The usefulness of rapid diagnostic tests in the new context of low malaria transmission in zanzibar.

BACKGROUND\ud \ud We assessed if histidine-rich-protein-2 (HRP2) based rapid diagnostic test (RDT) remains an efficient tool for Plasmodium falciparum case detection among fever patients in Zanzibar and if primary health care workers continue to adhere to RDT results in the new epidemiological context of low malaria transmission. Further, we evaluated the performance of RDT within the newly adopted integrated management of childhood illness (IMCI) algorithm in Zanzibar.\ud \ud METHODS AND FINDINGS\ud \ud We enrolled 3890 patients aged ≥2 months with uncomplicated febrile illness in this health facility based observational study conducted in 12 primary health care facilities in Zanzibar, between May-July 2010. One patient had an inconclusive RDT result. Overall 121/3889 (3.1%) patients were RDT positive. The highest RDT positivity rate, 32/528 (6.1%), was found in children aged 5-14 years. RDT sensitivity and specificity against PCR was 76.5% (95% CI 69.0-83.9%) and 99.9% (95% CI 99.7-100%), and against blood smear microscopy 78.6% (95% CI 70.8-85.1%) and 99.7% (95% CI 99.6-99.9%), respectively. All RDT positive, but only 3/3768 RDT negative patients received anti-malarial treatment. Adherence to RDT results was thus 3887/3889 (99.9%). RDT performed well in the IMCI algorithm with equally high adherence among children <5 years as compared with other age groups.\ud \ud CONCLUSIONS\ud \ud The sensitivity of HRP-2 based RDT in the hands of health care workers compared with both PCR and microscopy for P. falciparum case detection was relatively low, whereas adherence to test results with anti-malarial treatment was excellent. Moreover, the results provide evidence that RDT can be reliably integrated in IMCI as a tool for improved childhood fever management. However, the relatively low RDT sensitivity highlights the need for improved quality control of RDT use in primary health care facilities, but also for more sensitive point-of-care malaria diagnostic tools in the new epidemiological context of low malaria transmission in Zanzibar.\ud \ud TRIAL REGISTRATION\ud \ud ClinicalTrials.gov NCT01002066

Rapid diagnostic tests for molecular surveillance of Plasmodium falciparum malaria -assessment of DNA extraction methods and field applicability

Background: The need for new malaria surveillance tools and strategies is critical, given improved global malaria control and regional elimination efforts. High quality Plasmodium falciparum DNA can reliably be extracted from malaria rapid diagnostic tests (RDTs). Together with highly sensitive molecular assays, wide scale collection of used RDTs may serve as a modern tool for improved malaria case detection and drug resistance surveillance. However, comparative studies of DNA extraction efficiency from RDTs and the field applicability are lacking. The aim of this study was to compare and evaluate different methods of DNA extraction from RDTs and to test the field applicability for the purpose of molecular epidemiological investigations. Methods: DNA was extracted from two RDT devices (Paracheck-PfW and SD Bioline Malaria Pf/Pan (R)), seeded in vitro with 10-fold dilutions of cultured 3D7 P. falciparum parasites diluted in malaria negative whole blood. The level of P. falciparum detection was determined for each extraction method and RDT device with multiple nested-PCR and real-time PCR assays. The field applicability was tested on 855 paired RDT (Paracheck-Pf) and filter paper (Whatman (R) 3MM) blood samples (734 RDT negative and 121 RDT positive samples) collected from febrile patients in Zanzibar 2010. RDT positive samples were genotyped at four key single nucleotide polymorphisms (SNPs) in pfmdr1 and pfcrt as well as for pfmdr1 copy number, all associated with anti-malarial drug resistance. Results: The P. falciparum DNA detection limit varied with RDT device and extraction method. Chelex-100 extraction performed best for all extraction matrixes. There was no statistically significant difference in PCR detection rates in DNA extracted from RDTs and filter paper field samples. Similarly there were no significant differences in the PCR success rates and genotyping outcomes for the respective SNPs in the 121 RDT positive samples. Conclusions: The results support RDTs as a valuable source of parasite DNA and provide evidence for RDT-DNA extraction for improved malaria case detection, molecular drug resistance surveillance, and RDT quality control.ACT Consortium through Bill and Melinda Gates Foundation; Swedish International Development Agency (SIDA) [SWE 2009-193]; Swedish Civil Contingencies Agency (MSB) [2010-7991]; Swedish Medical Research Council (VR) [2009-3785]; Goljes Foundationinfo:eu-repo/semantics/publishedVersio

Febrile Illness Management in Children under Five Years of Age: A Qualitative Pilot Study on Primary Health Care Workers' Practices in Zanzibar.

