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1.  A double blind, randomised controlled trial of glycerol adjuvant therapy in adult bacterial meningitis in a high HIV seroprevalence setting in Malawi 
The Lancet infectious diseases  2011;11(4):293-300.
Summary
Background
Southern Africa has a high incidence of bacterial meningitis in adults, often associated with HIV co-infection. Even with appropriate antibiotic therapy, mortality exceeds 50% and is not improved with corticosteroids. Glycerol adjuvant therapy reduced mortality and long-term morbidity (deafness) in bacterial meningitis in children and is being promoted. If similarly effective in adults, glycerol would provide a cheap, available adjuvant therapy in Africa.
Methods
Following a dose-finding study, we conducted a randomised double-blind placebo-controlled trial of oral glycerol in adults with bacterial meningitis. Patients with clinical and CSF findings suggestive of bacterial meningitis were randomised either to glycerol or an equivalent volume of sugar solution. The primary outcome was mortality at 40 days with secondary outcomes including disability and mortality restricted to pneumococcal disease.
Findings
75ml glycerol QDS was best tolerated and was used for the main study. 265 patients were randomised to receive glycerol or placebo. The trial was stopped early on the advice of the Data and Safety Monitoring Board (DSMB) following a planned interim analysis. Mortality by day 40 was 61/125 (49%) in the placebo and 86/136 (69%) in the glycerol arms, Adjusted Odds Ratio 2·4 (95% CI 1·3-4·2 p0·003). There was no benefit from glycerol for death and disability by day 40 by intention to treat or in predefined subgroups. Two serious adverse events occurred possibly due to study drug.
Interpretation
Oral glycerol therapy did not improve mortality in adults with bacterial meningitis and cannot be recommended as a suitable adjuvant therapy in resource-poor settings with a high HIV prevalence.
doi:10.1016/S1473-3099(10)70317-0
PMCID: PMC3999512  PMID: 21334262
2.  A Mixed Methods Study of a Health Worker Training Intervention to Increase Syndromic Referral for Gambiense Human African Trypanosomiasis in South Sudan 
Background
Active screening by mobile teams is considered the most effective method for detecting gambiense-type human African trypanosomiasis (HAT) but constrained funding in many post-conflict countries limits this approach. Non-specialist health care workers (HCWs) in peripheral health facilities could be trained to identify potential cases for testing based on symptoms. We tested a training intervention for HCWs in peripheral facilities in Nimule, South Sudan to increase knowledge of HAT symptomatology and the rate of syndromic referrals to a central screening and treatment centre.
Methodology/Principal Findings
We trained 108 HCWs from 61/74 of the public, private and military peripheral health facilities in the county during six one-day workshops and assessed behaviour change using quantitative and qualitative methods. In four months prior to training, only 2/562 people passively screened for HAT were referred from a peripheral HCW (0 cases detected) compared to 13/352 (2 cases detected) in the four months after, a 6.5-fold increase in the referral rate observed by the hospital. Modest increases in absolute referrals received, however, concealed higher levels of referral activity in the periphery. HCWs in 71.4% of facilities followed-up had made referrals, incorporating new and pre-existing ideas about HAT case detection into referral practice. HCW knowledge scores of HAT symptoms improved across all demographic sub-groups. Of 71 HAT referrals made, two-thirds were from new referrers. Only 11 patients completed the referral, largely because of difficulties patients in remote areas faced accessing transportation.
Conclusions/Significance
The training increased knowledge and this led to more widespread appropriate HAT referrals from a low base. Many referrals were not completed, however. Increasing access to screening and/or diagnostic tests in the periphery will be needed for greater impact on case-detection in this context. These data suggest it may be possible for peripheral HCWs to target the use of rapid diagnostic tests for HAT.
Author Summary
Human African trypanosomiasis (HAT or sleeping sickness) is a fatal but treatable disease affecting poor people in sub-Saharan Africa. Most HAT diagnostic equipment, infrastructure and expertise is located in hospitals. The expense of expanding testing services to remote areas using mobile teams severely restricts their use. Non-specialist healthcare workers (HCWs) in first-line (primary) health care facilities can contribute to control by identifying patients in need of testing based on their symptoms. We therefore trained first-line HCWs to recognise potential syndromic cases of HAT and refer them to a hospital screening service. Against a low baseline of HCW HAT referral experience, four months after the intervention, HCW knowledge of HAT symptoms increased and HCWs in 71.4% of facilities across the county had made referrals, incorporating new and pre-existing ideas about HAT case detection into referral practice. There was only a modest increase in numbers of referred patients received at the hospital for screening, however, largely because of distance. In an era where approaches to HAT case detection and control must increasingly be integrated into health referral systems, it is vital to understand the opportunities and challenges associated with syndromic case detection in first line facilities to design effective interventions.
doi:10.1371/journal.pntd.0002742
PMCID: PMC3961197  PMID: 24651696
3.  Cost-Effectiveness Analysis of Introducing RDTs for Malaria Diagnosis as Compared to Microscopy and Presumptive Diagnosis in Central and Peripheral Public Health Facilities in Ghana 
Cost-effectiveness information on where malaria rapid diagnostic tests (RDTs) should be introduced is limited. We developed incremental cost-effectiveness analyses with data from rural health facilities in Ghana with and without microscopy. In the latter, where diagnosis had been presumptive, the introduction of RDTs increased the proportion of patients who were correctly treated in relation to treatment with antimalarials, from 42% to 65% at an incremental societal cost of Ghana cedis (GHS)12.2 (US$8.3) per additional correctly treated patients. In the “microscopy setting” there was no advantage to replacing microscopy by RDT as the cost and proportion of correctly treated patients were similar. Results were sensitive to a decrease in the cost of RDTs, which cost GHS1.72 (US$1.17) per test at the time of the study and to improvements in adherence to negative tests that was just above 50% for both RDTs and microscopy.
doi:10.4269/ajtmh.13-0033
PMCID: PMC3795104  PMID: 23980131
4.  Syndromic Algorithms for Detection of Gambiense Human African Trypanosomiasis in South Sudan 
Background
Active screening by mobile teams is considered the best method for detecting human African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense but the current funding context in many post-conflict countries limits this approach. As an alternative, non-specialist health care workers (HCWs) in peripheral health facilities could be trained to identify potential cases who need testing based on their symptoms. We explored the predictive value of syndromic referral algorithms to identify symptomatic cases of HAT among a treatment-seeking population in Nimule, South Sudan.
