Extended Malaria Parasite Clearance Time in African Children Following Artemisinincombination Therapy Enhances Transmission\ud to Anopheles Mosquitoes

Artemisinin resistance was recently shown to have spread or emerged on the Thailand/Myanmar border. Evidence is accumulating that the parasite clearance time after artemisinin-based combination therapy (ACT) is increasing in settings in Asia and Africa. It is currently unknown if an extended parasite clearance time after ACTs has consequences for the individual patient or confers a higher malaria transmission potential. 298 children in Mbita, Western Kenya, with uncomplicated falciparum malaria were randomized to artemether-lumefantrine (AL, n = 153) ordihydroartemisinin-piperaquine (DP, n = 145). Parasite carriage post-treatment was determined by microscopy and qPCR, gametocyte carriage by quantitative nucleic acid sequence based amplication. Infectiousness to mosquitoes was determined by mosquito membrane feeding assays. Both drugs were efficacious as judged by standard trial outcomes. Sub-patent residual parasitaemia on day 3 was detected by qPCR in 36.11% (95% CI 25.11 - 48.29) of children treated with AL, and in 30.16% (95% CI 19.23 - 43.02) of children treated with DP. After adjustment for age, treatment arm and enrolment parasite density, children with an extended parasite clearance time were significantly more likely to have microscopically detected recurrent parasitaemia during follow-up (Odds Ratio: 19.51, 95% CI 5.24 - 72.71, p < 0.001). Children with an extended parasite clearance time were also more likely to be infectious to mosquitoes (Odds Ratio 2.76; 95% CI 1.14 - 6.67, p = 0.02) and gave rise to a higher oocyst load in mosquitoes (Incidence Rate Ratio 2.80, 95% CI 1.49 - 5.24, p = 0.001). Our findings indicate that an extended parasite clearance time after ACTs has consequences for the individual patient and for the population at large due to higher transmission potential. The high prevalence of residual subpatent parasitaemia after treatment may be due to novel parasite genotypes with reduced drug sensitivity, inadequate population-level immunity, or the higher sensitivity of qPCR for detection of persisting parasites.\u

Epidemiological, clinical, and public health response characteristics of a large outbreak of diphtheria among the Rohingya population in Cox's Bazar, Bangladesh, 2017 to 2019: A retrospective study.

BACKGROUND: Unrest in Myanmar in August 2017 resulted in the movement of over 700,000 Rohingya refugees to overcrowded camps in Cox's Bazar, Bangladesh. A large outbreak of diphtheria subsequently began in this population. METHODS AND FINDINGS: Data were collected during mass vaccination campaigns (MVCs), contact tracing activities, and from 9 Diphtheria Treatment Centers (DTCs) operated by national and international organizations. These data were used to describe the epidemiological and clinical features and the control measures to prevent transmission, during the first 2 years of the outbreak. Between November 10, 2017 and November 9, 2019, 7,064 cases were reported: 285 (4.0%) laboratory-confirmed, 3,610 (51.1%) probable, and 3,169 (44.9%) suspected cases. The crude attack rate was 51.5 cases per 10,000 person-years, and epidemic doubling time was 4.4 days (95% confidence interval [CI] 4.2-4.7) during the exponential growth phase. The median age was 10 years (range 0-85), and 3,126 (44.3%) were male. The typical symptoms were sore throat (93.5%), fever (86.0%), pseudomembrane (34.7%), and gross cervical lymphadenopathy (GCL; 30.6%). Diphtheria antitoxin (DAT) was administered to 1,062 (89.0%) out of 1,193 eligible patients, with adverse reactions following among 229 (21.6%). There were 45 deaths (case fatality ratio [CFR] 0.6%). Household contacts for 5,702 (80.7%) of 7,064 cases were successfully traced. A total of 41,452 contacts were identified, of whom 40,364 (97.4%) consented to begin chemoprophylaxis; adherence was 55.0% (N = 22,218) at 3-day follow-up. Unvaccinated household contacts were vaccinated with 3 doses (with 4-week interval), while a booster dose was administered if the primary vaccination schedule had been completed. The proportion of contacts vaccinated was 64.7% overall. Three MVC rounds were conducted, with administrative coverage varying between 88.5% and 110.4%. Pentavalent vaccine was administered to those aged 6 weeks to 6 years, while tetanus and diphtheria (Td) vaccine was administered to those aged 7 years and older. Lack of adequate diagnostic capacity to confirm cases was the main limitation, with a majority of cases unconfirmed and the proportion of true diphtheria cases unknown. CONCLUSIONS: To our knowledge, this is the largest reported diphtheria outbreak in refugee settings. We observed that high population density, poor living conditions, and fast growth rate were associated with explosive expansion of the outbreak during the initial exponential growth phase. Three rounds of mass vaccinations targeting those aged 6 weeks to 14 years were associated with only modestly reduced transmission, and additional public health measures were necessary to end the outbreak. This outbreak has a long-lasting tail, with Rt oscillating at around 1 for an extended period. An adequate global DAT stockpile needs to be maintained. All populations must have access to health services and routine vaccination, and this access must be maintained during humanitarian crises

Micro-epidemiological structuring of Plasmodium falciparum parasite populations in regions with varying transmission intensities in Africa

