Unravelling factors associated with malaria parasitaemia among children 6-24 months to inform malaria interventions in Nigeria: evidence from 2021 Malaria Indicator Survey.

BACKGROUND: As an additional two million malaria cases were reported in 2021 compared to the previous year, concerted efforts toward achieving a steady decline in malaria cases are needed to achieve malaria elimination goals. This work aimed at determining the factors associated with malaria parasitaemia among children 6-24 months for better targeting of malaria interventions. METHODS: A cross-sectional study analysed 2021 Nigeria Malaria Indicator Survey dataset. Data from 3058 children 6-24 months were analyzed. The outcome variable was children 6-24 months whose parasitaemia was determined using a rapid diagnostic test (RDT). Independent variables include child age in months, mothers' age, mothers' education, region, place of residence, household ownership and child use of insecticide-treated net (ITN), exposure to malaria messages and knowledge of ways to prevent malaria. Logistic regression analysis was conducted to examine possible factors associated with malaria parasitaemia in children 6-24 months. RESULTS: Findings revealed that 28.7% of the 3058 children aged 6-24 months tested positive for malaria by RDT. About 63% of children 12-17 months (aOR = 1.63, 95% CI 1.31-2.03) and 91% of children 18 to 24 months (aOR = 1.91, 95% CI 1.51-2.42) were more likely to have a positive malaria test result. Positive malaria test result was also more likely in rural areas (aOR = 1.79, 95% CI 2.02-24.46), northeast (aOR = 1.54, 95% CI 1.02-2.31) and northwest (aOR = 1.63, 95% CI 1.10-2.40) region. In addition, about 39% of children who slept under ITN had a positive malaria test result (aOR = 1.39 95% CI 1.01-1.90). While children of mothers with secondary (aOR = 0.40, 95% CI 0.29-0.56) and higher (aOR = 0.26, 95% CI 0.16-0.43) levels of education and mothers who were aware of ways of avoiding malaria (aOR = 0.69, 95% CI 0.53-0.90) were less likely to have a malaria positive test result. CONCLUSION: As older children 12 to 24 months, children residing in the rural, northeast, and northwest region are more likely to have malaria, additional intervention should target them in an effort to end malaria.

A conceptual framework on the role of backward integration in sustainable access to malaria intervention commodities in Nigeria.

BACKGROUND: Over the last two decades, global stakeholders and the Nigerian government have invested approximately $2 billion in malaria control, reducing parasite prevalence to 23% from 42% to 2010. However, there is a risk that the modest gains will be reversed due to unmet resource gaps. Backward integration is presented in this paper as a viable option for sustainable funding of malaria intervention commodities in Nigeria. METHODS: Following a critical appraisal of the resource profile and malaria expenditure, a conceptual framework on backward integration as a means of ensuring long-term supply of malaria intervention commodities was developed. The study analysed secondary annual data from the National Malaria Elimination Programme to estimate commodity needs for the period 2018-2020, as well as total resources committed and the financial gap. RESULTS: The funds needed to implement national malaria interventions from 2018 to 2020 totaled US$ 1,122,332,318, of which US$ 531,228,984 (47.3%) were funded. The Nigerian government contributed 2.5%, the Global Fund (26.7%), the President's Malaria Initiative (16.5%), and the UK Department for International Development (6.2%). The funding shortfall was $591,103,335, or 52.7% of the needs. Various funding scenarios were evaluated for their relative merits and limitations, including advocacy for more external funding, bank borrowing, increased domestic resources, and backward integration. CONCLUSIONS: The study concluded that backward integration should be used, based on a government-led public-private partnership that will increase local production of malaria intervention commodities that are accessible and affordable through market-based demand and supply arrangements.

Efficacy and safety of pyronaridine-artesunate versus artemether-lumefantrine in the treatment of acute uncomplicated malaria in children in South-West Nigeria: an open-labelled randomized controlled trial.

