, 2.7–11.1; P<0.001) and from 81% to 95% (OR, 4.1, 95%CI, 1.7–9.9; P = 0.002) in the DHA-PPQ and AM-LM groups, respectively. In parallel, Kaplan-Meier estimated risks of apparent recrudescent infection by day 84 increased from 7% to 14% (P = 0.1) and from 6% to 15% (P = 0.05) with DHA-PPQ and AM-LM, respectively. Coinciding with decreasing transmission in the study area, clinical tolerance to parasitemia (defined as absence of fever) declined between 2005–2006 and 2007–2008 (OR body temperature >37.5°C, 2.8, 1.9–4.1; P<0.001). Neither in vitro sensitivity of parasites to DHA nor levels of antibodies against parasite extract accounted for parasite clearance rates or changes thereof.

Conclusions

The significant, albeit small, decline through time of parasitological response rates to treatment with ACTs may be due to the emergence of parasites with reduced drug sensitivity, to the coincident reduction in population-level clinical immunity, or both. Maintaining the efficacy of artemisinin-based therapy in Africa would benefit from a better understanding of the mechanisms underlying reduced parasite clearance rates.

Trial Registration

Controlled-Trials.com ISRCTN88705995

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)

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

Background

Hypoglycaemia is an independent risk factor for death in severe malaria and a recognized adverse treatment effect of parenteral quinine. In 2006 our hospital changed quinine treatment policy from 15 mg/kg loading (plus 10 mg/kg 12-hourly) to 20 mg/kg loading (plus 10 mg/kg 8-hourly) to comply with new WHO guidelines. This presented us with the opportunity to examine whether there was any dose relationship of quinine and hypoglycaemia occurrence.

Methods

Retrospective case notes review of all children admitted to hospital with severe falciparum malaria between April 2002 - July 2009, before and after the introduction of the new WHO quinine regimen. Four-hourly bedside glucose levels were measured until intravenous quinine was discontinued. Clinical events immediately preceding or concurrent with each episode of hypoglycaemia (glucose < = 3.0 mmol/l) were recorded.

Results

954 children received the old quinine regime and 283 received the new regime. We found no evidence of an increased prevalence of hypoglycaemia (< = 3.0 mmol/L) on the new regime compared to former (15% vs. 15%); similar findings were noted for profound hypoglycaemia (< 2.2 mmols/L) 8% v 5%, P = 0.07. Episodes were co-incident with disease severity markers: coma (57%), circulatory failure (38%) and respiratory distress (21%) but less commonly with seizures (10%). Disruption of maintenance fluids and/or blood transfusion concurred with 42% of the hypoglycaemia episodes. Post admission hypoglycaemia increased odds of fatal outcome (24%) compared to euglycaemic counterparts (8%), odds ratio = 3.45 (95% confidence interval = 2.30-5.16) P < 0.01.

Conclusion

There was no evidence to indicate a dose relationship between quinine and occurrence of hypoglycaemia. Hypoglycaemia concurred with severity features, disruption of glucose infusion and transfusion. Careful glucose monitoring should be targeted to these complications where resources are limited.

Background

HIV infection, malnutrition and invasive bacterial infections (IBI) are reported among children with severe malaria. However, it is unclear whether their co-occurrence with falciparum parasitization and severe disease is by chance, or by association among children in malaria endemic areas.

Methods

We examined 3,068 consecutive paediatric admissions to a Kenyan district hospital with clinical features of severe malaria, and 592 community controls. We performed multivariable regression analysis with each case weighted for their probability of being due to falciparum malaria using estimates of the fraction of severe disease attributable to malaria at different parasite densities derived from cross sectional parasitological surveys from well children in the same community.

Results

HIV infection was present in 133/1071 (12%, 95%CI 11 to 15%) consecutive parasitemic admissions. Parasite densities were higher in HIV infected children. The odds of admission associated with HIV infection for admission with true severe falciparum malaria were 9.6 (95%CI 4.9 to 19), however this effect was restricted to children age ≥1 year. Malnutrition was present in 507/2,048 (25%, 95%CI 23 to 27%) consecutive parasitemic admissions. The odds associated with malnutrition for admission with true severe falciparum malaria were 4.0 (95%CI 2.9 to 5.5). IBI was detected in 127/2,048 (6.2%, 95%CI 5.2 to 7.3%) of consecutive parasitemic admissions. All three comorbidities were associated with increased case fatality.

