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Thesis (M. Sc.(Microbiology)) -- University of the North, 1987 / Refer to the document

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Los genotipos de Plasmodium vivax, junto con la densidad parasitaria pueden estar relacionados al grado de severidad de la malaria. El conocimiento de esta relación puede ayudar a un mejor manejo de la enfermedad, tratamiento con drogas y elaboración de posibles vacunas. El objetivo del trabajo fue determinar el número de genotipos de Plasmodium vivax presentes en la Amazonía Peruana. Para la genotipificación se usó el gen que codifica la proteína de superficie del merozoito (MSP3 alfa) y el polimorfismo generado por secuencias repetitivas de nucleótidos (TR) encontrado en un segmento de 100 Kilobases (Kb) de Plamodium vivax “sinténico” al cromosoma 3 de Plasmodium falciparum. Se trabajó con 302 muestras de sangre de pacientes, a todas ellas se les realizó el examen de la gota gruesa y frotis para el diagnóstico y conocimiento de la densidad parasitaria, dicho diagnóstico fue confirmado por Nested PCR. A las muestras confirmadas se les realizó la genotipificación. Con el marcador MSP3 alfa se identificaron 9 genotipos, de los cuales uno de ellos se encontró asociado a severidad de la enfermedad (P7) (P<0.05, OR>1), y otro relacionado con infecciones mixtas (P9), 1/9 (11%). Para los TR se seleccionaron 9 pares de “primers” de un total de 33. Encontrándose 102 genotipos diferentes de los cuales 24/102 (24%) fueron infecciones por genotipos mixtos. El hecho que exista una inserción en el tamaño de su ADN originalmente reportado, aumenta la posibilidad que se dé la enfermedad en forma más severa. Estos resultados indicarían que poblaciones de Plasmodium vivax son altamente diversos y que infecciones por múltiples clonas se darían en la región hipoendémica de la Amazonía Peruana, las cuales podrían representar un desafío para evaluación posterior de drogas y vacunas. / Genotypes of Plasmodium vivax along with parasite density may be associated with the severity level of malaria, and knowledge of this relation can help to better understand the disease, drug treatments and the development of new vaccines. The object of this project was to determine the number of Plasmodium vivax genotypes present in the Peruvian Amazon. This genotyping utilized the gene encoding a merozoite surface protein (MSP3 alpha) and the polymorphism generated by a sequence of nucleotide repeats (TR) found in a 100 kilobases (Kb) de Plasmodium vivax syntenic chromosome 3 of Plasmodium falciparum. In this project we used 302 blood samples from patients. A blood droplet and droplet smear were obtained for the diagnostic and observation of parasite density; these results were later confirmed through Nested PCR. All samples were submitted for genotyping. Using the marker MSP3 alpha, 9 genotypes were identified, one was found associated with disease severity (P7) (P<0.05, OR>1) and other with mixed infections (P9) 1/9 (11%). For the TR, 9 pairs of primers were selected from a pool of 33 describing 102 different genotypes of which 24 (24 %) were mixed infections. Observation supported by the existence of a DNA insertion that increases the original size of the sequence, increasing the possibility that the disease become more severe. These results would indicate that populations of Plasmodium vivax are highly diverse and can result in multiple infections by different clones in hypoendemic regions such as the Peruvian Amazon, making later evaluation of drugs and vaccines more challenging.