Methodology/Principal Findings
Symptom data from 462 patients (27 cases) presenting for a HAT test via passive screening over a 7 month period were collected to construct and evaluate over 14,000 four item syndromic algorithms considered simple enough to be used by peripheral HCWs. For comparison, algorithms developed in other settings were also tested on our data, and a panel of expert HAT clinicians were asked to make referral decisions based on the symptom dataset. The best performing algorithms consisted of three core symptoms (sleep problems, neurological problems and weight loss), with or without a history of oedema, cervical adenopathy or proximity to livestock. They had a sensitivity of 88.9–92.6%, a negative predictive value of up to 98.8% and a positive predictive value in this context of 8.4–8.7%. In terms of sensitivity, these out-performed more complex algorithms identified in other studies, as well as the expert panel. The best-performing algorithm is predicted to identify about 9/10 treatment-seeking HAT cases, though only 1/10 patients referred would test positive.
Conclusions/Significance
In the absence of regular active screening, improving referrals of HAT patients through other means is essential. Systematic use of syndromic algorithms by peripheral HCWs has the potential to increase case detection and would increase their participation in HAT programmes. The algorithms proposed here, though promising, should be validated elsewhere.
Author Summary
Human African trypanosomiasis (HAT or sleeping sickness) is an almost always fatal disease affecting poor people in rural, conflict-affected areas of sub-Saharan Africa. It is difficult to diagnose. Effective treatment exists, but because diagnostic and treatment services are usually based only in hospitals, many HAT patients in rural areas are never detected. Control programmes aim periodically to extend testing services via mobile teams (active screening) but their expense and operational issues severely restrict their use. We explored the predictive value of different combinations of symptoms that were present in a treatment-seeking population to identify people infected with HAT. Through this approach, we identified a simple four-symptom referral algorithm that, if replicable, has the potential to identify one HAT patient for every ten patients referred through subsequent testing. It would identify most symptomatic HAT patients who seek treatment, if systematically applied by non-specialist healthcare workers already working in these areas. As these types of health workers are rarely included in formal HAT control efforts, teaching this algorithm also represents an opportunity to decentralise life-saving knowledge, and contribute to endemic populations' long-term empowerment and ability to help control this disease.
doi:10.1371/journal.pntd.0002003
PMCID: PMC3547858  PMID: 23350005
5.  Likely Health Outcomes for Untreated Acute Febrile Illness in the Tropics in Decision and Economic Models; A Delphi Survey 
PLoS ONE  2011;6(2):e17439.
Background
Modelling is widely used to inform decisions about management of malaria and acute febrile illnesses. Most models depend on estimates of the probability that untreated patients with malaria or bacterial illnesses will progress to severe disease or death. However, data on these key parameters are lacking and assumptions are frequently made based on expert opinion. Widely diverse opinions can lead to conflicting outcomes in models they inform.
Methods and Findings
A Delphi survey was conducted with malaria experts aiming to reach consensus on key parameters for public health and economic models, relating to the outcome of untreated febrile illnesses. Survey questions were stratified by malaria transmission intensity, patient age, and HIV prevalence. The impact of the variability in opinion on decision models is illustrated with a model previously used to assess the cost-effectiveness of malaria rapid diagnostic tests. Some consensus was reached around the probability that patients from higher transmission settings with untreated malaria would progress to severe disease (median 3%, inter-quartile range (IQR) 1–5%), and the probability that a non-malaria illness required antibiotics in areas of low HIV prevalence (median 20%). Children living in low transmission areas were considered to be at higher risk of progressing to severe malaria (median 30%, IQR 10–58%) than those from higher transmission areas (median 13%, IQR 7–30%). Estimates of the probability of dying from severe malaria were high in all settings (medians 60–73%). However, opinions varied widely for most parameters, and did not converge on resurveying.
Conclusions
This study highlights the uncertainty around potential consequences of untreated malaria and bacterial illnesses. The lack of consensus on most parameters, the wide range of estimates, and the impact of variability in estimates on model outputs, demonstrate the importance of sensitivity analysis for decision models employing expert opinion. Results of such models should be interpreted cautiously. The diversity of expert opinion should be recognised when policy options are debated.
doi:10.1371/journal.pone.0017439
PMCID: PMC3044764  PMID: 21390277
6.  In Tanzania, Hemolysis after a Single Dose of Primaquine Coadministered with an Artemisinin Is Not Restricted to Glucose-6-Phosphate Dehydrogenase-Deficient (G6PD A−) Individuals▿  
The current interest in malaria elimination has led to a renewed interest in drugs that can be used for mass administration to minimize malaria transmission. Primaquine (PQ) is the only generally available drug with a strong activity against mature Plasmodium falciparum gametocytes, the parasite stage responsible for transmission. Despite concerns about PQ-induced hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals, a single dose of PQ may be safe and efficacious in clearing gametocytes that persist after conventional treatment. As part of a mass drug intervention, we determined the hemolytic effect of sulfadoxine-pyrimethamine (SP) plus artesunate (AS) plus a single dose of primaquine (PQ; 0.75 mg/kg of body weight) in children aged 1 to 12 years. Children were randomized to receive SP+AS+PQ or placebo; those with a hemoglobin (Hb) level below 8 g/dl were excluded from receiving PQ and received SP+AS. The Hb concentration was significantly reduced 7 days after SP+AS+PQ treatment but not after placebo or SP+AS treatment. This reduction in Hb was most pronounced in G6PD-deficient (G6PD A−) individuals (−2.5 g/dl; 95% confidence interval [95% CI], −1.2 to −3.8 g/dl) but was also observed in heterozygotes (G6PD A) (−1.6 g/dl; 95% CI, −0.9 to −2.2 g/dl) and individuals with the wild-type genotype (G6PD B) (−0.5 g/dl; 95% CI, −0.4 to −0.6 g/dl). Moderate anemia (Hb level of <8 g/dl) was observed in 40% (6/15 individuals) of the G6PD A−, 11.1% (3/27 individuals) of the G6PD A, and 4.5% (18/399 individuals) of the G6PD B individuals; one case of severe anemia (Hb level of <5 g/dl) was observed. PQ may cause moderate anemia when coadministered with artemisinins, and excluding individuals based on G6PD status alone may not be sufficient to prevent PQ-induced hemolysis.
doi:10.1128/AAC.01135-09
PMCID: PMC2863610  PMID: 20194698
7.  An Economic Evaluation of Home Management of Malaria in Uganda: An Interactive Markov Model 
PLoS ONE  2010;5(8):e12439.