Conclusions

HIV, malnutrition and IBI are biologically associated with severe disease due to falciparum malaria rather than being simply alternative diagnoses in co-incidentally parasitized children in an endemic area.

Whether the number of concurrent clones in asymptomatic Plasmodium falciparum infections reflects the degree of host protection was investigated in children living in areas with different levels of transmission on the coast of Kenya. The number of concurrent clones was determined on the basis of polymorphism in msp2, which encodes the vaccine candidate antigen merozoite surface protein 2. In a low-transmission area, most children had monoclonal infections, and diversity did not predict a risk of clinical malaria. In an area of moderate transmission, asymptomatic infections with 2 clones were, compared with 1 clone, associated with an increased risk of subsequent malaria. In a comparative assessment in a high-transmission area in Tanzania, multiclonal infections conferred a reduced risk. The different nonlinear associations between the number of clones and malaria morbidity suggest that levels of tolerance to multiclonal infections are transmission dependent as a result of cumulative exposure to antigenically diverse P. falciparum infections.

Background

Private medicine retailers (PMRs) are key partners in the home management of fevers in many settings. Current evidence on effectiveness for PMR interventions at scale is limited. This study presents evaluation findings of two different programs implemented at moderate scale targeting PMRs for malaria control in the Kisii and Kwale districts of Kenya. Key components of this evaluation were measurement of program performance, including coverage, PMR knowledge, practices, and utilization based on spatial analysis.

Methodology/Principal Findings

The study utilized mixed quantitative methods including retail audits and surrogate client surveys based on post-intervention cross-sectional surveys in intervention and control areas and mapping of intervention outlets. There was a large and significant impact on PMR knowledge and practices of the program in Kisii, with 60.5% of trained PMRs selling amodiaquine medicines in adequate doses compared to 2.8% of untrained ones (OR; 53.5: 95% CI 6.7, 428.3), a program coverage of 69.7% targeted outlets, and a potential utilization of about 30,000 children under five. The evaluation in Kwale also indicates a significant impact with 18.8% and 2.3% intervention and control PMRs selling amodiaquine with correct advice, respectively (OR; 9.4: 95% CI 1.1, 83.7), a program coverage of 25.3% targeted outlets, and a potential utilization of about 48,000 children under five. A provisional benchmark of 7.5 km was a reasonable threshold distance for households to access PMR services.

Conclusions/Significance

This evaluation show that PMR interventions operationalized in the district level settings are likely to impact PMR knowledge and practices and lead to increased coverage of appropriate treatment to target populations. There is value of evaluating different dimensions of public health programs, including quality, spatial access, and implementation practice. This approach strengthens the potential contribution of pragmatic study designs to evaluating public health programs in the real world.

Background

Seizures are common in children admitted with severe falciparum malaria and are associated with neuro-cognitive impairments. Prolonged febrile seizures are associated with hippocampal damage and impaired memory. It was hypothesized that severe malaria causes impaired everyday memory which may be associated with hippocampal damage.

Methods

An everyday memory battery was administered on 152 children with cerebral malaria (CM) (mean age, 7 y 4 months [SD 13 months]; 77 males) 156 children (mean age, 7 y 4 months [SD, 14 months]; 72 males) with malaria plus complex seizures (MS) and 179 children (mean age, 7 y 6 months [SD, 13 months]; 93 males) unexposed to either condition.

Results

CM was associated with poorer everyday memory [95% CI, -2.46 to -0.36, p = 0.004] but not MS [95% CI, -0.91 to 1.16, p = 1.00] compared to unexposed children. Children with exposure to CM performed more poorly in recall [95% CI, -0.79 to -0.04, p = 0.024] and recognition subtests [95% CI, -0.90 to -0.17, p = 0.001] but not in prospective memory tests compared to controls. The health factors that predicted impaired everyday memory outcome in children with exposure to CM was profound coma [95% CI, 0.02 to 0.88, p = 0.037] and multiple episodes of hypoglycaemia [95% CI, 0.05 to 0.78, p = 0.020], but not seizures.