Los genotipos de Plasmodium vivax, junto con la densidad parasitaria pueden estar relacionados al grado de severidad de la malaria. El conocimiento de esta relación puede ayudar a un mejor manejo de la enfermedad, tratamiento con drogas y elaboración de posibles vacunas. El objetivo del trabajo fue determinar el número de genotipos de Plasmodium vivax presentes en la Amazonía Peruana. Para la genotipificación se usó el gen que codifica la proteína de superficie del merozoito (MSP3 alfa) y el polimorfismo generado por secuencias repetitivas de nucleótidos (TR) encontrado en un segmento de 100 Kilobases (Kb) de Plamodium vivax “sinténico” al cromosoma 3 de Plasmodium falciparum. Se trabajó con 302 muestras de sangre de pacientes, a todas ellas se les realizó el examen de la gota gruesa y frotis para el diagnóstico y conocimiento de la densidad parasitaria, dicho diagnóstico fue confirmado por Nested PCR. A las muestras confirmadas se les realizó la genotipificación. Con el marcador MSP3 alfa se identificaron 9 genotipos, de los cuales uno de ellos se encontró asociado a severidad de la enfermedad (P7) (P<0.05, OR>1), y otro relacionado con infecciones mixtas (P9), 1/9 (11%). Para los TR se seleccionaron 9 pares de “primers” de un total de 33. Encontrándose 102 genotipos diferentes de los cuales 24/102 (24%) fueron infecciones por genotipos mixtos. El hecho que exista una inserción en el tamaño de su ADN originalmente reportado, aumenta la posibilidad que se dé la enfermedad en forma más severa. Estos resultados indicarían que poblaciones de Plasmodium vivax son altamente diversos y que infecciones por múltiples clonas se darían en la región hipoendémica de la Amazonía Peruana, las cuales podrían representar un desafío para evaluación posterior de drogas y vacunas. / Genotypes of Plasmodium vivax along with parasite density may be associated with the severity level of malaria, and knowledge of this relation can help to better understand the disease, drug treatments and the development of new vaccines. The object of this project was to determine the number of Plasmodium vivax genotypes present in the Peruvian Amazon. This genotyping utilized the gene encoding a merozoite surface protein (MSP3 alpha) and the polymorphism generated by a sequence of nucleotide repeats (TR) found in a 100 kilobases (Kb) de Plasmodium vivax syntenic chromosome 3 of Plasmodium falciparum. In this project we used 302 blood samples from patients. A blood droplet and droplet smear were obtained for the diagnostic and observation of parasite density; these results were later confirmed through Nested PCR. All samples were submitted for genotyping. Using the marker MSP3 alpha, 9 genotypes were identified, one was found associated with disease severity (P7) (P<0.05, OR>1) and other with mixed infections (P9) 1/9 (11%). For the TR, 9 pairs of primers were selected from a pool of 33 describing 102 different genotypes of which 24 (24 %) were mixed infections. Observation supported by the existence of a DNA insertion that increases the original size of the sequence, increasing the possibility that the disease become more severe. These results would indicate that populations of Plasmodium vivax are highly diverse and can result in multiple infections by different clones in hypoendemic regions such as the Peruvian Amazon, making later evaluation of drugs and vaccines more challenging. / Tesis

A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy. December 2, 2014. / Malaria is a public health problem for more than 2 billion people globally. About 219 million cases of malaria occur worldwide and 660, 000 people die, most (91%) in the African region despite decades of efforts to control the disease. Although the disease is preventable, it is life-threatening and parasitically transmitted by the bite of the female Anopheles mosquito. A deterministic mathematical model with intervention strategies is developed in order to investigate the effectiveness, optimal control and cost effectiveness of Indoor Residual Spraying (IRS), Insecticide Treated Nets (ITNs) and treatment on the transmission dynamics of malaria in Karonga District, Malawi. The effective reproduction number is analytically computed, and existence and stability conditions of the equilibria are explored. The model does not exhibit backward bifurcation. A structured questionnaire was developed, a one-toone interview with a randomly sampled set of individuals conducted to assess the knowledge level of inhabitants of Karonga district about the disease in general and their awareness and application of the intervention strategies. Applying Pontryagin’s Maximum Principle which uses both the Langragian and Hamiltonian principles with respect to a constant time dependent, we derive the necessary conditions for the optimal control of the disease. An economic evaluation of the strategies is carried out by performing a cost-effectiveness analysis to determine the most cost-effective combination of the three intervention measures. The incremental cost-effectiveness ratio (ICER) is calculated in order to compare the costs and effectiveness of all the possible combinations of the three measures. The results show that the combination of treatment, ITNs and IRS is the most cost-effective combination strategy for malaria control. Numerical simulations indicate that the prevention strategies lead to the reduction of both the mosquito population and infected human individuals. Effective treatment consolidates the prevention strategies. Thus, malaria can be eradicated by deployment of combined strategies such as vector control via ITNs and IRS complemented with timely treatment of infected people.

abstract: Malaria is a vector-borne parasitic disease affecting tropical and subtropical regions. Regardless control efforts, malaria incidence is still incredible high with 219 million clinical cases and an estimated 660,000 related deaths (WHO, 2012). In this project, different population genetic approaches were explored to characterize parasite populations. The goal was to create a framework that considered temporal and spatial changes of Plasmodium populations in malaria surveillance. This is critical in a vector borne disease in areas of low transmission where there is not accurate information of when and where a patient was infected. In this study, fragment analysis data and single nucleotide polymorphism (SNPs) from South American samples were used to characterize Plasmodium population structure, patterns of migration and gene flow, and discuss approaches to differentiate reinfection vs. recrudescence cases in clinical trials. A Bayesian approach was also applied to analyze the Plasmodium population history by inferring genealogies using microsatellites data. Specifically, fluctuations in the parasite population and the age of different parasite lineages were evaluated through time in order to relate them with the malaria control plan in force. These studies are important to understand the turnover or persistence of "clones" circulating in a specific area through time and consider them in drug efficacy studies. Moreover, this methodology is useful for assessing changes in malaria transmission and for more efficiently manage resources to deploy control measures in locations that act as parasite "sources" for other regions. Overall, these results stress the importance of monitoring malaria demographic changes when assessing the success of elimination programs in areas of low transmission. / Dissertation/Thesis / Ph.D. Microbiology 2014