Background
Home management of malaria (HMM), promoting presumptive treatment of febrile children in the community, is advocated to improve prompt appropriate treatment of malaria in Africa. The cost-effectiveness of HMM is likely to vary widely in different settings and with the antimalarial drugs used. However, no data on the cost-effectiveness of HMM programmes are available.
Methods/Principal Findings
A Markov model was constructed to estimate the cost-effectiveness of HMM as compared to conventional care for febrile illnesses in children without HMM. The model was populated with data from Uganda, but is designed to be interactive, allowing the user to adjust certain parameters, including the antimalarials distributed. The model calculates the cost per disability adjusted life year averted and presents the incremental cost-effectiveness ratio compared to a threshold value. Model output is stratified by level of malaria transmission and the probability that a child would receive appropriate care from a health facility, to indicate the circumstances in which HMM is likely to be cost-effective. The model output suggests that the cost-effectiveness of HMM varies with malaria transmission, the probability of appropriate care, and the drug distributed. Where transmission is high and the probability of appropriate care is limited, HMM is likely to be cost-effective from a provider perspective. Even with the most effective antimalarials, HMM remains an attractive intervention only in areas of high malaria transmission and in medium transmission areas with a lower probability of appropriate care. HMM is generally not cost-effective in low transmission areas, regardless of which antimalarial is distributed. Considering the analysis from the societal perspective decreases the attractiveness of HMM.
Conclusion
Syndromic HMM for children with fever may be a useful strategy for higher transmission settings with limited health care and diagnosis, but is not appropriate for all settings. HMM may need to be tailored to specific settings, accounting for local malaria transmission intensity and availability of health services.
doi:10.1371/journal.pone.0012439
PMCID: PMC2929190  PMID: 20805977
8.  The Impact of Phenotypic and Genotypic G6PD Deficiency on Risk of Plasmodium vivax Infection: A Case-Control Study amongst Afghan Refugees in Pakistan 
PLoS Medicine  2010;7(5):e1000283.
Analyses of a case-control study among Afghan refugees in Pakistan find that a G6PD (glucose-6-phosphate dehydrogenase) “Mediterranean” type deficiency confers substantial protection against Plasmodium vivax malaria.
Background
The most common form of malaria outside Africa, Plasmodium vivax, is more difficult to control than P. falciparum because of the latent liver hypnozoite stage, which causes multiple relapses and provides an infectious reservoir. The African (A−) G6PD (glucose-6-phosphate dehydrogenase) deficiency confers partial protection against severe P. falciparum. Recent evidence suggests that the deficiency also confers protection against P. vivax, which could explain its wide geographical distribution in human populations. The deficiency has a potentially serious interaction with antirelapse therapies (8-aminoquinolines such as primaquine). If the level of protection was sufficient, antirelapse therapy could become more widely available. We therefore tested the hypothesis that G6PD deficiency is protective against vivax malaria infection.
Methods and Findings
A case-control study design was used amongst Afghan refugees in Pakistan. The frequency of phenotypic and genotypic G6PD deficiency in individuals with vivax malaria was compared against controls who had not had malaria in the previous two years. Phenotypic G6PD deficiency was less common amongst cases than controls (cases: 4/372 [1.1%] versus controls 42/743 [5.7%]; adjusted odds ratio [AOR] 0.18 [95% confidence interval (CI) 0.06–0.52], p = 0.001). Genetic analysis demonstrated that the G6PD deficiency allele identified (Mediterranean type) was associated with protection in hemizygous deficient males (AOR = 0.12 [95% CI 0.02–0.92], p = 0.041). The deficiency was also protective in females carrying the deficiency gene as heterozygotes or homozygotes (pooled AOR = 0.37 [95% CI 0.15–0.94], p = 0.037).
Conclusions
G6PD deficiency (Mediterranean type) conferred significant protection against vivax malaria infection in this population whether measured by phenotype or genotype, indicating a possible evolutionary role for vivax malaria in the selective retention of the G6PD deficiency trait in human populations. Further work is required on the genotypic protection associated with other types of G6PD deficiency and on developing simple point-of-care technologies to detect it before administering antirelapse therapy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria is a parasitic infection transmitted to people through the bite of an infected mosquito. Although Plasmodium falciparum is responsible for most malaria deaths, P. vivax is the commonest, most widespread cause of malaria outside sub-Saharan Africa. Like other malaria parasites, P. vivax has a complex life cycle. Infected mosquitoes inject a parasitic form known as sporozoites into people where they replicate inside liver cells without causing symptoms. About 8–9 days later, merozoites (another parasitic form) are released from the liver cells and invade red blood cells. Here, they replicate rapidly before bursting out and infecting more red blood cells. This increase in the parasitic burden causes malaria's characteristic symptoms (debilitating and recurring chills and fevers). P. vivax infections are usually treated with chloroquine (although resistance to this drug is now emerging) but patients must also take primaquine, a drug that kills hypnozoites, a form of P. vivax that hibernates in the liver. Hypnozoites can cause a relapse months after the initial bout of malaria and make P. vivax malaria harder to control than P. faciparum malaria.
Why Was This Study Done?
