Reducing Stock-Outs of Life Saving Malaria Commodities Using Mobile Phone Text-Messaging: SMS for Life Study in Kenya

Background

Health facility stock-outs of life saving malaria medicines are common across Africa. Innovative ways of addressing this problem are urgently required. We evaluated whether SMS based reporting of stocks of artemether-lumefantrine (AL) and rapid diagnostic tests (RDT) can result in reduction of stock-outs at peripheral facilities in Kenya.

Methods/Findings

All 87 public health facilities in five Kenyan districts were included in a 26 week project. Weekly facility stock counts of four AL packs and RDTs were sent via structured incentivized SMS communication process from health workers’ personal mobile phones to a web-based system accessed by district managers. The mean health facility response rate was 97% with a mean formatting error rate of 3%. Accuracy of stock count reports was 79% while accuracy of stock-out reports was 93%. District managers accessed the system 1,037 times at an average of eight times per week. The system was accessed in 82% of the study weeks. Comparing weeks 1 and 26, stock-out of one or more AL packs declined by 38 percentage-points. Total AL stock-out declined by 5 percentage-points and was eliminated by the end of the project. Stock-out declines of individual AL packs ranged from 14 to 32 percentage-points while decline in RDT stock-outs was 24 percentage-points. District managers responded to 44% of AL and 73% of RDT stock-out signals by redistributing commodities between facilities. In comparison with national trends, stock-out declines in study areas were greater, sharper and more sustained.

Conclusions

Use of simple SMS technology ensured high reporting rates of reasonably accurate, real-time facility stock data that were used by district managers to undertake corrective actions to reduce stock-outs. Future work on stock monitoring via SMS should focus on assessing response rates without use of incentives and demonstrating effectiveness of such interventions on a larger scale.     

Using community-owned resource persons to provide early diagnosis and treatment and estimate malaria burden at community level in north-eastern Tanzania

ABSTRACT: BACKGROUND: Although early diagnosis and prompt treatment is an important strategy for control of malaria, using fever to initiate presumptive treatment with expensive artemisinin combination therapy is a major challenge; particularly in areas with declining burden of malaria. This study was conducted using community-owned resource persons (CORPs) to provide early diagnosis and treatment of malaria, and collect data for estimation of malaria burden in four villages of Korogwe district, north-eastern Tanzania. METHODS: In 2006, individuals with history of fever within 24 hours or fever (axillary temperature [greater than or equal to]37.5degreesC) at presentation were presumptively treated using sulphadoxine/pyrimethamine. Between 2007 and 2010, individuals aged five years and above, with positive rapid diagnostic tests (RDTs) were treated with artemether/lumefantrine (AL) while under-fives were treated irrespective of RDT results. Reduction in anti-malarial consumption was determined by comparing the number of cases that would have been presumptively treated and those that were actually treated based on RDTs results. Trends of malaria incidence and slide positivity rates were compared between lowlands and highlands. RESULTS: Of 15,729 cases attended, slide positivity rate was 20.4% and declined by >72.0% from 2008, reaching <10.0% from 2009 onwards; and the slide positivity rates were similar in lowlands and highlands from 2009 onwards. Cases with fever at presentation declined slightly, but remained at >40.0% in under-fives and >20.0% among individuals aged five years and above. With use of RDTs, cases treated with AL decreased from <58.0% in 2007 to <11.0% in 2010 and the numbers of adult courses saved were 3,284 and 1,591 in lowlands and highlands respectively. Malaria incidence declined consistently from 2008 onwards; and the highest incidence of malaria shifted from children aged <10 years to individuals aged 10-19 years from 2009. CONCLUSIONS: With basic training, supervision and RDTs, CORPs successfully provided early diagnosis and treatment and reduced consumption of anti-malarials. Progressively declining malaria incidence and slide positivity rates suggest that all fever cases should be tested with RDTs before treatment. Data collected by CORPs was used to plan phase 1b MSP3 malaria vaccine trial and will be used for monitoring and evaluation of different health interventions. The current situation indicates that there is a remarkable changing pattern of malaria and these areas might be moving from control to pre-elimination levels.     