In Zanzibar, malaria prevalence dropped substantially in the last decade and presently most febrile patients seen in primary health care facilities (PHCF) test negative for malaria. The availability of rapid diagnostic tests (RDTs) allows rural health workers to reliably rule out malaria in fever patients. However, additional diagnostic tools to identify alternative fever causes are scarce, often leaving RDT-negative patients without a clear diagnosis and management plan. This pilot study aimed to explore health workers' practices with febrile children and identify factors influencing their diagnostic and management decisions in non-malarial fever patients. Semi-structured key informant interviews were conducted with 12 health workers in six PHCFs in North A district, Zanzibar, April to June 2011. Interviews were coded using Atlas.ti to identify emerging themes that play a role in the diagnosis and management of febrile children. The following themes were identified: 1) health workers use caregivers' history of illness and RDT results for initial diagnostic and management decisions, but suggest caregivers need more education to prevent late presentation and poor health outcomes; 2) there is uncertainty regarding viral versus bacterial illness and health workers feel additional point-of-care diagnostic tests would help with differential diagnoses; 3) stock-outs of medications and limited caregivers' resources are barriers to delivering good care; 4) training, short courses and participation in research as well as; 5) weather also influences diagnostic decision-making. This pilot study found that health workers in Zanzibar use caregiver history of fever and results of malaria RDTs to guide management of febrile children. However, since most febrile children test negative for malaria, health workers believe additional training and point-of-care tests would improve their ability to diagnose and manage non-malarial fevers. Educating caregivers on signs and symptoms of febrile illness, as well as the introduction of additional tests to differentiate between viral and bacterial illness, would be important steps to get children to PHCFs earlier and decrease unnecessary antibiotic prescribing without compromising patient safety. More research is needed to expand an understanding of what would improve fever management in other resource-limited settings with decreasing malaria

Accuracy of Malaria Rapid Diagnostic Tests in Community Studies and their Impact on Treatment of Malaria in an Area with Declining Malaria Burden in North-Eastern Tanzania.

Despite some problems related to accuracy and applicability of malaria rapid diagnostic tests (RDTs), they are currently the best option in areas with limited laboratory services for improving case management through parasitological diagnosis and reducing over-treatment. This study was conducted in areas with declining malaria burden to assess; 1) the accuracy of RDTs when used at different community settings, 2) the impact of using RDTs on anti-malarial dispensing by community-owned resource persons (CORPs) and 3) adherence of CORPs to treatment guidelines by providing treatment based on RDT results. Data were obtained from: 1) a longitudinal study of passive case detection of fevers using CORPs in six villages in Korogwe; and 2) cross-sectional surveys (CSS) in six villages of Korogwe and Muheza districts, north-eastern, Tanzania. Performance of RDTs was compared with microscopy as a gold standard, and factors affecting their accuracy were explored using a multivariate logistic regression model. Overall sensitivity and specificity of RDTs in the longitudinal study (of 23,793 febrile cases; 18,154 with microscopy and RDTs results) were 88.6% and 88.2%, respectively. In the CSS, the sensitivity was significantly lower (63.4%; χ2=367.7, p<0.001), while the specificity was significantly higher (94.3%; χ2=143.1, p<0.001) when compared to the longitudinal study. As determinants of sensitivity of RDTs in both studies, parasite density of<200 asexual parasites/μl was significantly associated with high risk of false negative RDTs (OR≥16.60, p<0.001), while the risk of false negative test was significantly lower among cases with fever (axillary temperature ≥37.5 °C) (OR≤0.63, p≤0.027). The risk of false positive RDT (as a determinant of specificity) was significantly higher in cases with fever compared to afebrile cases (OR≥2.40, p<0.001). Using RDTs reduced anti-malarials dispensing from 98.9% to 32.1% in cases aged ≥5 years. Although RDTs had low sensitivity and specificity, which varied widely depending on fever and parasite density, using RDTs reduced over-treatment with anti-malarials significantly. Thus, with declining malaria prevalence, RDTs will potentially identify majority of febrile cases with parasites and lead to improved management of malaria and non-malaria fevers

Antibiotic use among patients with febrile illness in a low malaria endemicity setting in Uganda