Some mutations (DNA changes) protect their human carriers against specific disease-causing organisms. These mutations occur at high frequencies in populations where these organisms are common. For example, the widespread distribution of mutations that cause a deficiency in an enzyme called glucose-6-phosphate dehydrogenase (G6PD) mirrors the distribution of malaria and the African (A−) form of G6PD deficiency, a type of G6PD deficiency that is common in people of African origin, is known to provide partial protection against severe P. falciparum malaria—P. falciparum does not thrive in G6PD-deficient red blood cells. In areas where P. vivax malaria is common, Mediterranean and Asian variants of G6PD deficiency are more widespread than A− G6PD, so the question is, do these variants protect against P. vivax malaria? In this case-control study (a study in which the characteristics of people with and without a specific condition are compared), the researchers investigate whether G6PD deficiency protects against P. vivax infection in a population of Afghan refugees living in Pakistan.
What Did the Researchers Do and Find?
The researchers enrolled 372 Afghan refugees who had had P. vivax malaria during the previous two years and 743 refugees who had not had malaria over the same period. They measured G6PD activity in the participants' blood to detect “phenotypic” G6PD deficiency (reduced enzyme activity) and looked for the Mediterranean variant of the G6PD gene in the participants (“genotypic” G6PD deficiency). 5.7% of the controls but only 1.1% of the cases had phenotypic G6PD deficiency. Statistical analyses indicated that participants with reduced G6PD levels were about one-fifth as likely to develop P. vivax malaria as those with normal G6PD levels after allowing for other factors that might affect their susceptibility to malaria, an adjusted odds ratio (AOR) of 0.18. The genetic analysis indicated that the Mediterranean G6PD gene variant provided protection against P. vivax infection in men (AOR 0.12) and in women carrying either one or two defective copies of the G6PD gene (AOR 0.37); because the G6PD gene is on the X chromosome, men have only one copy of the gene but women have two copies.
What Do These Findings Mean?
These findings indicate that Mediterranean-type G6PD deficiency protects against P. vivax malaria infection in this population of Afghan refugees. Although further studies are needed to determine whether other G6PD variants protect against P. vivax malaria, these findings suggest that P. vivax malaria might be responsible for the retention of the G6PD deficiency trait in some human populations. In addition, these findings may have implications for the treatment of P. vivax malaria. Currently, in most places where P. vivax malaria is common, primaquine is not given routinely because primaquine can trigger red blood cell death (hemolytic anemia) in G6PD-deficient people and tests for G6PD deficiency are rarely available. These findings suggest that the risk of exposure to primaquine among people infected with P. vivax might be lower than previously assumed, because G6PD deficiency is less common among P. vivax-infected patients than among the general population. Nevertheless, these findings are unlikely to increase the use of primaquine immediately. Such an increase, the researchers suggest, will only occur if a simple test for G6PD deficiency is developed.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000283.
Information is available from the World Health Organization on malaria (in several languages)
The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish)
Information is available from the Wellcome Trust on all aspects of malaria, including a news item about G6PD deficiency protecting against severe P. falciparum malaria
MedlinePlus provides links to additional information on malaria (in English and Spanish)
The Malaria Vaccine Initiative has a fact sheet on Plasmodium vivax malaria
Vivaxmalaria provides information about P. vivax
More about G6PD deficiency can be found on KidsHealth from the Nemours Children's Health System
doi:10.1371/journal.pmed.1000283
PMCID: PMC2876136  PMID: 20520804
9.  WHO guidelines for antimicrobial treatment in children admitted to hospital in an area of intense Plasmodium falciparum transmission: prospective study 
Objectives To assess the performance of WHO’s “Guidelines for care at the first-referral level in developing countries” in an area of intense malaria transmission and identify bacterial infections in children with and without malaria.
Design Prospective study.
Setting District hospital in Muheza, northeast Tanzania.
Participants Children aged 2 months to 13 years admitted to hospital for febrile illness.
Main outcome measures Sensitivity and specificity of WHO guidelines in diagnosing invasive bacterial disease; susceptibility of isolated organisms to recommended antimicrobials.
Results Over one year, 3639 children were enrolled and 184 (5.1%) died; 2195 (60.3%) were blood slide positive for Plasmodium falciparum, 341 (9.4%) had invasive bacterial disease, and 142 (3.9%) were seropositive for HIV. The prevalence of invasive bacterial disease was lower in slide positive children (100/2195, 4.6%) than in slide negative children (241/1444, 16.7%). Non-typhi Salmonella was the most frequently isolated organism (52/100 (52%) of organisms in slide positive children and 108/241 (45%) in slide negative children). Mortality among children with invasive bacterial disease was significantly higher (58/341, 17%) than in children without invasive bacterial disease (126/3298, 3.8%) (P<0.001), and this was true regardless of the presence of P falciparum parasitaemia. The sensitivity and specificity of WHO criteria in identifying invasive bacterial disease in slide positive children were 60.0% (95% confidence interval 58.0% to 62.1%) and 53.5% (51.4% to 55.6%), compared with 70.5% (68.2% to 72.9%) and 48.1% (45.6% to 50.7%) in slide negative children. In children with WHO criteria for invasive bacterial disease, only 99/211(47%) of isolated organisms were susceptible to the first recommended antimicrobial agent.
Conclusions In an area exposed to high transmission of malaria, current WHO guidelines failed to identify almost a third of children with invasive bacterial disease, and more than half of the organisms isolated were not susceptible to currently recommended antimicrobials. Improved diagnosis and treatment of invasive bacterial disease are needed to reduce childhood mortality.
doi:10.1136/bmj.c1350
PMCID: PMC2847687  PMID: 20354024
10.  Global health partnerships 
BMJ : British Medical Journal  2007;334(7594):595-596.
Changes to training and revalidation may impede the UK's support of health care in developing countries
doi:10.1136/bmj.39147.396285.BE
PMCID: PMC1832020  PMID: 17379863
11.  Rapid testing for malaria in settings where microscopy is available and peripheral clinics where only presumptive treatment is available: a randomised controlled trial in Ghana 
Objective To test in West Africa the impact of rapid diagnostic tests on the prescription of antimalarials and antibiotics both where microscopy is used for the diagnosis of malaria and in clinical (peripheral) settings that rely on clinical diagnosis.
