Pattern and spatial distribution of plague in Lushoto, north-eastern Tanzania

A review of plague records from 1986 to 2002 and household interviews were carried out in the plague endemic villages to establish a pattern and spatial distribution of the disease in Lushoto district, Tanzania. Spatial data of households and village centres were collected and mapped using a hand held Global Positioning System and Geographical Information System. During the 16-year period, there were 6249 cases of plague of which 5302 (84.8%) were bubonic, 391 (6.3%) septicaemic, and 438 (7.0%) pneumonic forms. A total of 118 (1.9%) cases were not categorized. Females and individuals aged 7-18 years old were the most affected groups accounting for 54.4% (95% CI: 52.4–56.0) and 47.0% (95% CI: 45–49) of all reported cases, respectively. Most cases were found in villages at high altitudes (1700-1900m); and there was a decline in case fatality rate (CFR) in areas that experienced frequent outbreaks. Overall, there was a reduction in mean reporting time (from symptoms onset to admission) to an average of 1.35 days (95% CI: 1.30–1.40) over the years, although this remained high among adult patients (>18 years). Despite the decrease in the number of cases and CFR over the years, our findings indicate that Lushoto district experiences human plague epidemic every year; with areas at high altitudes being more prone to outbreaks. The continued presence of plague in this focus warrants further studies. Nonetheless, our findings provide a platform for development of an epidemic preparedness plan to contain future outbreaks.. Keywords: plague, epidemics, pattern, spatial distribution, Tanzania Tanzania Health Research Bulletin Vol. 9 (1) 2007: pp. 12-1

Population pharmacokinetic and pharmacodynamic properties of intramuscular quinine in Tanzanian children with severe Falciparum malaria.

Although artesunate is clearly superior, parenteral quinine is still used widely for the treatment of severe malaria. A loading-dose regimen has been recommended for 30 years but is still often not used. A population pharmacokinetic study was conducted with 75 Tanzanian children aged 4 months to 8 years with severe malaria who received quinine intramuscularly; 69 patients received a loading dose of 20 mg quinine dihydrochloride (salt)/kg of body weight. Twenty-one patients had plasma quinine concentrations detectable at baseline. A zero-order absorption model with one-compartment disposition pharmacokinetics described the data adequately. Body weight was the only significant covariate and was implemented as an allometric function on clearance and volume parameters. Population pharmacokinetic parameter estimates (and percent relative standard errors [%RSE]) of elimination clearance, central volume of distribution, and duration of zero-order absorption were 0.977 liters/h (6.50%), 16.7 liters (6.39%), and 1.42 h (21.5%), respectively, for a typical patient weighing 11 kg. Quinine exposure was reduced at lower body weights after standard weight-based dosing; there was 18% less exposure over 24 h in patients weighing 5 kg than in those weighing 25 kg. Maximum plasma concentrations after the loading dose were unaffected by body weight. There was no evidence of dose-related drug toxicity with the loading dosing regimen. Intramuscular quinine is rapidly and reliably absorbed in children with severe falciparum malaria. Based on these pharmacokinetic data, a loading dose of 20 mg salt/kg is recommended, provided that no loading dose was administered within 24 h and no routine dose was administered within 12 h of admission. (This study has been registered with Current Controlled Trials under registration number ISRCTN 50258054.)

Implementation research of a cluster randomized trial evaluating the implementation and effectiveness of intermittent preventive treatment for malaria using dihydroartemisinin-piperaquine on reducing malaria burden in school-aged children in Tanzania: methodology, challenges, and mitigation