Diagnosing Severe Falciparum Malaria in Parasitaemic African Children: A Prospective Evaluation of Plasma PfHRP2 Measurement

Background

In African children, distinguishing severe falciparum malaria from other severe febrile illnesses with coincidental Plasmodium falciparum parasitaemia is a major challenge. P. falciparum histidine-rich protein 2 (PfHRP2) is released by mature sequestered parasites and can be used to estimate the total parasite burden. We investigated the prognostic significance of plasma PfHRP2 and used it to estimate the malaria-attributable fraction in African children diagnosed with severe malaria.

Methods and Findings

Admission plasma PfHRP2 was measured prospectively in African children (from Mozambique, The Gambia, Kenya, Tanzania, Uganda, Rwanda, and the Democratic Republic of the Congo) aged 1 month to 15 years with severe febrile illness and a positive P. falciparum lactate dehydrogenase (pLDH)-based rapid test in a clinical trial comparing parenteral artesunate versus quinine (the AQUAMAT trial, ISRCTN 50258054). In 3,826 severely ill children, Plasmadium falciparum PfHRP2 was higher in patients with coma (p = 0.0209), acidosis (p<0.0001), and severe anaemia (p<0.0001). Admission geometric mean (95%CI) plasma PfHRP2 was 1,611 (1,350–1,922) ng/mL in fatal cases (n = 381) versus 1,046 (991–1,104) ng/mL in survivors (n = 3,445, p<0.0001), without differences in parasitaemia as assessed by microscopy. There was a U-shaped association between log₁₀ plasma PfHRP2 and risk of death. Mortality increased 20% per log₁₀ increase in PfHRP2 above 174 ng/mL (adjusted odds ratio [AOR] 1.21, 95%CI 1.05–1.39, p = 0.009). A mechanistic model assuming a PfHRP2-independent risk of death in non-malaria illness closely fitted the observed data and showed malaria-attributable mortality less than 50% with plasma PfHRP2≤174 ng/mL. The odds ratio (OR) for death in artesunate versus quinine-treated patients was 0.61 (95%CI 0.44–0.83, p = 0.0018) in the highest PfHRP2 tertile, whereas there was no difference in the lowest tertile (OR 1.05; 95%CI 0.69–1.61; p = 0.82). A limitation of the study is that some conclusions are drawn from a mechanistic model, which is inherently dependent on certain assumptions. However, a sensitivity analysis of the model indicated that the results were robust to a plausible range of parameter estimates. Further studies are needed to validate our findings.

Conclusions

Plasma PfHRP2 has prognostic significance in African children with severe falciparum malaria and provides a tool to stratify the risk of “true” severe malaria-attributable disease as opposed to other severe illnesses in parasitaemic African children. Please see later in the article for the Editors'' Summary.     

Rapid Assessment of Malaria Transmission Using Age-Specific Sero-Conversion Rates

Background

Malaria transmission intensity is a crucial determinant of malarial disease burden and its measurement can help to define health priorities. Rapid, local estimates of transmission are required to focus resources better but current entomological and parasitological methods for estimating transmission intensity are limited in this respect. An alternative is determination of antimalarial antibody age-specific sero-prevalence to estimate sero-conversion rates (SCR), which have been shown to correlate with transmission intensity. This study evaluated SCR generated from samples collected from health facility attendees as a tool for a rapid assessment of malaria transmission intensity.

Methodology and Principal Findings

The study was conducted in north east Tanzania. Antibodies to Plasmodium falciparum merozoite antigens MSP-1₁₉ and AMA-1 were measured by indirect ELISA. Age-specific antibody prevalence was analysed using a catalytic conversion model based on maximum likelihood to generate SCR. A pilot study, conducted near Moshi, found SCRs for AMA-1 were highly comparable between samples collected from individuals in a conventional cross-sectional survey and those collected from attendees at a local health facility. For the main study, 3885 individuals attending village health facilities in Korogwe and Same districts were recruited. Both malaria parasite prevalence and sero-positivity were higher in Korogwe than in Same. MSP-1₁₉ and AMA-1 SCR rates for Korogwe villages ranged from 0.03 to 0.06 and 0.07 to 0.21 respectively. In Same district there was evidence of a recent reduction in transmission, with SCR among those born since 1998 [MSP-1₁₉ 0.002 to 0.008 and AMA-1 0.005 to 0.014 ] being 5 to 10 fold lower than among individuals born prior to 1998 [MSP-1₁₉ 0.02 to 0.04 and AMA-1 0.04 to 0.13]. Current health facility specific estimates of SCR showed good correlations with malaria incidence rates in infants in a contemporaneous clinical trial (MSP-1₁₉ r² = 0.78, p<0.01 & AMA-1 r² = 0.91, p<0.001).