Design Randomised, controlled, open label clinical trial.
Setting Four clinics in the rural Dangme West district of southern Ghana, one in which microscopy is used for diagnosis of malaria (“microscopy setting”) and three where microscopy is not available and diagnosis of malaria is made on the basis of clinical symptoms (“clinical setting”).
Participants Patients with suspected malaria.
Interventions Patients were randomly assigned to either a rapid diagnostic test or the current diagnostic method at the clinic (microscopy or clinical diagnosis). A blood sample for a research microscopy slide was taken for all patients.
Main outcome measures The primary outcome was the prescription of antimalarials to patients of any age whose double read research slide was negative for malaria. The major secondary outcomes were the correct prescription of antimalarials, the impact of test results on antibiotic prescription, and the correct prescription of antimalarials in children under 5 years.
Results Of the 9236 patients screened, 3452 were randomised in the clinical setting and 3811 in the microscopy setting. Follow-up to 28 days was 97.6% (7088/7263). In the microscopy setting, 722 (51.6%) of the 1400 patients with negative research slides in the rapid diagnostic test arm were treated for malaria compared with 764 (55.0%) of the 1389 patients in the microscopy arm (adjusted odds ratio 0.87, 95% CI 0.71 to 1.1; P=0.16). In the clinical setting, 578 (53.9%) of the 1072 patients in the rapid diagnostic test arm with negative research slides were treated for malaria compared with 982 (90.1%) of the 1090 patients with negative slides in the clinical diagnosis arm (odds ratio 0.12, 95% CI 0.04 to 0.38; P=0.001). The use of rapid diagnostic tests led to better targeting of antimalarials and antibiotics in the clinical but not the microscopy setting, in both children and adults. There were no deaths in children under 5 years at 28 days follow-up in either arm.
Conclusion Where microscopy already exists, introducing rapid diagnostic tests had limited impact on prescriber behaviour. In settings where microscopy was not available, however, using rapid diagnostic tests led to a significant reduction in the overprescription of antimalarials, without any evidence of clinical harm, and to better targeting of antibiotics.
Trial registration ClinicalTrials.gov NCT00493922.
doi:10.1136/bmj.c930
PMCID: PMC2833239  PMID: 20207689
12.  Randomized Trial of Artesunate+Amodiaquine, Sulfadoxine-Pyrimethamine+Amodiaquine, Chlorproguanal-Dapsone and SP for Malaria in Pregnancy in Tanzania 
PLoS ONE  2009;4(4):e5138.
Background
Malaria in pregnancy is serious, and drug resistance in Africa is spreading. Drugs have greater risks in pregnancy and determining the safety and efficacy of drugs in pregnancy is therefore a priority. This study set out to determine the efficacy and safety of several antimalarial drugs and combinations in pregnant women with uncomplicated malaria.
Methods
Pregnant women with non-severe, slide proven, falciparum malaria were randomised to one of 4 regimes: sulfadoxine-pyrimethamine [SP]; chlorproguanil-dapsone [CD]; SP+amodiaquine [SP+AQ] or amodiaquine+artesunate [AQ+AS]. Randomisation was on a 1∶2∶2∶2 ratio. Women were admitted for treatment, and followed at days 7, 14, 21, 28 after the start of treatment, at delivery and 6 weeks after delivery to determine adverse events, clinical and parasitological outcomes. Primary outcome was parasitological failure by day 28.
Results
1433 pregnant women were screened, of whom 272 met entry criteria and were randomised; 28 to SP, 81 to CD, 80 to SP+AQ and 83 to AQ+AS. Follow-up to day 28 post treatment was 251/272 (92%), and to 6 weeks following delivery 91%. By day 28 parasitological failure rates were 4/26 (15%, 95%CI 4–35) in the SP, 18/77 (23%, 95%CI 14–34) in the CD, 1/73 (1% 95%CI 7–0.001) in the SP+AQ and 7/75 (9% 95%CI 4–18) in the AQ+AS arms respectively. After correction by molecular markers for reinfection the parasitological failure rates at day 28 were 18% for CD, 1% for SP+AQ and 4.5% for AQ+AS. There were two maternal deaths during the trial. There was no apparent excess of stillbirths or adverse birth outcomes in any arm. Parasitological responses were strikingly better in pregnant women than in children treated with the same drugs at this site.
Conclusions
Failure rates with monotherapy were unacceptably high. The two combinations tested were efficacious and appeared safe. It should not be assumed that efficacy in pregnancy is the same as in children.
Trial Registration
ClinicalTrials.gov NCT00146731
doi:10.1371/journal.pone.0005138
PMCID: PMC2662423  PMID: 19352498
13.  Guidelines for Field Surveys of the Quality of Medicines: A Proposal 
PLoS Medicine  2009;6(3):e1000052.
Paul Newton and colleagues propose guidelines for conducting and reporting field surveys of the quality of medicines.
doi:10.1371/journal.pmed.1000052
PMCID: PMC2659710  PMID: 19320538
15.  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
16.  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
17.  A Randomised Trial of an Eight-Week, Once Weekly Primaquine Regimen to Prevent Relapse of Plasmodium vivax in Northwest Frontier Province, Pakistan 
PLoS ONE  2008;3(8):e2861.
Background
Vivax malaria remains a major cause of morbidity in the subtropics. To undermine the stability of the disease, drugs are required that prevent relapse and provide reservoir reduction. A 14-day course of primaquine (PQ) is effective but cannot safely be used in routine practice because of its interaction with glucose-6-phosphate dehydrogenase (G6PD) deficiency for which testing is seldom available. Safe and effective use of PQ without the need for G6PD testing would be ideal. The efficacy and safety of an 8-week, once weekly PQ regimen was compared with current standard treatment (chloroquine alone) and a 14-day PQ regimen.