BACKGROUND: In Nigeria, declining responsiveness to artemether-lumefantrine (AL), the artemisinin-based combination therapy (ACT) of choice since 2005, has been reported. Pyronaridine-artesunate (PA) is a newer fixed-dose ACT recently prequalified by the WHO for the treatment of uncomplicated falciparum malaria. However, PA data from the Nigerian pediatric population is scarce. Therefore, the efficacy and safety of PA and AL using the WHO 28-day anti-malarial therapeutic efficacy study protocol in Ibadan, southwest Nigeria, were compared. METHODS: In an open-labelled, randomized, controlled clinical trial, 172 children aged 3-144 months with a history of fever and microscopically confirmed uncomplicated Plasmodium falciparum malaria were enrolled in southwest Nigeria. Enrollees were randomly assigned to receive PA or AL at standard dosages according to body weight for 3 days. Venous blood was obtained for hematology, blood chemistry, and liver function tests on days 0, 3, 7, and 28 as part of the safety evaluation. RESULTS: 165 (95.9%) of the enrolled individuals completed the study. About half (52.3%; 90/172) of enrollees were male. Eighty-seven (50.6%) received AL, while 85 (49.4%) received PA. Day 28, adequate clinical and parasitological response for PA was 92.7% [(76/82) 95% CI 83.1, 95.9] and 71.1% [(59/83) 95% CI 60.4, 79.9] for AL (0.001). Fever and parasite clearance were similar in both groups. Two of six and eight of 24 parasite recurrences were observed among PA- and AL-treated children, respectively. PCR-corrected Day-28 cure rates for PA were 97.4% (76/78) and 88.1% (59/67) for AL (= 0.04) in the per-protocol population after new infections were censored. Hematological recovery at day 28 was significantly better among PA-treated patients (34.9% 2.8) compared to those treated with AL (33.1% 3.0) (0.002). Adverse events in both treatment arms were mild and similar to the symptoms of malaria infection. Blood chemistry and liver function tests were mostly within normal limits, with an occasional marginal rise. CONCLUSION: PA and AL were well-tolerated. PA was significantly more efficacious than AL in both the PCR-uncorrected and PCR-corrected per-protocol populations during this study. The results of this study support the inclusion of PA in the anti-malarial treatment guidelines in Nigeria. RETROSPECTIVE TRIAL REGISTRATION: Clinicaltrials.gov: NCT05192265.

Anti-Gametocyte Antigen Humoral Immunity and Gametocytemia During Treatment of Uncomplicated Falciparum Malaria: A Multi-National Study.

Introduction: Understanding the human immune response to Plasmodium falciparum gametocytes and its association with gametocytemia is essential for understanding the transmission of malaria as well as progressing transmission blocking vaccine candidates. Methods: In a multi-national clinical efficacy trial of artemisinin therapies (13 sites of varying transmission over South-East Asia and Africa), we measured Immunoglobulin G (IgG) responses to recombinant P. falciparum gametocyte antigens expressed on the gametocyte plasma membrane and leading transmission blocking vaccine candidates Pfs230 (Pfs230c and Pfs230D1M) and Pfs48/45 at enrolment in 1,114 participants with clinical falciparum malaria. Mixed effects linear and logistic regression were used to determine the association between gametocyte measures (gametocytemia and gametocyte density) and antibody outcomes at enrolment. Results: Microscopy detectable gametocytemia was observed in 11% (127/1,114) of participants at enrolment, and an additional 9% (95/1,114) over the follow-up period (up to day 42) (total 20% of participants [222/1,114]). IgG levels in response to Pfs230c, Pfs48/45 and Pfs230D1M varied across study sites at enrolment (p < 0.001), as did IgG seroprevalence for anti-Pfs230c and D1M IgG (p < 0.001), but not for anti-Pfs48/45 IgG (p = 0.159). In adjusted analyses, microscopy detectable gametocytemia at enrolment was associated with an increase in the odds of IgG seropositivity to the three gametocyte antigens (Pfs230c OR [95% CI], p: 1.70 [1.10, 2.62], 0.017; Pfs48/45: 1.45 [0.85, 2.46], 0.174; Pfs230D1M: 1.70 [1.03, 2.80], 0.037), as was higher gametocyte density at enrolment (per two-fold change in gametocyte density Pfs230c OR [95% CI], p: 1.09 [1.02, 1.17], 0.008; Pfs48/45: 1.05 [0.98, 1.13], 0.185; Pfs230D1M: 1.07 [0.99, 1.14], 0.071). Conclusion: Pfs230 and Pfs48/45 antibodies are naturally immunogenic targets associated with patent gametocytemia and increasing gametocyte density across multiple malaria endemic settings, including regions with emerging artemisinin-resistant P. falciparum.

Molecular profiling of the artemisinin resistance Kelch 13 gene in Plasmodium falciparum from Nigeria.