Conclusions

SCRs generated from age-specific anti-malarial antibody prevalence data collected via health facility surveys were robust and credible. Analysis of SCR allowed detection of a recent drop in malaria transmission in line with recent data from other areas in the region. This health facility-based approach represents a potential tool for rapid assessment of recent trends in malaria transmission intensity, generating valuable data for local and national malaria control programs to target, monitor and evaluate their control strategies.     

Toussaintines A-E: antimicrobial indolidinoids, a cinnamoylhydrobenzofuranoid and a cinnamoylcyclohexenoid from Toussaintia orientalis leaves

Toussaintine A (N-cinnamoyl-5,6-dehydro-4-hydroxyindolidin-2,7-dione), toussaintine B (N-cinnamoyl-5,6-dehydro-4,7-dihydroxyindolidin-2-one), toussaintine C (N-cinnamoyl-5,6-dehydro-4-hydroxyindolidin-7-one), toussaintine D (N-cinnamoyl-2-amino-4-hydroxy-7-oxo-2,3,8,9-tetrahydrobenzofuran) and toussaintine E (N-cinnamoyl-1-acetoxymethyl-2-amino-1-hydroxycyclox-5-en-4-one) were isolated as antibacterial and antifungal constituents of the leaves of Toussaintia orientalis Verdc. (Annonaceae) and their structures established from analysis of spectroscopic data. The compounds belong to a series of variously cyclized aminocinnamoyl tetraketide derivatives, showing the importance of rarely occurring Annonaceae species as sources of structurally diverse natural products.     

IgG responses to Anopheles gambiae salivary antigen gSG6 detect variation in exposure to malaria vectors and disease risk

Assessment of exposure to malaria vectors is important to our understanding of spatial and temporal variations in disease transmission and facilitates the targeting and evaluation of control efforts. Recently, an immunogenic Anopheles gambiae salivary protein (gSG6) was identified and proposed as the basis of an immuno-assay determining exposure to Afrotropical malaria vectors. In the present study, IgG responses to gSG6 and 6 malaria antigens (CSP, AMA-1, MSP-1, MSP-3, GLURP R1, and GLURP R2) were compared to Anopheles exposure and malaria incidence in a cohort of children from Korogwe district, Tanzania, an area of moderate and heterogeneous malaria transmission. Anti-gSG6 responses above the threshold for seropositivity were detected in 15% (96/636) of the children, and were positively associated with geographical variations in Anopheles exposure (OR 1.25, CI 1.01-1.54, p?=?0.04). Additionally, IgG responses to gSG6 in individual children showed a strong positive association with household level mosquito exposure. IgG levels for all antigens except AMA-1 were associated with the frequency of malaria episodes following sampling. gSG6 seropositivity was strongly positively associated with subsequent malaria incidence (test for trend p?=?0.004), comparable to malaria antigens MSP-1 and GLURP R2. Our results show that the gSG6 assay is sensitive to micro-epidemiological variations in exposure to Anopheles mosquitoes, and provides a correlate of malaria risk that is unrelated to immune protection. While the technique requires further evaluation in a range of malaria endemic settings, our findings suggest that the gSG6 assay may have a role in the evaluation and planning of targeted and preventative anti-malaria interventions.     