Methods and Principal Findings
200 microscopically confirmed Plasmodium vivax patients were randomly assigned to either once weekly 8-week PQ (0.75mg/kg/week), once weekly 8-week placebo, or 14-day PQ (0.5mg/kg/day) in North West Frontier Province, Pakistan. All patients were treated with a standard chloroquine dose and tested for G6PD deficiency. Deficient patients were assigned to the 8-week PQ group. Failure was defined as any subsequent episode of vivax malaria over 11 months of observation. There were 22/71 (31.0%) failures in the placebo group and 1/55 (1.8%) and 4/75 (5.1%) failures in the 14-day and 8-week PQ groups, respectively. Adjusted odds ratios were: for 8-week PQ vs. placebo-0.05 (95%CI: 0.01-0.2, p<0.001) and for 14-day PQ vs. placebo-0.01 (95%CI: 0.002-0.1, p<0.001). Restricted analysis allowing for a post-treatment prophylactic effect confirmed that the 8-week regimen was superior to current treatment. Only one G6PD deficient patient presented. There were no serious adverse events.
Conclusions
A practical radical treatment for vivax malaria is essential for control and elimination of the disease. The 8-week PQ course is more effective at preventing relapse than current treatment with chloroquine alone. Widespread use of the 8-week regimen could make an important contribution to reservoir reduction or regional elimination where G6PD testing is not available.
Trial Registration
ClinicalTrials.gov NCT00158587
doi:10.1371/journal.pone.0002861
PMCID: PMC2481394  PMID: 18682739
18.  Imported malaria and high risk groups: observational study using UK surveillance data 1987-2006 
BMJ : British Medical Journal  2008;337(7661):103-106.
Objective To examine temporal, geographic, and sociodemographic trends in case reporting and case fatality of malaria in the United Kingdom.
Setting National malaria reference laboratory surveillance data in the UK.
Design Observational study using prospectively gathered surveillance data and data on destinations from the international passenger survey.
Participants 39 300 cases of proved malaria in the UK between 1987 and 2006.
Main outcome measures Plasmodium species; sociodemographic details (including age, sex, and country of birth and residence); mortality; destination, duration, and purpose of international travel; and use of chemoprophylaxis.
Results Reported cases of imported malaria increased significantly over the 20 years of the study; an increasing proportion was attributable to Plasmodium falciparum (P falciparum/P vivax reporting ratio 1.3:1 in 1987-91 and 5.4:1 in 2002-6). P vivax reports declined from 3954 in 1987-91 to 1244 in 2002-6. Case fatality of reported P falciparum malaria did not change over this period (7.4 deaths per 1000 reported cases). Travellers visiting friends and relatives, usually in a country in Africa or Asia from which members of their family migrated, accounted for 13 215/20 488 (64.5%) of all malaria reported, and reports were geographically concentrated in areas where migrants from Africa and South Asia to the UK have settled. People travelling for this purpose were at significantly higher risk of malaria than other travellers and were less likely to report the use of any chemoprophylaxis (odds ratio of reported chemoprophylaxis use 0.23, 95% confidence interval 0.21 to 0.25).
Conclusions Despite the availability of highly effective preventive measures, the preventable burden from falciparum malaria has steadily increased in the UK while vivax malaria has decreased. Provision of targeted and appropriately delivered preventive messages and services for travellers from migrant families visiting friends and relatives should be a priority.
doi:10.1136/bmj.a120
PMCID: PMC2453297  PMID: 18599471
19.  Impact of rapid screening tests on acquisition of meticillin resistant Staphylococcus aureus: cluster randomised crossover trial 
BMJ : British Medical Journal  2008;336(7650):927-930.
Objective To determine whether introducing a rapid test for meticillin resistant Staphylococcus aureus (MRSA) screening leads to a reduction in MRSA acquisition on hospital general wards.
Design Cluster randomised crossover trial.
Setting Medical, surgical, elderly care, and oncology wards of a London teaching hospital on two sites.
Main outcome measure MRSA acquisition rate (proportion of patients negative for MRSA who became MRSA positive).
Participants All patients admitted to the study wards who were MRSA negative on admission and screened for MRSA on discharge.
Intervention Rapid polymerase chain reaction based screening test for MRSA compared with conventional culture.
Results Of 9608 patients admitted to study wards, 8374 met entry criteria and 6888 had full data (82.3%); 3335 in the control arm and 3553 in the rapid test arm. The overall MRSA carriage rate on admission was 6.7%. Rapid tests led to a reduction in median reporting time from admission, from 46 to 22 hours (P<0.001). Rapid testing also reduced the number of inappropriate pre-emptive isolation days between the control and intervention arms (399 v 277, P<0.001). This was not seen in other measurements of resource use. MRSA was acquired by 108 (3.2%) patients in the control arm and 99 (2.8%) in the intervention arm. When predefined confounding factors were taken into account the adjusted odds ratio was 0.91 (95% confidence interval 0.61 to 1.234). Rates of MRSA transmission, wound infection, and bacteraemia were not statistically different between the two arms.
Conclusion A rapid test for MRSA led to the quick receipt of results and had an impact on bed usage. No evidence was found of a significant reduction in MRSA acquisition and on these data it is unlikely that the increased costs of rapid tests can be justified compared with alternative control measures against MRSA.
Trial registration Clinical controlled trials ISRCTN75590122.
doi:10.1136/bmj.39525.579063.BE
PMCID: PMC2335244  PMID: 18417521
20.  The impact of response to the results of diagnostic tests for malaria: cost-benefit analysis 
BMJ : British Medical Journal  2008;336(7637):202-205.
Objective Rapid diagnostic tests for malaria seem cost effective in standard analyses, but these do not take account of clinicians’ response to test results. This study tested the impact of clinicians’ response to rapid diagnostic test or microscopy results on the costs and benefits of testing at different levels of malaria transmission and in different age groups.
Design Cost-benefit analysis using a decision tree model and clinical data on the effectiveness of diagnostic tests for malaria, their costs, and clinicians’ response to test results.
Setting Tanzania.
Methods Data were obtained from a clinical trial of 2425 patients carried out in three settings of varying transmission.