Discussion

The findings show that exposure to CM was associated with a specific impairment of everyday memory. Seizures commonly observed in severe malaria may not have a causal relationship with poor outcome, but rather be associated with profound coma and repeated metabolic insults (multi-hypoglycaemia) that are strongly associated with impaired everyday memory.

Summary

Small hospitals sit at the apex of the pyramid of primary care in many low-income country health systems. If the Millennium Development Goal for child survival is to be achieved hospital care for severely ill, referred children will need to be improved considerably in parallel with primary care in many countries. Yet we know little about how to achieve this. We describe the evolution and final design of an intervention study attempting to improve hospital care for children in Kenyan district hospitals. We believe our experience illustrates many of the difficulties involved in reconciling epidemiological rigour and feasibility in studies at a health system rather than an individual level and the importance of the depth and breadth of analysis when trying to provide a plausible answer to the question - does it work? While there are increasing calls for more health systems research in low-income countries the importance of strong, broadly-based local partnerships and long term commitment even to initiate projects are not always appreciated.

Background

Case management guidelines use a limited set of clinical features to guide assessment and treatment for common childhood diseases in poor countries. Using video records of clinical signs we assessed agreement among experts and assessed whether Kenyan health workers could identify signs defined by expert consensus.

Methodology

104 videos representing 11 clinical sign categories were presented to experts using a web questionnaire. Proportionate agreement and agreement beyond chance were calculated using kappa and the AC1 statistic. 31 videos were selected and presented to local health workers, 20 for which experts had demonstrated clear agreement and 11 for which experts could not demonstrate agreement.

Principal Findings

Experts reached very high level of chance adjusted agreement for some videos while for a few videos no agreement beyond chance was found. Where experts agreed Kenyan hospital staff of all cadres recognised signs with high mean sensitivity and specificity (sensitivity: 0.897–0.975, specificity: 0.813–0.894); years of experience, gender and hospital had no influence on mean sensitivity or specificity. Local health workers did not agree on videos where experts had low or no agreement. Results of different agreement statistics for multiple observers, the AC1 and Fleiss' kappa, differ across the range of proportionate agreement.

Conclusion

Videos provide a useful means to test agreement amongst geographically diverse groups of health workers. Kenyan health workers are in agreement with experts where clinical signs are clear-cut supporting the potential value of assessment and management guidelines. However, clinical signs are not always clear-cut. Video recordings offer one means to help standardise interpretation of clinical signs.

Background

There have been resurgent efforts in Africa to estimate the public health impact of malaria control interventions such as insecticide treated nets (ITNs) following substantial investments in scaling-up coverage in the last five years. Little is known, however, on the effectiveness of ITN in areas of Africa that support low transmission. This hinders the accurate estimation of impact of ITN use on disease burden and its cost-effectiveness in low transmission settings.

Methods and Principal Findings

Using a stratified two-stage cluster sample design, four cross-sectional studies were undertaken between March-June 2007 across three livelihood groups in an area of low intensity malaria transmission in South Central Somalia. Information on bed net use; age; and sex of all participants were recorded. A finger prick blood sample was taken from participants to examine for parasitaemia. Mantel-Haenzel methods were used to measure the effect of net use on parasitaemia adjusting for livelihood; age; and sex. A total of 10,587 individuals of all ages were seen of which 10,359 provided full information. Overall net use and parasite prevalence were 12.4% and 15.7% respectively. Age-specific protective effectiveness (PE) of bed net ranged from 39% among <5 years to 72% among 5–14 years old. Overall PE of bed nets was 54% (95% confidence interval 44%–63%) after adjusting for livelihood; sex; and age.