Safety of the malaria vaccine candidate, RTS,S/AS01E in 5 to 17 month old Kenyan and Tanzanian Children

The malaria vaccine candidate, RTS,S/AS01(E), showed promising protective efficacy in a trial of Kenyan and Tanzanian children aged 5 to 17 months. Here we report on the vaccine's safety and tolerability. The experimental design was a Phase 2b, two-centre, double-blind (observer- and participant-blind), randomised (1∶1 ratio) controlled trial. Three doses of study or control (rabies) vaccines were administered intramuscularly at 1 month intervals. Solicited adverse events (AEs) were collected for 7 days after each vaccination. There was surveillance and reporting for unsolicited adverse events for 30 days after each vaccination. Serious adverse events (SAEs) were recorded throughout the study period which lasted for 14 months after dose 1 in Korogwe, Tanzania and an average of 18 months post-dose 1 in Kilifi, Kenya. Blood samples for safety monitoring of haematological, renal and hepatic functions were taken at baseline, 3, 10 and 14 months after dose 1. A total of 894 children received RTS,S/AS01(E) or rabies vaccine between March and August 2007. Overall, children vaccinated with RTS,S/AS01(E) had fewer SAEs (51/447) than children in the control group (88/447). One SAE episode in a RTS,S/AS01(E) recipient and nine episodes among eight rabies vaccine recipients met the criteria for severe malaria. Unsolicited AEs were reported in 78% of subjects in the RTS,S/AS01(E) group and 74% of subjects in the rabies vaccine group. In both vaccine groups, gastroenteritis and pneumonia were the most frequently reported unsolicited AE. Fever was the most frequently observed solicited AE and was recorded after 11% of RTS,S/AS01(E) doses compared to 31% of doses of rabies vaccine. The candidate vaccine RTS,S/AS01(E) showed an acceptable safety profile in children living in a malaria-endemic area in East Africa. More data on the safety of RTS,S/AS01(E) will become available from the Phase 3 programme.     

Sequence variation does not confound the measurement of plasma PfHRP2 concentration in African children presenting with severe malaria

ABSTRACT: BACKGROUND: Plasmodium falciparum histidine-rich protein PFHRP2 measurement is used widely for diagnosis, and more recently for severity assessment in falciparum malaria. The Pfhrp2 gene is highly polymorphic, with deletion of the entire gene reported in both laboratory and field isolates. These issues potentially confound the interpretation of PFHRP2 measurements. METHODS: Studies designed to detect deletion of Pfhrp2 and its paralog Pfhrp3 were undertaken with samples from patients in seven countries contributing to the largest hospital-based severe malaria trial (AQUAMAT). The quantitative relationship between sequence polymorphism and PFHRP2 plasma concentration was examined in samples from selected sites in Mozambique and Tanzania. RESULTS: There was no evidence for deletion of either Pfhrp2 or Pfhrp3 in the 77 samples with lowest PFHRP2 plasma concentrations across the seven countries. Pfhrp2 sequence diversity was very high with no haplotypes shared among 66 samples sequenced. There was no correlation between Pfhrp2 sequence length or repeat type and PFHRP2 plasma concentration. CONCLUSIONS: These findings indicate that sequence polymorphism is not a significant cause of variation in PFHRP2 concentration in plasma samples from African children. This justifies the further development of plasma PFHRP2 concentration as a method for assessing African children who may have severe falciparum malaria. The data also add to the existing evidence base supporting the use of rapid diagnostic tests based on PFHRP2 detection.     

High Resistance of Plasmodium falciparum to Sulphadoxine/Pyrimethamine in Northern Tanzania and the Emergence of dhps Resistance Mutation at Codon 581

Background

Sulphadoxine-pyrimethamine (SP) a widely used treatment for uncomplicated malaria and recommended for intermittent preventive treatment of malaria in pregnancy, is being investigated for intermittent preventive treatment of malaria in infants (IPTi). High levels of drug resistance to SP have been reported from north-eastern Tanzania associated with mutations in parasite genes. This study compared the in vivo efficacy of SP in symptomatic 6–59 month children with uncomplicated malaria and in asymptomatic 2–10 month old infants.