Accurate assessment and monitoring of the Plasmodium falciparum Kelch 13 (pfk13) gene associated with artemisinin resistance is critical to understand the emergence and spread of drug-resistant parasites in malaria-endemic regions. In this study, we evaluated the genomic profile of the pfk13 gene associated with artemisinin resistance in P. falciparum in Nigerian children by targeted sequencing of the pfk13 gene. Genomic DNA was extracted from 332 dried blood (DBS) spot filter paper samples from three Nigerian States. The pfk13 gene was amplified by nested polymerase chain reaction (PCR), and amplicons were sequenced to detect known and novel polymorphisms across the gene. Consensus sequences of samples were mapped to the reference gene sequence obtained from the National Center for Biotechnology Information (NCBI). Out of the 13 single nucleotide polymorphisms (SNPs) detected in the pfk13 gene, five (F451L, N664I, V487E, V692G and Q661H) have not been reported in other endemic countries to the best of our knowledge. Three of these SNPs (V692G, N664I and Q661H) and a non-novel SNP, C469C, were consistent with late parasitological failure (LPF) in two States (Enugu and Plateau States). There was no validated mutation associated with artemisinin resistance in this study. However, a correlation of our study with in vivo and in vitro phenotypes is needed to establish the functional role of detected mutations as markers of artemisinin resistance in Nigeria. This baseline information will be essential in tracking and monitoring P. falciparum resistance to artemisinin in Nigeria.

To what extent are the antimalarial markets in African countries ready for a transition to triple artemisinin-based combination therapies?

INTRODUCTION: Triple artemisinin-based combination therapies (TACTs) are being developed as a response to artemisinin and partner drug resistance in the treatment of falciparum malaria in Southeast Asia. In African countries, where current artemisinin-based combination therapies (ACTs) are still effective, TACTs have the potential to benefit the larger community and future patients by mitigating the risk of drug resistance. This study explores the extent to which the antimalarial drug markets in African countries are ready for a transition to TACTs. METHODS: A qualitative study was conducted in Nigeria and Burkina Faso and comprised in-depth interviews (n = 68) and focus group discussions (n = 11) with key actor groups in the innovation system of antimalarial therapies. RESULTS: Evidence of ACT failure in African countries and explicit support for TACTs by the World Health Organization (WHO) and international funders were perceived important determinants for the market prospects of TACTs in Nigeria and Burkina Faso. At the country level, slow regulatory and implementation procedures were identified as potential barriers towards rapid TACTs deployment. Integrating TACTs in public sector distribution channels was considered relatively straightforward. More challenges were expected for integrating TACTs in private sector distribution channels, which are characterized by patient demand and profit motives. Finally, several affordability and acceptability issues were raised for which ACTs were suggested as a benchmark. CONCLUSION: The market prospects of TACTs in Nigeria and Burkina Faso will depend on the demonstration of the added value of TACTs over ACTs, their advocacy by the WHO, the inclusion of TACTs in financial and regulatory arrangements, and their alignment with current distribution and deployment practices. Further clinical, health-economic and feasibility studies are required to inform decision makers about the broader implications of a transition to TACTs in African counties. The recent reporting of artemisinin resistance and ACT failure in Africa might change important determinants of the market readiness for TACTs.

Geopolitical zones differentials in intermittent preventive treatment in pregnancy (IPTp) and long lasting insecticidal nets (LLIN) utilization in Nigeria.