Conclusions and Significance

Bed nets confer high protection against parasite infection in South Central Somalia. In such areas where baseline transmission is low, however, the absolute reductions in parasitaemia due to wide-scale net use will be relatively small raising questions on the cost-effectiveness of covering millions of people living in such settings in Africa with nets. Further understanding of the progress of disease upon infection against the cost of averting its consequent burden in low transmission areas of Africa is therefore required.

The authors argue that research organizations and funders should combine efforts to produce an open-source solution for trial data management.

Background

Birth asphyxia kills 0.7 to 1.6 million newborns a year globally with 99% of deaths in developing countries. Effective newborn resuscitation could reduce this burden of disease but the training of health-care providers in low income settings is often outdated. Our aim was to determine if a simple one day newborn resuscitation training (NRT) alters health worker resuscitation practices in a public hospital setting in Kenya.

Methods/Principal Findings

We conducted a randomised, controlled trial with health workers receiving early training with NRT (n = 28) or late training (the control group, n = 55). The training was adapted locally from the approach of the UK Resuscitation Council. The primary outcome was the proportion of appropriate initial resuscitation steps with the frequency of inappropriate practices as a secondary outcome. Data were collected on 97 and 115 resuscitation episodes over 7 weeks after early training in the intervention and control groups respectively. Trained providers demonstrated a higher proportion of adequate initial resuscitation steps compared to the control group (trained 66% vs control 27%; risk ratio 2.45, [95% CI 1.75–3.42], p<0.001, adjusted for clustering). In addition, there was a statistically significant reduction in the frequency of inappropriate and potentially harmful practices per resuscitation in the trained group (trained 0.53 vs control 0.92; mean difference 0.40, [95% CI 0.13–0.66], p = 0.004).

Conclusions/Significance

Implementation of a simple, one day newborn resuscitation training can be followed immediately by significant improvement in health workers' practices. However, evidence of the effects on long term performance or clinical outcomes can only be established by larger cluster randomised trials.

Trial Registration

Controlled-Trials.com ISRCTN92218092

A recently proposed mechanism of protection for haemoglobin C (HbC; β6Glu→Lys) links an abnormal display of PfEMP1, an antigen involved in malaria pathogenesis, on the surface of HbC infected erythrocytes together with the observation of reduced cytoadhesion of parasitized erythrocytes and impaired rosetting in vitro. We investigated the impact of this hypothesis on the development of acquired immunity against Plasmodium falciparum variant surface antigens (VSA) encoding PfEMP1 in HbC in comparison with HbA and HbS carriers of Burkina Faso. We measured: i) total IgG against a single VSA, A4U, and against a panel of VSA from severe malaria cases in human sera from urban and rural areas of Burkina Faso of different haemoglobin genotypes (CC, AC, AS, SC, SS); ii) total IgG against recombinant proteins of P. falciparum asexual sporozoite, blood stage antigens, and parasite schizont extract; iii) total IgG against tetanus toxoid. Results showed that the reported abnormal cell-surface display of PfEMP1 on HbC infected erythrocytes observed in vitro is not associated to lower anti- PfEMP1 response in vivo. Higher immune response against the VSA panel and malaria antigens were observed in all adaptive genotypes containing at least one allelic variant HbC or HbS in the low transmission urban area whereas no differences were detected in the high transmission rural area. In both contexts the response against tetanus toxoid was not influenced by the β-globin genotype. These findings suggest that both HbC and HbS affect the early development of naturally acquired immunity against malaria. The enhanced immune reactivity in both HbC and HbS carriers supports the hypothesis that the protection against malaria of these adaptive genotypes might be at least partially mediated by acquired immunity against malaria.

Summary

Background

The potential of insecticide-treated bednets (ITNs) to contribute to child survival has been well documented in randomised controlled trials. ITN coverage has increased rapidly in Kenya from 7% in 2004 to 67% in 2006. We aimed to assess the extent to which this investment has led to improvements in child survival.

Methods

A dynamic cohort of about 3500 children aged 1–59 months were enumerated three times at yearly intervals in 72 rural clusters located in four districts of Kenya. The effect of ITN use on mortality was assessed with Poisson regression to take account of potential effect-modifying and confounding covariates.