<p>Abstract</p> <p>Background</p> <p>Uganda embraced the World Health Organization guidelines that recommend a universal 'test and treat' strategy for malaria, mainly by use of rapid diagnostic test (RDT) and microscopy. However, little is known how increased parasitological diagnosis for malaria influences antibiotic treatment among patients with febrile illness.</p> <p>Methods</p> <p>Data collection was carried out within a feasibility trial of presumptive diagnosis of malaria (control) and two diagnostic interventions (microscopy or RDT) in a district of low transmission intensity. Five primary level health centres (HCs) were randomized to each diagnostic arm (diagnostic method in a defined group of patients). All 52,116 outpatients (presumptive 16,971; microscopy 17,508; and RDT 17,638) aged 5 months to ninety five years presenting with fever (by statement or measured) were included. Information from outpatients and laboratory registers was extracted weekly from March 2010 to July 2011. The proportion of patients who were prescribed antibiotics was calculated among those not tested for malaria, those who tested positive and in those who tested negative.</p> <p>Results</p> <p>Seven thousand and forty (41.5%) patients in the presumptive arm were prescribed antibiotics. Of the patients not tested for malaria, 1,537 (23.9%) in microscopy arm and 810 (56.2%) in RDT arm were prescribed antibiotics. Among patients who tested positive for malaria, 845 (25.8%) were prescribed antibiotics in the RDT and 273(17.6%) in the microscopy arm. Among patients who tested negative for malaria, 7809 (61.4%) were prescribed antibiotics in the RDT and 3749 (39.3%) in the microscopy arm. Overall the prescription of antibiotics was more common for children less than five years of age 5,388 (63%) compared to those five years and above 16798 (38.6%).</p> <p>Conclusion</p> <p>Prescription of antibiotics in patients with febrile illness is high. Testing positive for malaria reduces antibiotic treatment but testing negative for malaria increases use of antibiotics.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00565071">NCT00565071</a></p

Comparative Field Evaluation of Combinations of Long-Lasting Insecticide Treated Nets and Indoor Residual Spraying, Relative to Either Method Alone, for Malaria Prevention in an Area where the main Vector is Anopheles Arabiensis.

Long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) are commonly used together in the same households to improve malaria control despite inconsistent evidence on whether such combinations actually offer better protection than nets alone or IRS alone. Comparative tests were conducted using experimental huts fitted with LLINs, untreated nets, IRS plus untreated nets, or combinations of LLINs and IRS, in an area where Anopheles arabiensis is the predominant malaria vector species. Three LLIN types, Olyset®, PermaNet 2.0® and Icon Life® nets and three IRS treatments, pirimiphos-methyl, DDT, and lambda cyhalothrin, were used singly or in combinations. We compared, number of mosquitoes entering huts, proportion and number killed, proportions prevented from blood-feeding, time when mosquitoes exited the huts, and proportions caught exiting. The tests were done for four months in dry season and another six months in wet season, each time using new intact nets. All the net types, used with or without IRS, prevented >99% of indoor mosquito bites. Adding PermaNet 2.0® and Icon Life®, but not Olyset® nets into huts with any IRS increased mortality of malaria vectors relative to IRS alone. However, of all IRS treatments, only pirimiphos-methyl significantly increased vector mortality relative to LLINs alone, though this increase was modest. Overall, median mortality of An. arabiensis caught in huts with any of the treatments did not exceed 29%. No treatment reduced entry of the vectors into huts, except for marginal reductions due to PermaNet 2.0® nets and DDT. More than 95% of all mosquitoes were caught in exit traps rather than inside huts. Where the main malaria vector is An. arabiensis, adding IRS into houses with intact pyrethroid LLINs does not enhance house-hold level protection except where the IRS employs non-pyrethroid insecticides such as pirimiphos-methyl, which can confer modest enhancements. In contrast, adding intact bednets onto IRS enhances protection by preventing mosquito blood-feeding (even if the nets are non-insecticidal) and by slightly increasing mosquito mortality (in case of LLINs). The primary mode of action of intact LLINs against An. arabiensis is clearly bite prevention rather than insecticidal activity. Therefore, where resources are limited, priority should be to ensure that everyone at risk consistently uses LLINs and that the nets are regularly replaced before being excessively torn. Measures that maximize bite prevention (e.g. proper net sizes to effectively cover sleeping spaces, stronger net fibres that resist tears and burns and net use practices that preserve net longevity), should be emphasized

"Test and treat" or presumptive treatment for malaria in high transmission situations? A reflection on the latest WHO guidelines

Recent WHO guidelines recommend a universal "test and treat" strategy for malaria, mainly by use of rapid diagnostic test (RDT) in all areas. The evidence for this approach is questioned here as there is a risk of over-reliance on parasitological diagnosis in high transmission situations, which still exist. In such areas, when a patient has fever or other malaria symptoms, the presence of Plasmodium spp neither reliably confirms malaria as the cause of the fever, nor excludes the possibility of other diseases. This is because the patient may be an asymptomatic carrier of malaria parasites and suffer from another disease

Prevalence of Malaria Parasitemia and Purchase of Artemisinin-Based Combination Therapies (ACTs) among Drug Shop Clients in Two Regions in Tanzania with ACT Subsidies.