Results At moderate and low levels of malaria transmission, rapid diagnostic tests were more cost beneficial than microscopy, and both more so than presumptive treatment, but only where response was consistent with test results. At the levels of prescription of antimalarial drugs to patients with negative tests that have been found in observational studies and trials, neither test methodis likely to be cost beneficial, incurring costs 10-250% higher, depending on transmission rate, than would have been the case with fully consistent responses to all test results. Microscopy becomes more cost beneficial than rapid diagnostic tests when its sensitivity under operational conditions approaches that of rapid diagnostic tests.
Conclusions Improving diagnostic methods, including rapid diagnostic tests, can reduce costs and enhance the benefits of effective antimalarial drugs, but only if the consistency of response to test results is also improved. Investing in methods to improve rational response to tests is essential. Economic evaluations of diagnostic tests should take into account whether clinicians’ response is consistent with test results.
doi:10.1136/bmj.39395.696065.47
PMCID: PMC2213875  PMID: 18199700
21.  Imported malaria and high risk groups: observational study using UK surveillance data 1987-2006 
Objective To examine temporal, geographic, and sociodemographic trends in case reporting and case fatality of malaria in the United Kingdom.
Setting National malaria reference laboratory surveillance data in the UK.
Design Observational study using prospectively gathered surveillance data and data on destinations from the international passenger survey.
Participants 39 300 cases of proved malaria in the UK between 1987 and 2006.
Main outcome measures Plasmodium species; sociodemographic details (including age, sex, and country of birth and residence); mortality; destination, duration, and purpose of international travel; and use of chemoprophylaxis.
Results Reported cases of imported malaria increased significantly over the 20 years of the study; an increasing proportion was attributable to Plasmodium falciparum (P falciparum/P vivax reporting ratio 1.3:1 in 1987-91 and 5.4:1 in 2002-6). P vivax reports declined from 3954 in 1987-91 to 1244 in 2002-6. Case fatality of reported P falciparum malaria did not change over this period (7.4 deaths per 1000 reported cases). Travellers visiting friends and relatives, usually in a country in Africa or Asia from which members of their family migrated, accounted for 13 215/20 488 (64.5%) of all malaria reported, and reports were geographically concentrated in areas where migrants from Africa and South Asia to the UK have settled. People travelling for this purpose were at significantly higher risk of malaria than other travellers and were less likely to report the use of any chemoprophylaxis (odds ratio of reported chemoprophylaxis use 0.23, 95% confidence interval 0.21 to 0.25).
Conclusions Despite the availability of highly effective preventive measures, the preventable burden from falciparum malaria has steadily increased in the UK while vivax malaria has decreased. Provision of targeted and appropriately delivered preventive messages and services for travellers from migrant families visiting friends and relatives should be a priority.
doi:10.1136/bmj.a120
PMCID: PMC2453297  PMID: 18599471
22.  Rapid diagnostic tests compared with malaria microscopy for guiding outpatient treatment of febrile illness in Tanzania: randomised trial 
BMJ : British Medical Journal  2007;334(7590):403.
Objective To compare rapid diagnostic tests (RDTs) for malaria with routine microscopy in guiding treatment decisions for febrile patients.
Design Randomised trial.
Setting Outpatient departments in northeast Tanzania at varying levels of malaria transmission.
Participants 2416 patients for whom a malaria test was requested.
Intervention Staff received training on rapid diagnostic tests; patients sent for malaria tests were randomised to rapid diagnostic test or routine microscopy
Main outcome measure Proportion of patients with a negative test prescribed an antimalarial drug.
Results Of 7589 outpatient consultations, 2425 (32%) had a malaria test requested. Of 1204 patients randomised to microscopy, 1030 (86%) tested negative for malaria; 523 (51%) of these were treated with an antimalarial drug. Of 1193 patients randomised to rapid diagnostic test, 1005 (84%) tested negative; 540 (54%) of these were treated for malaria (odds ratio 1.13, 95% confidence interval 0.95 to 1.34; P=0.18). Children aged under 5 with negative rapid diagnostic tests were more likely to be prescribed an antimalarial drug than were those with negative slides (P=0.003). Patients with a negative test by any method were more likely to be prescribed an antibiotic (odds ratio 6.42, 4.72 to 8.75; P<0.001). More than 90% of prescriptions for antimalarial drugs in low-moderate transmission settings were for patients for whom a test requested by a clinician was negative for malaria.
Conclusions Although many cases of malaria are missed outside the formal sector, within it malaria is massively over-diagnosed. This threatens the sustainability of deployment of artemisinin combination treatment, and treatable bacterial diseases are likely to be missed. Use of rapid diagnostic tests, with basic training for clinical staff, did not in itself lead to any reduction in over-treatment for malaria. Interventions to improve clinicians' management of febrile illness are essential but will not be easy.
Trial registration Clinical trials NCT00146796.
doi:10.1136/bmj.39073.496829.AE
PMCID: PMC1804187  PMID: 17259188
23.  Severe malaria in children in Yemen: two site observational study 
BMJ : British Medical Journal  2006;333(7573):827.
Objectives To assess the burden of malaria on health services, describe the clinical presentation of severe malaria in children, and identify factors associated with mortality by means of a prospective observational study.
Setting Two public hospitals in Taiz (mountain hinterland) and Hodeidah (coastal plain), Yemen.
Participants Children aged 6 months to 10 years.
Results Of 12 301 paediatric admissions, 2071 (17%) were for suspected severe malaria. The proportion of such admissions varied according to the season (from 1% to 40%). Falciparum malaria was confirmed in 1332 children; 808 had severe disease as defined by the World Health Organization. Main presentations were respiratory distress (322/808, 40%), severe anaemia (291/800, 37%), and cerebral malaria (60/808, 8%). Twenty two of 26 children who died had a neurological presentation. No deaths occurred in children with severe anaemia but no other signs of severity. In multivariate analysis, a Blantyre coma score ≤ 2, history of fits, female sex, and hyperlactataemia predicted mortality; severe anaemia, respiratory distress, and hyperparasitaemia were not significant predictors of mortality.