Findings

100 children died over 2 years. Overall mortality rates were much the same in the first and second years of the study (14·5 per 1000 person-years in the first year and 15·4 per 1000 person-years in the second). After adjustment for age, time period, and a number of other possible confounding variables, ITN use was associated with a 44% reduction in mortality (mortality rate ratio 0·56, 95% CI 0·33–0·96; p=0·04). This level of protection corresponds to about seven deaths averted for every 1000 ITNs distributed.

Interpretation

A combined approach of social marketing followed by mass free distribution of ITNs translated into child survival effects that are comparable with those seen in previous randomised controlled trials.

Background

“FFM ME-TRAP” is sequential immunisation with two attenuated poxvirus vectors (FP9 and modified vaccinia virus Ankara) delivering the pre-erythrocytic malaria antigen ME-TRAP. Over nine months follow-up in our original study, there was no evidence that FFM ME-TRAP provided protection against malaria. The incidence of malaria was slightly higher in children who received FFM ME-TRAP, but this was not statistically significant (hazard ratio 1.5, 95% CI 1.0-2.3). Although the study was unblinded, another nine months follow-up was planned to monitor the incidence of malaria and other serious adverse events.

Methods and Findings

405 children aged 1–6 yrs were initially randomized to vaccination with either FFM ME-TRAP or control (rabies vaccine). 380 children were still available for follow-up after the first nine months. Children were seen weekly and whenever they were unwell for nine months monitoring. The axillary temperature was measured, and blood films taken when febrile. The primary analysis was time to parasitaemia >2,500/µl. During the second nine months monitoring, 49 events met the primary endpoint (febrile malaria with parasites >2,500/µl) in the Intention To Treat (ITT) group. 23 events occurred among the 189 children in the FFM ME-TRAP group, and 26 among the 194 children in the control group. In the full 18 months of monitoring, there were 63 events in the FFM ME-TRAP group and 60 in the control group (HR = 1.2, CI 0.84-1.73, p = 0.35). There was no evidence that the HR changed over the 18 months (test for interaction between time and vaccination p = 0.11).

Conclusions

Vaccination with FFM ME-TRAP was not protective against malaria in this study. Malaria incidence during 18 months of surveillance was similar in both vaccine groups.

Trial Registration

Controlled-Trials.com ISRCTN88335123

Background

Global malaria control strategies highlight the need to increase early uptake of effective antimalarials for childhood fevers in endemic settings, based on a presumptive diagnosis of malaria in this age group. Many control programmes identify private medicine sellers as important targets to promote effective early treatment, based on reported widespread inadequate childhood fever treatment practices involving the retail sector. Data on adult use of over-the-counter (OTC) medicines is limited. This study aimed to assess childhood and adult patterns of OTC medicine use to inform national medicine retailer programmes in Kenya and other similar settings.

Methods

Large-scale cluster randomized surveys of treatment seeking practices and malaria parasite prevalence were conducted for recent fevers in children under five years and recent acute illnesses in adults in three districts in Kenya with differing malaria endemicity.

Results

A total of 12, 445 households were visited and data collected on recent illnesses in 11, 505 children and 19, 914 adults. OTC medicines were the most popular first response to fever in children with fever (47.0%; 95% CI 45.5, 48.5) and adults with acute illnesses (56.8%; 95% CI 55.2, 58.3). 36.9% (95% CI 34.7, 39.2) adults and 22.7% (95% CI 20.9, 24.6) children using OTC medicines purchased antimalarials, with similar proportions in low and high endemicity districts. 1.9% (95% CI 0.8, 4.2) adults and 12.1% (95% CI 16.3,34.2) children used multidose antimalarials appropriately. Although the majority of children and adults sought no further treatment, self-referral to a health facility within 72 hours of illness onset was the commonest pattern amongst those seeking further help.