BACKGROUND: The coverage of long lasting insecticidal nets (LLIN) and intermittent preventive treatment of malaria in pregnancy (IPTp) uptake for the prevention of malaria commonly vary by geography. Many sub-Saharan Africa (SSA) countries, including Nigeria are adopting the use of LLIN and IPTp to fight malaria. Albeit, the coverage of these interventions to prevent malaria across geographical divisions have been understudied in many countries. In this study, we aimed to explore the differentials in LLIN and IPTp uptake across Nigerian geopolitical zones. METHODS: We analyzed data from Nigeria Multiple Indicator Cluster Survey (MICS) 2016-17. The outcome variables were IPTp and LLIN uptake among women of childbearing age (15-49 years). A total sample of 24,344 women who had given birth were examined for IPTp use and 36,176 women for LLIN use. Percentages, Chi-square test and multivariable logit models plots were used to examine the geopolitical zones differentials in IPTp and LLIN utilization. Data was analyzed at 5% level of significance. RESULTS: The overall prevalence of IPTp was 76.0% in Nigeria. Moreover, there were differences across geopolitical zones: North Central (71.3%), North East (76.9%), North West (78.2%), South East (76.1%), South South (79.7%) and South West (72.4%) respectively. Furthermore, the prevalence of LLIN was 87.7%% in Nigeria. Also, there were differences across geopolitical zones: North Central (89.1%), North East (91.8%), North West (90.0%), South East (77.3%), South South (81.1%) and South West (69.8%) respectively. Women who have access to media use, married, educated and non-poor were more likely to uptake IPTp. On the other hand, rural dwellers and those with media use were more likely to use LLIN. Conversely, married, educated, non-poor and women aged 25-34 and 35+ were less likely to use LLIN. CONCLUSION: Though the utilization of IPTp and LLIN was relatively high, full coverage are yet to be achieved. There was geopolitical zones differentials in the prevalence of IPTp and LLIN in Nigeria. Promoting the utilization of IPTp and LLINs across the six geopolitical zones through intensive health education and widespread mass media campaigns will help to achieve the full scale IPTp and LLIN utilization.

Genetic diversity and population structure of Plasmodium falciparum in Nigeria: insights from microsatellite loci analysis.

BACKGROUND: Malaria remains a public health burden especially in Nigeria. To develop new malaria control and elimination strategies or refine existing ones, understanding parasite population diversity and transmission patterns is crucial. METHODS: In this study, characterization of the parasite diversity and structure of Plasmodium falciparum isolates from 633 dried blood spot samples in Nigeria was carried out using 12 microsatellite loci of P. falciparum. These microsatellite loci were amplified via semi-nested polymerase chain reaction (PCR) and fragments were analysed using population genetic tools. RESULTS: Estimates of parasite genetic diversity, such as mean number of different alleles (13.52), effective alleles (7.13), allelic richness (11.15) and expected heterozygosity (0.804), were high. Overall linkage disequilibrium was weak (0.006, P < 0.001). Parasite population structure was low (Fst: 0.008-0.105, AMOVA: 0.039). CONCLUSION: The high level of parasite genetic diversity and low population structuring in this study suggests that parasite populations circulating in Nigeria are homogenous. However, higher resolution methods, such as the 24 SNP barcode and whole genome sequencing, may capture more specific parasite genetic signatures circulating in the country. The results obtained can be used as a baseline for parasite genetic diversity and structure, aiding in the formulation of appropriate therapeutic and control strategies in Nigeria.

Outcome of vision screening by community health workers at immunization outlets in Nigeria to support access to early visual evaluation in children aged 0-2 years.

PURPOSE: Routine eye examination in early life is not the practice in most resource-limited countries. Delay in the presentation for eye problems is typical. Community health officers are often consulted by caregivers for all health problems during routine immunization and well-baby clinics in primary healthcare for children aged 0-2 years. This study evaluated the value and limitation of interview, Bruckner red reflex test, and instrument vision screener by noneye care middle-level staff of rural and urban well-baby immunization clinics, in early detection and referral for childhood eye disorders. MATERIALS AND METHODS: This was a cross-sectional study. Middle-level community health workers (CHWs) working at well-baby/immunization clinics were trained to perform vision screening using interview of caregivers, red reflex eye examination with ophthalmoscope, and instrument vision screener (Welch Allyn SPOT™ Vision Screener) without mydriatic drugs during routine immunization of children aged 0-2 years. IRB approval was obtained. RESULTS: Over a 6-month period in 2017, the CHWs screened 5609 children. Overall, 628 (11.2%) patients were referred to the tertiary child eye care unit. Referred cases included cataract, glaucoma, congenital nasolacrimal duct obstruction, ophthalmia neonatorum, retinoblastoma, and significant refractive errors. Referral from the interview of mothers was enhanced if specific questions to elicit visual function were asked. Bruckner red reflex test was more effective than instrument vision screener in the detection of cataract and life-threatening diseases such as retinoblastoma. Instrument vision screener was preferred by parents and better at detecting amblyopic risk factors. CONCLUSION: Preschool vision screening during routine immunization by primary healthcare workers in resource-limited settings was effective. Whenever instrument vision screener does not give any recommendation during screening, consider vision- or life-threatening pathology and refer.