BACKGROUND: It has been more than 20 years since the malaria epidemiologic shift to school-aged children was noted. In the meantime, school-aged children (5-15 years) have become increasingly more vulnerable with asymptomatic malaria prevalence reaching up to 70%, making them reservoirs for subsequent transmission of malaria in the endemic communities. Intermittent Preventive Treatment of malaria in schoolchildren (IPTsc) has proven to be an effective tool to shrink this reservoir. As of 3(rd) June 2022, the World Health Organization recommends IPTsc in moderate and high endemic areas. Even so, for decision-makers, the adoption of scientific research recommendations has been stifled by real-world implementation challenges. This study presents methodology, challenges faced, and mitigations used in the evaluation of the implementation of IPTsc using dihydroartemisinin-piperaquine (DP) in three councils (Handeni District Council (DC), Handeni Town Council (TC) and Kilindi DC) of Tanga Region, Tanzania so as to understand the operational feasibility and effectiveness of IPTsc on malaria parasitaemia and clinical malaria incidence. METHODS: The study deployed an effectiveness-implementation hybrid design to assess feasibility and effectiveness of IPTsc using DP, the interventional drug, against standard of care (control). Wards in the three study councils were the randomization unit (clusters). Each ward was randomized to implement IPTsc or not (control). In all wards in the IPTsc arm, DP was given to schoolchildren three times a year in four-month intervals. In each council, 24 randomly selected wards (12 per study arm, one school per ward) were chosen as representatives for intervention impact evaluation. Mixed design methods were used to assess the feasibility and acceptability of implementing IPTsc as part of a more comprehensive health package for schoolchildren. The study reimagined an existing school health programme for Neglected Tropical Diseases (NTD) control include IPTsc implementation. RESULTS: The study shows IPTsc can feasibly be implemented by integrating it into existing school health and education systems, paving the way for sustainable programme adoption in a cost-effective manner. CONCLUSIONS: Through this article other interested countries may realise a feasible plan for IPTsc implementation. Mitigation to any challenge can be customized based on local circumstances without jeopardising the gains expected from an IPTsc programme. Trial registration clinicaltrials.gov, NCT04245033. Registered 28 January 2020, https://clinicaltrials.gov/ct2/show/NCT04245033

Evaluation of a PfHRP2 and a pLDH-based Rapid Diagnostic Test for the Diagnosis of Severe Malaria in 2 Populations of African Children

This comparative study in 1898 children in 2 different African population shows that a pfHRP2-based rapid diagnostic test is a reliable diagnostic for diagnosing severe falciparum malaria in these settings and performs better than routine microscopy or a pLDH based test

Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine.

BACKGROUND: The RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the circumsporozoite protein locus. METHODS: We used polymerase chain reaction-based next-generation sequencing of DNA extracted from samples from 4985 participants to survey circumsporozoite protein polymorphisms. We evaluated the effect that polymorphic positions and haplotypic regions within the circumsporozoite protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination. RESULTS: In the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P=0.04 for differential vaccine efficacy). The vaccine efficacy based on the hazard ratio was 62.7% (95% CI, 51.6 to 71.3) against matched infections versus 54.2% (95% CI, 49.9 to 58.1) against mismatched infections (P=0.06). In the group of infants 6 to 12 weeks of age, there was no evidence of differential allele-specific vaccine efficacy. CONCLUSIONS: These results suggest that among children 5 to 17 months of age, the RTS,S vaccine has greater activity against malaria parasites with the matched circumsporozoite protein allele than against mismatched malaria. The overall vaccine efficacy in this age category will depend on the proportion of matched alleles in the local parasite population; in this trial, less than 10% of parasites had matched alleles. (Funded by the National Institutes of Health and others.)

Effect of trimethoprim-sulphamethoxazole on the risk of malaria in HIV-infected Ugandan children living in an area of widespread antifolate resistance