Conclusion

In these surveys, OTC medicines were popular first treatments for fever in children or acute illnesses in adults. The proportions using OTC antimalarials were similar in areas of high and low malaria endemicity. In all districts, adults were more likely to self-treat with OTC antimalarial medicines than febrile children were to receive them, and less likely to use them in recommended ways. Government health centres were the most common second resort for treatment and were often used within 72 hours. In view of these practices, more research is needed to assess the impact on the popularity of private medicine sellers of strengthened public sector policies on access to malaria treatment and insecticide-treated bed nets. Improved targeting of OTC antimalarials to high risk groups, better communication strategies regarding adult as well as children's dosages, and facilitating more rapid referral to trained health workers where needed are important challenges to private medicine seller programmes.

Objective:

The objective was to measure the efficacy of the vaccination regimen FFM ME-TRAP in preventing episodes of clinical malaria among children in a malaria endemic area. FFM ME-TRAP is sequential immunisation with two attenuated poxvirus vectors (FP9 and modified vaccinia virus Ankara), which both deliver the pre-erythrocytic malaria antigen construct multiple epitope–thrombospondin-related adhesion protein (ME-TRAP).

Design:

The trial was randomised and double-blinded.

Setting:

The setting was a rural, malaria-endemic area of coastal Kenya.

Participants:

We vaccinated 405 healthy 1- to 6-year-old children.

Interventions:

Participants were randomised to vaccination with either FFM ME-TRAP or control (rabies vaccine).

Outcome Measures:

Following antimalarial drug treatment children were seen weekly and whenever they were unwell during nine months of monitoring. The axillary temperature was measured, and blood films taken when febrile. The primary analysis was time to a parasitaemia of over 2,500 parasites/μl.

Results:

The regime was moderately immunogenic, but the magnitude of T cell responses was lower than in previous studies. In intention to treat (ITT) analysis, time to first episode was shorter in the FFM ME-TRAP group. The cumulative incidence of febrile malaria was 52/190 (27%) for FFM ME-TRAP and 40/197 (20%) among controls (hazard ratio = 1.52). This was not statistically significant (95% confidence interval [CI] 1.0–2.3; p = 0.14 by log-rank). A group of 346 children were vaccinated according to protocol (ATP). Among these children, the hazard ratio was 1.3 (95% CI 0.8–2.1; p = 0.55 by log-rank). When multiple malaria episodes were included in the analyses, the incidence rate ratios were 1.6 (95% CI 1.1–2.3); p = 0.017 for ITT, and 1.4 (95% CI 0.9–2.1); p = 0.16 for ATP. Haemoglobin and parasitaemia in cross-sectional surveys at 3 and 9 mo did not differ by treatment group. Among children vaccinated with FFM ME-TRAP, there was no correlation between immunogenicity and malaria incidence.

Conclusions:

No protection was induced against febrile malaria by this vaccine regimen. Future field studies will require vaccinations with stronger immunogenicity in children living in malarious areas.

Editorial Commentary

Background: Malaria kills over a million people a year worldwide, and young children in sub-Saharan are particularly at risk. Cheap, safe, and effective vaccines are needed. One strategy involves a double-vaccination process. This approach (termed “prime-boost”) uses two different delivery methods to transmit the same antigen (part of a protein from the malaria parasite that can trigger an immune response). The two-step vaccination is designed to achieve a greater immune response than with just one vaccination. One research group, based in Oxford in the UK, is using an antigen called “ME-TRAP,” which is delivered using first a strain of modified fowlpox virus (called FP9), then a weakened vaccinia virus (called MVA). Previous studies done in adult UK volunteers have been promising, achieving an immune response and some protection against malaria when volunteers were deliberately infected. However, this approach has not been tested in the group most in need of a vaccine—young African children. Therefore a field trial was conducted among 405 healthy children aged 1–6 years, in a region of Kenya with year-round malaria transmission. Children were randomized to receive either the sequence of vaccines delivering ME-TRAP or to receive a rabies vaccine (as control, but which still gives the children some benefit for taking part in the trial). The children were followed up for nine months, and the primary aim of the trial was to compare the occurrence of clinical malaria (fever combined with malaria parasites in the blood) in the two groups.