Throughout Africa, many people seek care for malaria in private-sector drug shops where diagnostic testing is often unavailable. Recently, subsidized artemisinin-based combination therapies (ACTs), a first-line medication for uncomplicated malaria, were made available in these drug shops in Tanzania. This study assessed the prevalence of malaria among and purchase of ACTs by drug shop clients in the setting of a national ACT subsidy program and sub-national drug shop accreditation program. A cross-sectional survey of drug shop clients was performed in two regions in Tanzania, one with a government drug shop accreditation program and one without, from March-May, 2012. Drug shops were randomly sampled from non-urban districts. Shop attendants were interviewed about their education, training, and accreditation status. Clients were interviewed about their symptoms and medication purchases, then underwent a limited physical examination and laboratory testing for malaria. Malaria prevalence and predictors of ACT purchase were assessed using univariate analysis and multiple logistic regression. Amongst 777 clients from 73 drug shops, the prevalence of laboratory-confirmed malaria was 12% (95% CI: 6-18%). Less than a third of clients with malaria had purchased ACTs, and less than a quarter of clients who purchased ACTs tested positive for malaria. Clients were more likely to have purchased ACTs if the participant was <5 years old (aOR: 6.6; 95% CI: 3.9-11.0) or the shop attendant had >5 years, experience (aOR: 2.8; 95% CI: 1.2-6.3). Having malaria was only a predictor of ACT purchase in the region with a drug shop accreditation program (aOR: 3.4; 95% CI: 1.5-7.4).\ud Malaria is common amongst persons presenting to drug shops with a complaint of fever. The low proportion of persons with malaria purchasing ACTs, and the high proportion of ACTs going to persons without malaria demonstrates a need to better target who receives ACTs in these drug shops

Diagnostic Testing of Pediatric Fevers: Meta-Analysis of 13 National Surveys Assessing Influences of Malaria Endemicity and Source of Care on Test Uptake for Febrile Children under Five Years.

In 2010, the World Health Organization revised guidelines to recommend diagnosis of all suspected malaria cases prior to treatment. There has been no systematic assessment of malaria test uptake for pediatric fevers at the population level as countries start implementing guidelines. We examined test use for pediatric fevers in relation to malaria endemicity and treatment-seeking behavior in multiple sub-Saharan African countries in initial years of implementation. We compiled data from national population-based surveys reporting fever prevalence, care-seeking and diagnostic use for children under five years in 13 sub-Saharan African countries in 2009-2011/12 (n = 105,791). Mixed-effects logistic regression models quantified the influence of source of care and malaria endemicity on test use after adjusting for socioeconomic covariates. Results were stratified by malaria endemicity categories: low (PfPR2-10<5%), moderate (PfPR2-10 5-40%), high (PfPR2-10>40%). Among febrile under-fives surveyed, 16.9% (95% CI: 11.8%-21.9%) were tested. Compared to hospitals, febrile children attending non-hospital sources (OR: 0.62, 95% CI: 0.56-0.69) and community health workers (OR: 0.31, 95% CI: 0.23-0.43) were less often tested. Febrile children in high-risk areas had reduced odds of testing compared to low-risk settings (OR: 0.51, 95% CI: 0.42-0.62). Febrile children in least poor households were more often tested than in poorest (OR: 1.63, 95% CI: 1.39-1.91), as were children with better-educated mothers compared to least educated (OR: 1.33, 95% CI: 1.16-1.54). Diagnostic testing of pediatric fevers was low and inequitable at the outset of new guidelines. Greater testing is needed at lower or less formal sources where pediatric fevers are commonly managed, particularly to reach the poorest. Lower test uptake in high-risk settings merits further investigation given potential implications for diagnostic scale-up in these areas. Findings could inform continued implementation of new guidelines to improve access to and equity in point-of-care diagnostics use for pediatric fevers