Conclusions Severe malaria puts a high burden on health services in Yemen. Although presentation is similar to African series, some important differences exist. Case fatality is higher in girls.
doi:10.1136/bmj.38959.368819.BE
PMCID: PMC1618439  PMID: 17053235
24.  Cost-Effectiveness Study of Three Antimalarial Drug Combinations in Tanzania 
PLoS Medicine  2006;3(10):e373.
Background
As a result of rising levels of drug resistance to conventional monotherapy, the World Health Organization (WHO) and other international organisations have recommended that malaria endemic countries move to combination therapy, ideally with artemisinin-based combinations (ACTs). Cost is a major barrier to deployment. There is little evidence from field trials on the cost-effectiveness of these new combinations.
Methods and Findings
An economic evaluation of drug combinations was designed around a randomised effectiveness trial of combinations recommended by the WHO, used to treat Tanzanian children with non-severe slide-proven malaria. Drug combinations were: amodiaquine (AQ), AQ with sulfadoxine-pyrimethamine (AQ+SP), AQ with artesunate (AQ+AS), and artemether-lumefantrine (AL) in a six-dose regimen. Effectiveness was measured in terms of resource savings and cases of malaria averted (based on parasitological failure rates at days 14 and 28). All costs to providers and to patients and their families were estimated and uncertain variables were subjected to univariate sensitivity analysis. Incremental analysis comparing each combination to monotherapy (AQ) revealed that from a societal perspective AL was most cost-effective at day 14. At day 28 the difference between AL and AQ+AS was negligible; both resulted in a gross savings of approximately US$1.70 or a net saving of US$22.40 per case averted. Varying the accuracy of diagnosis and the subsistence wage rate used to value unpaid work had a significant effect on the number of cases averted and on programme costs, respectively, but this did not change the finding that AL and AQ+AS dominate monotherapy.
Conclusions
In an area of high drug resistance, there is evidence that AL and AQ+AS are the most cost-effective drugs despite being the most expensive, because they are significantly more effective than other options and therefore reduce the need for further treatment. This is not necessarily the case in parts of Africa where recrudescence following SP and AQ treatment (and their combination) is lower so that the relative advantage of ACTs is smaller, or where diagnostic services are not accurate and as a result much of the drug goes to those who do not have malaria.
A randomised effectiveness trial of antimalarial drug combinations used to treat Tanzanian children found artemether-lumefantrine to be the most cost-effective.
Editors' Summary
Background.
For many years, malaria was treated with a course of a single drug. This type of treatment made it easy for malaria parasites to become resistant to antimalarial drugs. This is a major factor contributing to the continuing high death rate from the disease. However, although parasites can easily adapt to resist one drug, adapting to combinations of two or three drugs is much harder. Scientists have therefore developed combinations of antimalarial drugs. One component of these combinations is artemisinin—derived from a Chinese shrub. However, these combination therapies are much more expensive than the older treatments.
The regions worst affected by malaria—Africa and Asia—are also the poorest. And, in these areas, where both individual and government resources are scarce, antimalarial treatments must be cost-effective as well as clinically effective.
Why Was This Study Done?
Most of the estimated 1 million to 3 million people worldwide killed by malaria every year are young children in sub-Saharan Africa. Growing drug resistance, poor prevention programs, and a frequent inability of patients to pay for treatment mean that effective therapy is desperately needed in this part of the world. However, because of differences in drug resistance between regions, a drug combination will not work everywhere. In addition, because of low annual incomes (the average in Tanzania is US$120), heavy subsidies will probably be required to ensure that combination treatments are widely used. With several healthcare problems competing for resources, policymakers are likely to subsidize only the most cost-effective treatments. The researchers wanted to provide policymakers with information on how different combinations of malaria drugs compare in terms of costs, health effects, and cost-effectiveness, so that they can decide which treatment is best for their region.
What Did the Researchers Do and Find?
They compared three combinations that the World Health Organization recommends for countries when making the transition from single-drug therapy. The three combinations—amodiaquine (AQ) and sulfadoxine-pyrimethamine (SP); AQ and artesunate (AS); and artemether-lumefantrine (AL)—were used to treat Tanzanian children. The researchers wanted to find out how many cases of malaria each combination averted (which is also an indication of how much money it saved) and how much the treatment cost. They looked at costs and savings from the perspectives of both healthcare providers and patients.
Compared with no treatment, AL proved to be the most cost-effective; although it cost more for the provider (US$3.01 at day 28 of treatment) than the others, its effectiveness in getting rid of the parasite meant it would save the cost of future treatment. By day 28, AL had averted 382 cases of malaria compared with 279 for AQ+AS, 181 for AQ+SP, and 57 for AQ alone. Also, higher proportions of inaccurate diagnoses of malaria led to lower cost-effectiveness of treatments.
What Do These Findings Mean?
Despite being more expensive, newer drugs can be cost-effective where alternatives fail. Although AL was the most cost-effective in places (such as Tanzania) where the malaria parasites are highly resistant to SP and AQ, the picture is likely to change for other areas. In West Africa, for example, AQ resistance is lower, and AQ+SP and AQ+AS would probably be more cost-effective. And in areas where both these combinations are just as good as AL in preventing recurring disease, they would be more cost-effective than AL. However, since AQ and SP have been used singly for many years, the likelihood is that resistance to these drugs will continue to increase. Accurate diagnosis turns out to be very important for maintaining the cost-effectiveness of combination antimalarial therapies. This will be essential if they are to be incorporated as a sustainable part of local health policies. The researchers also point out that, depending on which perspective is taken (provider or patient), the cost-effectiveness of treatments differs, making it important to compare like with like.
Although investing in costly AL treatments and improving diagnostic capabilities will be a challenge for African governments that currently spend less than US$5 per person per year on healthcare, it will be necessary if they are to seriously tackle the malaria epidemic.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030373
The US enters for Disease Control and Prevention provides malaria information aimed at the general public, physicians, and health workers
The Wellcome Trust; also has malaria information for the general public and covers the science of malaria research, including a downloadable animation of the parasite's life cycle
Medicines for Malaria Venture (MMV) is a charity created to develop new antimalarial drugs through public-private partnerships
doi:10.1371/journal.pmed.0030373
PMCID: PMC1592341  PMID: 17032059

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