Acute Kidney Injuries in Children with Severe Malaria: A comparative study of diagnostic criteria based on serum cystatin C and creatinine levels.

OBJECTIVES: Serum creatinine levels are often used to diagnose acute kidney injury (AKI), but may not necessarily accurately reflect changes in glomerular filtration rate (GFR). This study aimed to compare the prevalence of AKI in children with severe malaria using diagnostic criteria based on creatinine values in contrast to cystatin C. METHODS: This prospective cross-sectional study was performed between June 2016 and May 2017 at the University of Ilorin Teaching Hospital, Ilorin, Nigeria. A total of 170 children aged 0.5-14 years old with severe malaria were included. Serum cystatin C levels were determined using a particle-enhanced immunoturbidmetric assay method, while creatinine levels were measured using the Jaffe reaction. Renal function assessed using cystatin C-derived estimated GFR (eGFR) was compared to that measured using three sets of criteria based on creatinine values including the Kidney Disease: Improved Global Outcomes (KDIGO) and World Health Organization (WHO) criteria as well as an absolute creatinine cut-off value of >1.5 mg/dL. RESULTS: Mean serum cystatin C and creatinine levels were 1.77 ± 1.37 mg/L and 1.23 ± 1.80 mg/dL, respectively (P = 0.002). According to the KDIGO, WHO and absolute creatinine criteria, the frequency of AKI was 32.4%, 7.6% and 16.5%, respectively. In contrast, the incidence of AKI based on cystatin C-derived eGFR was 51.8%. Overall, the rate of detection of AKI was significantly higher using cystatin C compared to the KDIGO, WHO and absolute creatinine criteria (P = 0.003, <0.001 and <0.001, respectively). CONCLUSION: Diagnostic criteria for AKI based on creatinine values may not indicate the actual burden of disease in children with severe malaria.

Comparative outcome of overhead and total body phototherapy for treatment of severe neonatal jaundice in Nigeria.

Background: In Nigeria, neonatal jaundice is commonly treated by overhead phototherapy with neonates lying supine, often with effective exposure of less than one half of the body surface. Total body exposure in phototherapy has been in use for less than 2 years in Nigeria, but is available in only five neonatal centres.Aim: To compare the effectiveness of total body exposure (TBPE) with the conventional partial exposure (COPT) for treatment of hyperbilirubinaemia.Methods: Eleven datasets from 10 neonatal units across Nigeria were retrieved. They included neonates with severe hyperbilirubinaemia treated with TBPE using the Firefly® device (MTTS Asia) as a test group. The remainder of the patients, the controls, were treated with COPT. Any requirement for exchange blood transfusion (EBT) in either group was documented. Total serum bilirubin (TSB) >213.8 µmol/L (12.5 mg/dL) was treated as severe hyperbilirubinaemia. The efficiency of the intervention was determined according to the time taken for a severe case to be downgraded to mild at ≤213.8 µmol/L.Results: A total of 486 patients were studied, 343 controls and 143 cases. Mean (SD) postnatal age was 6 days (0.7) for cases and 5 (0.9) for controls, for gestational age (GA) in completed weeks was 36 (0.5) for cases and 37 (0.7) for controls and for birthweight was 2.7 kg (0.25) for cases and 2.7 (0.22) for controls. Mean (SD) pre-intervention TSB was 299.3 (35.7) µmol/L for cases and 327.3 (13.9) for controls. Severity downgrade day was Day 2 (0.4) for cases and Day 5 (1.1) for controls. Overall relative EBT rate was 6% for cases and 55% for controls (p= 0.0001), and early preterm relative EBT rate was 0% for cases and 68% for controls (p < 0.01).Conclusion: TBPE was quicker and safer for reduction of hyperbilirubinaemia and patients rarely required EBT. TBPE is recommended for rapid reduction of serum bilirubin levels and the reduction of treatment costs, morbidity and mortality in low- and middle-income countries.Abbreviations: EBT, exchange blood transfusion; TBPE, total body exposure technique; COPT, conventional partial exposure; TSB, total serum bilirubin; SB, serum bilirubin; NNJ, neonatal jaundice; SCNU, special care neonatal unit; LMIC, low- and middle-income countries; HIC, high-income countries; LED, light-emitting diode.

Heiner Syndrome: An uncommon cause of failure to thrive.