Background: The first models of malaria transmission assumed a completely mixed and homogeneous population of parasites.  Recent models include spatial heterogeneity and variably mixed populations. However, there are few empiric estimates of parasite mixing with which to parametize such models. Methods: Here we genotype 276 single nucleotide polymorphisms (SNPs) in 5199 P. falciparum isolates from two Kenyan sites (Kilifi county and Rachuonyo South district) and one Gambian site (Kombo coastal districts) to determine the spatio-temporal extent of parasite mixing, and use Principal Component Analysis (PCA) and linear regression to examine the relationship between genetic relatedness and distance in space and time for parasite pairs. Results: Using 107, 177 and 82 SNPs that were successfully genotyped in 133, 1602, and 1034 parasite isolates from The Gambia, Kilifi and Rachuonyo South district, respectively, we show that there are no discrete geographically restricted parasite sub-populations, but instead we see a diffuse spatio-temporal structure to parasite genotypes.  Genetic relatedness of sample pairs is predicted by relatedness in space and time. Conclusions: Our findings suggest that targeted malaria control will benefit the surrounding community, but unfortunately also that emerging drug resistance will spread rapidly through the population

Modeling the cost effectiveness of malaria control interventions in the highlands of western Kenya

Tools that allow for in silico optimization of available malaria control strategies can assist the decision-making process for prioritizing interventions. The OpenMalaria stochastic simulation modeling platform can be applied to simulate the impact of interventions singly and in combination as implemented in Rachuonyo South District, western Kenya, to support this goal.; Combinations of malaria interventions were simulated using a previously-published, validated model of malaria epidemiology and control in the study area. An economic model of the costs of case management and malaria control interventions in Kenya was applied to simulation results and cost-effectiveness of each intervention combination compared to the corresponding simulated outputs of a scenario without interventions. Uncertainty was evaluated by varying health system and intervention delivery parameters.; The intervention strategy with the greatest simulated health impact employed long lasting insecticide treated net (LLIN) use by 80% of the population, 90% of households covered by indoor residual spraying (IRS) with deployment starting in April, and intermittent screen and treat (IST) of school children using Artemether lumefantrine (AL) with 80% coverage twice per term. However, the current malaria control strategy in the study area including LLIN use of 56% and IRS coverage of 70% was the most cost effective at reducing disability-adjusted life years (DALYs) over a five year period.; All the simulated intervention combinations can be considered cost effective in the context of available resources for health in Kenya. Increasing coverage of vector control interventions has a larger simulated impact compared to adding IST to the current implementation strategy, suggesting that transmission in the study area is not at a level to warrant replacing vector control to a school-based screen and treat program. These results have the potential to assist malaria control program managers in the study area in adding new or changing implementation of current interventions

Use of different transmission metrics to describe malaria epidemiology in the highlands of western Kenya.

Contains fulltext : 152908.pdf (publisher's version ) (Open Access

Malaria transmission after artemether-lumefantrine and dihydroartemisinin-piperaquine: a randomized trial.

BACKGROUND: Artemisinin-based combination therapy (ACT) reduces the potential for malaria transmission, compared with non-ACTs. It is unclear whether this effect differs between ACTs. METHODS: A total of 298 children (age, 6 months to 10 years) with uncomplicated falciparum malaria were randomized to artemether-lumefantrine (AL; n = 153) or dihydroartemisinin-piperaquine (DP; n = 145) in Mbita, a community in western Kenya. Gametocyte carriage was determined by molecular methods on days 0, 1, 2, 3, 7, 14, 28, and 42 after treatment initiation. The gametocyte infectiousness to mosquitoes was determined by mosquito-feeding assays on day 7 after beginning therapy. RESULTS: The cumulative risk of recurrent parasitemia on day 42 after initiation of treatment, unadjusted by polymerase chain reaction findings, was 20.7% (95% confidence interval [CI], 14.4-28.2) for AL, compared with 3.7% (95% CI, 1.2-8.5) for DP (P < .001). The mean duration of gametocyte carriage was 5.5 days (95% CI, 3.6-8.5) for AL and 15.3 days (95% CI, 9.7-24.2) for DP (P = .001). The proportion of mosquitoes that became infected after feeding on blood from AL-treated children was 1.88% (43 of 2293), compared with 3.50% (83 of 2371) for those that fed on blood from DP-treated children (P = .06); the oocyst burden among mosquitoes was lower among those that fed on blood from AL-treated children (P = .005) CONCLUSIONS: While DP was associated with a longer prophylactic time after treatment, gametocyte carriage and malaria transmission to mosquitoes was lower after AL treatment. CLINICAL TRIALS REGISTRATION: NCT00868465

Bewertung von Mensch-Maschine-Systemen Methoden und Problematik

TIB: RN 6360 (85-04) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Is asymptomatic malaria really asymptomatic? Hematological, vascular and inflammatory effects of asymptomatic malaria parasitemia

Asymptomatic malaria infections are highly prevalent in malaria endemic regions and most of these infections remain undiagnosed and untreated. Whereas conventional malaria symptoms are by definition absent, little is known on the more subtle health consequences of these infections. The aim of our study was to analyze the hematologic, vascular and inflammatory effects of patent and subpatent asymptomatic malaria parasitemia in children and adults on the Indonesian island Sumba. Both children and adults with parasitemia had increased high-sensitive C-reactive protein levels compared to aparasitemic individuals. In addition, children, but not adults with parasitemia also had lower platelet counts and Hb levels and higher levels of von Willebrand factor and platelet factor-4, markers of endothelial and platelet activation, respectively. These findings suggest that asymptomatic malaria infections have subtle health consequences, especially in children, and should be regarded as potentially harmful