Methodology and Principal Findings

An open label single arm (SP) standard 28 day in vivo WHO antimalarial efficacy protocol was used in 6 to 59 months old symptomatic children and a modified protocol used in 2 to 10 months old asymptomatic infants. Enrolment was stopped early (87 in the symptomatic and 25 in the asymptomatic studies) due to the high failure rate. Molecular markers were examined for recrudescence, re-infection and markers of drug resistance and a review of literature of studies looking for the 581G dhps mutation was carried out. In symptomatic children PCR-corrected early treatment failure was 38.8% (95% CI 26.8–50.8) and total failures by day 28 were 82.2% (95% CI 72.5–92.0). There was no significant difference in treatment failures between asymptomatic and symptomatic children. 96% of samples carried parasites with mutations at codons 51, 59 and 108 in the dhfr gene and 63% carried a double mutation at codons 437 and 540. 55% carried a third mutation with the addition of a mutation at codon 581 in the dhps gene. This triple: triple haplotype maybe associated with earlier treatment failure.

Conclusion

In northern Tanzania SP is a failed drug for treatment and its utility for prophylaxis is doubtful. The study found a new combination of parasite mutations that maybe associated with increased and earlier failure.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00361114","term_id":"NCT00361114"}}NCT00361114     

Effect of scheduled antimicrobial and nicotinamide treatment on linear growth in children in rural Tanzania: A factorial randomized,double-blind,placebo-controlled trial

BackgroundStunting among children in low-resource settings is associated with enteric pathogen carriage and micronutrient deficiencies. Our goal was to test whether administration of scheduled antimicrobials and daily nicotinamide improved linear growth in a region with a high prevalence of stunting and enteric pathogen carriage.Methods and findingsWe performed a randomized, 2 × 2 factorial, double-blind, placebo-controlled trial in the area around Haydom, Tanzania. Mother–child dyads were enrolled by age 14 days and followed with monthly home visits and every 3-month anthropometry assessments through 18 months. Those randomized to the antimicrobial arm received 2 medications (versus corresponding placebos): azithromycin (single dose of 20 mg/kg) at months 6, 9, 12, and 15 and nitazoxanide (3-day course of 100 mg twice daily) at months 12 and 15. Those randomized to nicotinamide arm received daily nicotinamide to the mother (250 mg pills months 0 to 6) and to the child (100 mg sachets months 6 to 18). Primary outcome was length-for-age z-score (LAZ) at 18 months in the modified intention-to-treat group. Between September 5, 2017 and August 31, 2018, 1,188 children were randomized, of whom 1,084 (n = 277 placebo/placebo, 273 antimicrobial/placebo, 274 placebo/nicotinamide, and 260 antimicrobial/nicotinamide) were included in the modified intention-to-treat analysis. The study was suspended for a 3-month period by the Tanzanian National Institute for Medical Research (NIMR) because of concerns related to the timing of laboratory testing and the total number of serious adverse events (SAEs); this resulted in some participants receiving their final study assessment late. There was a high prevalence of stunting overall (533/1,084, 49.2%). Mean 18-month LAZ did not differ between groups for either intervention (mean LAZ with 95% confidence interval [CI]: antimicrobial: −2.05 CI −2.13, −1.96, placebo: −2.05 CI −2.14, −1.97; mean difference: 0.01 CI −0.13, 0.11, p = 0.91; nicotinamide: −2.06 CI −2.13, −1.95, placebo: −2.04 CI −2.14, −1.98, mean difference 0.03 CI −0.15, 0.09, p = 0.66). There was no difference in LAZ for either intervention after adjusting for possible confounders (baseline LAZ, age in days at 18-month measurement, ward, hospital birth, birth month, years of maternal education, socioeconomic status (SES) quartile category, sex, whether the mother was a member of the Datoga tribe, and mother’s height). Adverse events (AEs) and SAEs were overall similar between treatment groups for both the nicotinamide and antimicrobial interventions. Key limitations include the absence of laboratory measures of pathogen carriage and nicotinamide metabolism to provide context for the negative findings.ConclusionsIn this study, we observed that neither scheduled administration of azithromycin and nitazoxanide nor daily provision of nicotinamide was associated with improved growth in this resource-poor setting with a high force of enteric infections. Further research remains critical to identify interventions toward improved early childhood growth in challenging conditions.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03268902","term_id":"NCT03268902"}}NCT03268902.

In a randomized trial, Mark DeBoer and colleagues investigate the effect of antimicrobial and nicotinamide interventions on child growth.