Heiner syndrome (HS) is a rare hypersensitivity reaction of an infant or young child to cow milk proteins. It is a disease characterised by failure to thrive, respiratory symptoms like cough, dyspnoea, wheeze and rhinitis with accompanying chest infiltrates on chest radiograph; gastrointestinal symptoms like vomiting, diarrhoea; and anaemia. The non-specific nature of the disease can result in delayed diagnosis and treatment and central to the condition is hypersensitivity to cow milk proteins. Several cases have been reported worldwide but there has been no report of this condition in Africa. We highlight the case of a sixteen week old child seen in our facility with features typical of Heiner syndrome. Clinicians should have a high index of suspicion for this condition especially in children predominantly on infant formula.

Provider and patient perceptions of malaria rapid diagnostic test use in Nigeria: a cross-sectional evaluation.

BACKGROUND: Nigeria commenced a phased programmatic deployment of rapid diagnostic tests (RDT) at the primary health care (PHC) facility levels since 2011. Despite various efforts, the national testing rate for malaria is still very low. The uptake of RDT has been variable. This study was undertaken to determine the provider and patient perceptions to RDT use at the PHC level in Nigeria with their implications for improving uptake and compliance. METHODS: A cross-sectional survey was conducted in 120 randomly selected PHCs across six states, across the six-geopolitical zones of Nigeria in January 2013. Health facility staff interviews were conducted to assess health workers (HW) perception, prescription practices and determinants of RDT use. Patient exit interviews were conducted to assess patient perception of RDT from ten patients/caregivers who met the eligibility criterion and were consecutively selected in each PHC, and to determine HW's compliance with RDT test results indirectly. Community members, each selected by their ward development committees in each Local Government Area were recruited for focus group discussion on their perceptions to RDT use. RESULTS: Health workers would use RDT results because of confidence in RDT results (95.4%) and its reduction in irrational use of artemisinin-based combination therapy (ACT) (87.2%). However, in Enugu state, RDT was not used by health workers because of the pervasive notion RDT that results were inaccurate. Among the 1207 exit interviews conducted, 549 (45.5%) had received RDT test. Compliance rate (administering ACT to positive patients and withholding ACT from negative patients) from patient exit interviews was 90.2%. Among caregivers/patients who had RDT done, over 95% knew that RDT tested for malaria, felt it was necessary and liked the test. Age of patients less than 5 years (p = 0.04) and "high" educational status (p = 0.0006) were factors influencing HW's prescription of ACT to RDT negative patients. CONCLUSION: The study demonstrated positive perception to RDT use by HW and among community members with good compliance rate among health workers at the PHC level. This positive perception should be explored in improving the current low level of malaria testing in Nigeria while addressing the influence of age on HW administration of ACT to RDT negative cases.

Status of the use and compliance with malaria rapid diagnostic tests in formal private health facilities in Nigeria.

BACKGROUND: Nigeria has the largest number of malaria-related deaths, accounting for a third of global malaria deaths. It is important that the country attains universal coverage of key malaria interventions, one of which is the policy of universal testing before treatment, which the country has recently adopted. However, there is a dearth of data on its implementation in formal private health facilities, where close to a third of the population seek health care. This study identified the level of use of malaria rapid diagnostic testing (RDT), compliance with test results and associated challenges in the formal private health facilities in Nigeria. METHODS: A cross-sectional study that involved a multi-stage, random sampling of 240 formal private health facilities from the country's six geo-political zones was conducted from July to August 2014. Data were collected using health facility records, healthcare workers' interviews and an exit survey of febrile patients seen at the facilities, in order to determine fever prevalence, level of testing of febrile patience, compliance with test results, and health workers' perceptions to RDT use. RESULTS: Data from the 201 health facilities analysed indicated a fever prevalence of 38.5% (112,521/292,430). Of the 2077 exit interviews for febrile patients, malaria testing was ordered in 73.8% (95% CI 71.7-75.7%). Among the 1270 tested, 61.8% (719/1270) were tested with microscopy and 38.2% (445/1270) with RDT. Compliance to malaria test result [administering arteminisin-based combination therapy (ACT) to positive patients and withholding ACT from negative patients] was 80.9% (95% CI 78.7-83%). Compliance was not influenced by the age of patients or type of malaria test. The health facilities have various cadres of the health workers knowledgeable on RDT with 70% knowing the meaning, while 84.5% knew what it assesses. However, there was clearly a preference for microscopy as only 20% reported performing only RDT. CONCLUSION: In formal private health facilities in Nigeria there is a high rate of malaria testing for febrile patients, high level of compliance with test results but relatively low level of RDT utilization. This calls for improved engagement of the formal private health sector with a view to achieving universal coverage targets on malaria testing.

Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: an individual patient data meta-analysis.

BACKGROUND: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up. METHODS: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive. RESULTS: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 >5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC1/2 since 2007. CONCLUSIONS: Several factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.

Genetic architecture of artemisinin-resistant Plasmodium falciparum.

We report a large multicenter genome-wide association study of Plasmodium falciparum resistance to artemisinin, the frontline antimalarial drug. Across 15 locations in Southeast Asia, we identified at least 20 mutations in kelch13 (PF3D7_1343700) affecting the encoded propeller and BTB/POZ domains, which were associated with a slow parasite clearance rate after treatment with artemisinin derivatives. Nonsynonymous polymorphisms in fd (ferredoxin), arps10 (apicoplast ribosomal protein S10), mdr2 (multidrug resistance protein 2) and crt (chloroquine resistance transporter) also showed strong associations with artemisinin resistance. Analysis of the fine structure of the parasite population showed that the fd, arps10, mdr2 and crt polymorphisms are markers of a genetic background on which kelch13 mutations are particularly likely to arise and that they correlate with the contemporary geographical boundaries and population frequencies of artemisinin resistance. These findings indicate that the risk of new resistance-causing mutations emerging is determined by specific predisposing genetic factors in the underlying parasite population.

Spread of artemisinin resistance in Plasmodium falciparum malaria.

BACKGROUND: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. METHODS: Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. RESULTS: The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. CONCLUSIONS: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.).

Malaria.

Although global morbidity and mortality have decreased substantially, malaria, a parasite infection of red blood cells, still kills roughly 2000 people per day, most of whom are children in Africa. Two factors largely account for these decreases; increased deployment of insecticide-treated bednets and increased availability of highly effective artemisinin combination treatments. In large trials, parenteral artesunate (an artemisinin derivative) reduced severe malaria mortality by 22·5% in Africa and 34·7% in Asia compared with quinine, whereas adjunctive interventions have been uniformly unsuccessful. Rapid tests have been an important addition to microscopy for malaria diagnosis. Chemopreventive strategies have been increasingly deployed in Africa, notably intermittent sulfadoxine-pyrimethamine treatment in pregnancy, and monthly amodiaquine-sulfadoxine-pyrimethamine during the rainy season months in children aged between 3 months and 5 years across the sub-Sahel. Enthusiasm for malaria elimination has resurfaced. This ambitious but laudable goal faces many challenges, including the worldwide economic downturn, difficulties in elimination of vivax malaria, development of pyrethroid resistance in some anopheline mosquitoes, and the emergence of artemisinin resistance in Plasmodium falciparum in southeast Asia. We review the epidemiology, clinical features, pathology, prevention, and treatment of malaria.

Predicting the clinical outcome of severe falciparum malaria in african children: findings from a large randomized trial.

BACKGROUND: Data from the largest randomized, controlled trial for the treatment of children hospitalized with severe malaria were used to identify such predictors of a poor outcome from severe malaria. METHODS: African children (<15 years) with severe malaria participated in a randomized comparison of parenteral artesunate and parenteral quinine in 9 African countries. Detailed clinical assessment was performed on admission. Parasite densities were assessed in a reference laboratory. Predictors of death were examined using a multivariate logistic regression model. RESULTS: Twenty indicators of disease severity were assessed, out of which 5 (base deficit, impaired consciousness, convulsions, elevated blood urea, and underlying chronic illness) were associated independently with death. Tachypnea, respiratory distress, deep breathing, shock, prostration, low pH, hyperparasitemia, severe anemia, and jaundice were statistically significant indicators of death in the univariate analysis but not in the multivariate model. Age, glucose levels, axillary temperature, parasite density, heart rate, blood pressure, and blackwater fever were not related to death in univariate models. CONCLUSIONS: Acidosis, cerebral involvement, renal impairment, and chronic illness are key independent predictors for a poor outcome in African children with severe malaria. Mortality is markedly increased in cerebral malaria combined with acidosis. Clinical Trial Registration. ISRCTN50258054.