What this trial shows: In the 387 children receiving vaccine and having at least one follow-up visit the vaccine did produce an immune response; however, this immune response did not seem to be protective, as the occurrence of malaria was slightly higher in the group receiving the candidate vaccine—although this difference was not statistically significant. Safety data were also collected; the number and severity of adverse events were similar between volunteers receiving the rabies vaccine and those receiving the candidate malaria vaccine, and any serious events were not judged to be linked to the vaccines by the trial's data safety monitoring board.

Strengths and limitations: The methods used in the trial were robust, using appropriate randomization procedures and blinding of participants and researchers. Outcome measures (clinical malaria, defined as fever together with parasites in the blood over 2,500/microliter) were clinically relevant. In order to detect cases of malaria in vaccinated children, health workers visited children weekly, and children with a temperature over 37.5 °C were tested for parasites in the blood. (In between the weekly visits, self-report and referral for assessment also allowed detection of cases.) This process of active detection of malaria cases (as opposed to obtaining data on clinical malaria only from self-report or referral) enables a smaller sample size to be used in the trial, but it is not clear whether this approach is more or less specific at picking up malaria cases than are passive methods. The researchers aimed to ensure that their case detection methods were specific; for children with normal temperature, but reported by their parents as feverish, parasite tests were done only if subsequent temperature readings were high.

Contribution to the evidence: Previous studies of ME-TRAP using the FP9 and MVA vectors have shown the candidate vaccine is safe and induces a strong immune response. The safety result was also supported by the findings of the current trial, conducted in young Kenyan children, but a 5-fold lower immune response was found compared to previous studies. The trial showed that this weak immune response was not effective at preventing clinical cases of malaria in this group of children, although it is not clear why the immune response was lower than expected.

Objectives:

Previous studies have shown that in children with severe malaria, resuscitation with albumin infusion results in a lower mortality than resuscitation with saline infusion. Whether the apparent benefit of albumin is due solely to its colloidal properties, and thus might also be achieved with other synthetic colloids, or due to the many other unique physiological properties of albumin is unknown. As albumin is costly and not readily available in Africa, examination of more affordable colloids is warranted. In order to inform the design of definitive phase III trials we compared volume expansion with Gelofusine (succinylated modified fluid gelatin 4% intravenous infusion) with albumin.

Design:

This study was a phase II safety and efficacy study.

Setting:

The study was conducted at Kilifi District Hospital, Kenya.

Participants:

The participants were children admitted with severe falciparum malaria (impaired consciousness or deep breathing), metabolic acidosis (base deficit > 8 mmol/l), and clinical features of shock.

Interventions:

The interventions were volume resuscitation with either 4.5% human albumin solution or Gelofusine.

Outcome Measures:

Primary endpoints were the resolution of shock and acidosis; secondary endpoints were in-hospital mortality and adverse events including neurological sequelae.

Results:

A total of 88 children were enrolled: 44 received Gelofusine and 44 received albumin. There was no significant difference in the resolution of shock or acidosis between the groups. Whilst no participant developed pulmonary oedema or fluid overload, fatal neurological events were more common in the group receiving gelatin-based intervention fluids. Mortality was lower in patients receiving albumin (1/44; 2.3%) than in those treated with Gelofusine (7/44; 16%) by intention to treat (Fisher's exact test, p = 0.06), or 1/40 (2.5%) and 4/40 (10%), respectively, for those treated per protocol (p = 0.36). Meta-analysis of published trials to provide a summary estimate of the effect of albumin on mortality showed a pooled relative risk of death with albumin administration of 0.19 (95% confidence interval 0.06–0.59; p = 0.004 compared to other fluid boluses).

Conclusions:

In children with severe malaria, we have shown a consistent survival benefit of receiving albumin infusion compared to other resuscitation fluids, despite comparable effects on the resolution of acidosis and shock. The lack of similar mortality benefit from Gelofusine suggests that the mechanism may involve a specific neuroprotective effect of albumin, rather than solely the effect of the administered colloid. Further exploration of the benefits of albumin is warranted in larger clinical trials.