<p>Abstract</p> <p>Background</p> <p>Daily trimethoprim-sulfamethoxazole (TS) protects against malaria, but efficacy may be diminished as anti-folate resistance increases. This study assessed the incidence of falciparum malaria and the prevalence of resistance-conferring <it>Plasmodium falciparum </it>mutations in HIV-infected children receiving daily TS and HIV-uninfected children not taking TS.</p> <p>Materials and methods</p> <p>Subjects were 292 HIV-infected and 517 uninfected children from two cohort studies in Kampala, Uganda observed from August 2006 to December 2008. Daily TS was given to HIV-infected, but not HIV-uninfected children and all participants were provided an insecticide-treated bed net. Standardized protocols were used to measure the incidence of malaria and identify markers of antifolate resistance.</p> <p>Results</p> <p>Sixty-five episodes of falciparum malaria occurred in HIV-infected and 491 episodes in uninfected children during the observation period. TS was associated with a protective efficacy of 80% (0.10 vs. 0.45 episodes per person year, p < 0.001), and efficacy did not vary over three consecutive 9.5 month periods (81%, 74%, 80% respectively, p = 0.506). The prevalences of <it>dhfr </it>51I, 108N, and 59R and <it>dhps </it>437G and 540E mutations were each over 90% among parasites infecting both HIV-infected and uninfected children. Prevalence of the <it>dhfr </it>164L mutation, which is associated with high-level resistance, was significantly higher in parasites from HIV-infected compared to uninfected children (8% vs. 1%, p = 0.001). Sequencing of the <it>dhfr </it>and <it>dhps </it>genes identified only one additional polymorphism, <it>dhps </it>581G, in 2 of 30 samples from HIV-infected and 0 of 54 samples from uninfected children.</p> <p>Conclusion</p> <p>Despite high prevalence of known anti-folate resistance-mediating mutations, TS prophylaxis was highly effective against malaria, but was associated with presence of <it>dhfr </it>164L mutation.</p

Predicting the Clinical Outcome of Severe Falciparum Malaria in African Children: Findings From a Large Randomized Trial

Four predictors were independently associated with an increased risk of death: acidosis, cerebral manifestations of malaria, elevated blood urea nitrogen, or signs of chronic illness. The standard base deficit was found to be the single most relevant predictor of death

Assessment of severe malaria in a multicenter, phase III, RTS, S/AS01 malaria candidate vaccine trial: case definition, standardization of data collection and patient care

BACKGROUND\ud \ud An effective malaria vaccine, deployed in conjunction with other malaria interventions, is likely to substantially reduce the malaria burden. Efficacy against severe malaria will be a key driver for decisions on implementation. An initial study of an RTS, S vaccine candidate showed promising efficacy against severe malaria in children in Mozambique. Further evidence of its protective efficacy will be gained in a pivotal, multi-centre, phase III study. This paper describes the case definitions of severe malaria used in this study and the programme for standardized assessment of severe malaria according to the case definition.\ud \ud METHODS\ud \ud Case definitions of severe malaria were developed from a literature review and a consensus meeting of expert consultants and the RTS, S Clinical Trial Partnership Committee, in collaboration with the World Health Organization and the Malaria Clinical Trials Alliance. The same groups, with input from an Independent Data Monitoring Committee, developed and implemented a programme for standardized data collection.The case definitions developed reflect the typical presentations of severe malaria in African hospitals. Markers of disease severity were chosen on the basis of their association with poor outcome, occurrence in a significant proportion of cases and on an ability to standardize their measurement across research centres. For the primary case definition, one or more clinical and/or laboratory markers of disease severity have to be present, four major co-morbidities (pneumonia, meningitis, bacteraemia or gastroenteritis with severe dehydration) are excluded, and a Plasmodium falciparum parasite density threshold is introduced, in order to maximize the specificity of the case definition. Secondary case definitions allow inclusion of co-morbidities and/or allow for the presence of parasitaemia at any density. The programmatic implementation of standardized case assessment included a clinical algorithm for evaluating seriously sick children, improvements to care delivery and a robust training and evaluation programme for clinicians.\ud \ud CONCLUSIONS\ud \ud The case definition developed for the pivotal phase III RTS, S vaccine study is consistent with WHO recommendations, is locally applicable and appropriately balances sensitivity and specificity in the diagnosis of severe malaria. Processes set up to standardize severe malaria data collection will allow robust assessment of the efficacy of the RTS, S vaccine against severe malaria, strengthen local capacity and benefit patient care for subjects in the trial.\ud \ud TRIAL REGISTRATION\ud \ud Clinicaltrials.gov NCT00866619

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 NCT00361114

Intermittent Preventive Treatment for Malaria in Papua New Guinean Infants Exposed to Plasmodium falciparum and P. vivax: A Randomized Controlled Trial

A three-arm randomized trial conducted among infants in Papua New Guinea estimates the preventive effect against malaria episodes of intermittent preventive treatment, in an area where children are exposed to both falciparum and vivax malaria