Editorial Commentary

Background: In Africa, children admitted to hospital with severe malaria are at high risk of death even though effective malaria treatment is available. Death typically occurs during a narrow time window after admission and before antimalarial treatments can start working. Acidosis (excessive acidity of the blood) is thought to predict death, but it is not clear how acidosis arises. One possibility is that hypovolemia (lowered blood fluid volume) is important, which would normally require urgent resuscitation with fluids. However, there is little evidence on what type of fluid should be given. In the trial reported here, carried out in Kenya's Kilifi District Hospital between 2004 and 2006, 88 children admitted with severe malaria were assigned to receive either albumin solution (a colloid solution made from blood protein) or Gelofusine (a synthetic colloid). The primary outcomes that the researchers were interested in were correction of shock and acidosis in the blood after 8 h. However, the researchers also looked at death rate in hospital and adverse events after treatment.

What this trial shows: The investigators found no significant differences in the primary outcomes (correction of shock and acidosis in the blood 8 h after fluids were started) between children given Gelofusine and those given albumin. However, they did see a difference in death rates between children given Gelofusine and those given albumin. Death rates in hospital were lower in the group given albumin, and this was statistically significant. The researchers then combined the data on death rates from this trial with data from two other trials with an albumin arm. This combined analysis also supported the suggestion that death rates with albumin were lower than with other fluids, either Gelofusine or salt solution.

Strengths and limitations: There is currently very little evidence from trials to guide the initial management of fluids in children with severe malaria. The results from this trial indicate that further research is a priority. However, the actual findings from this trial must be tested in larger trials that recruit enough children to establish reliably whether there is a difference in death rate between albumin treatment and treatment with other fluids. This trial was not originally planned to find a clinically relevant difference in death rate, and therefore does not definitively answer that question. Further trials would also need to use a random method to assign participants to the different treatments, rather than alternate blocks (as in this trial). A random method ensures greater comparability of the two groups in the trial, and reduces the chance of selection bias (where assignment of patients to different treatments can be distorted during the enrollment process).

Contribution to the evidence: This study adds data suggesting that fluid resuscitation with albumin solution, as compared to Gelofusine, may reduce the chance of death in children with severe malaria. However, this finding is not definitive and would need to be examined in further carefully controlled trials. If the finding is supported by further research, then a solution to the problems of high cost and limited availability of albumin will need to be found.

Background

Abnormal motor posturing is often observed in children with cerebral malaria, but the aetiology and pathogenesis is poorly understood. This study examined the risk factors and outcome of posturing in Kenyan children with cerebral malaria.

Methods

Records of children admitted to Kilifi district hospital with cerebral malaria from January, 1999 through December, 2001 were reviewed for posturing occurring on or after admission. The clinical characteristics, features of raised intracranial pressure, number of seizures and biochemical changes in patients that developed posturing was compared to patients who did not.

Results

Of the 417 children with complete records, 163 (39.1%) had posturing: 85 on admission and 78 after admission to hospital. Decorticate posturing occurred in 80, decerebrate in 61 and opisthotonic posturing in 22 patients. Posturing was associated with age ≥ 3 years (48.1 vs 35.8%, p = 0.01) and features of raised intracranial pressure on funduscopy (adjusted OR 2.1 95%CI 1.2–3.7, p = 0.009) but not other markers of severity of disease. Unlike decorticate posturing, decerebrate (adjusted OR 1.9 95%CI 1.0–3.5) and opisthotonic posturing (adjusted OR 2.9 95%CI 1.0–8.1) were, in addition, independently associated with recurrence of seizures after admission. Opisthotonus was also associated with severe metabolic acidosis (OR 4.2 95%CI 3.2–5.6, p < 0.001). Thirty one patients with posturing died. Of these, 19 (61.3%) had features suggestive of transtentorial herniation. Mortality and neurological deficits on discharge were greatest in those developing posturing after admission.

Conclusion

Abnormal motor posturing is a common feature of cerebral malaria in children. It is associated with features of raised intracranial pressure and recurrence of seizures, although intracranial hypertension may be the primary cause.