Malgré les efforts nationaux et internationaux, le paludisme reste un problème de santépublique majeur dans de nombreux pays et les systèmes de santé ont des difficultés pourévaluer son poids réel, le risque de transmission des plasmodiums et leur répartitiongéographique. Pourtant, l’hétérogénéité spatiale du paludisme peut être importante et dans cecontexte de concentration du risque, la lutte contre la maladie peut gagner à être focaliséedans certains lieux et certaines périodes. D’une part, l’environnement est un déterminantmajeur de la biodiversité du paludisme à cause du caractère vectoriel de la transmission et despréférences bioécologiques des vecteurs. D’autre part, les satellites en orbite peuvent fournirdes données environnementales, climatiques et météorologiques qui ont déjà été utilisées pourl’étude de maladies infectieuses. La « télé-épidémiologie » a été définie comme une approcheintégrée visant à associer des données médicales, épidémiologiques ou entomologiques deterrain à des données environnementales obtenues par satellites, en s’appuyant sur lacompréhension et la mesure des mécanismes physiques et biologiques qui sont en jeu. Dansles villes, il a déjà été possible de mettre en évidence, en utilisant des données satellites à deséchelles appropriés, des associations entre des éléments urbains cartographiés et desindicateurs paludométriques. Chez des voyageurs, dans l’objectif d’une évaluation du risquede contracter le paludisme ou de l’efficacité de mesures prophylactiques, il serait utile depouvoir évaluer et prédire les niveaux d’exposition à la transmission dans les différenteslocalités parcourues. L’objectif général des travaux de la présente thèse était d’identifier desfacteurs environnementaux mesurables par satellite et utilisables pour l’évaluation du risquede paludisme chez les voyageurs d’une part et en milieu urbain d’autre part.Tout d’abord, des données de télédétection ont été utilisées pour évaluer les niveauxd’expositions au risque de paludisme d’une population de militaires, dans le cadre d’un travailsur l’estimation de leurs facteurs de risque d’accès palustre. Les résultats ont montré que,même en prenant en compte les facteurs de confusion de l’âge et de l’observance de lachimioprophylaxie, l’environnement était le principal facteur associé au risque de survenued’accès palustres.En parallèle, une large collecte de données entomologiques a été effectuée pendant cinq ansdans la ville de Dakar et a permis de mettre en évidence une très forte hétérogénéité spatiale ettemporelle de la transmission du paludisme dans la ville. Les informations collectées ont étécentralisées dans une base de données géoréférencée (SIG - Système d’InformationGéographique) contenant toutes les variables entomologiques, environnementales,météorologiques, biologiques et physiques relevées sur le terrain ou par satellites.Puis un travail de modélisation du risque entomologique dans la capitale du Sénégal, basé surles données collectées sur le terrain et sur des données environnementales issues d’imagessatellites a été mené. Une première étape a permis de mettre en évidence les évolutions deszones à risque de transmission et d’affirmer que le pourcentage de la population dakaroise àfort risque de transmission avait diminué entre 1996 et 2007. Une deuxième étape a conduit àl’élaboration de 1) une carte des gîtes larvaires accompagné d’un indice de productivité dansla ville de Dakar, 2) une carte des densités d’agressivité des anophèles adultes, puis 3) cescartes étaient rendues dynamiques, c'est-à-dire que les variations temporelles liées auxvariations de leurs déterminants météorologiques étaient prises en compte.Les résultats des travaux de thèse ont montré que des données de télédétection associées à unegrande quantité de données de terrain peuvent permettre l’ajustement de modèles prédictifs etla construction de cartes de risque entomologique, en milieu urbain ou pour des populationsmobiles. / Despite national an international efforts, malaria remains a major public health in manycountries and sanitary systems are hindered by the lack of information on the actual burden ofmalaria, on the plasmodium transmission risk and on their geographical distribution.Nevertheless, spatial heterogeneity can be important and in this context, malaria control couldbe improved if could be focused in place and time. On one hand, the environment is a majordeterminant of malaria biodiversity, because of the vectorial transmission and the vectorsbioecological preferences. On another hand, orbiting satellites can provide environmental,climatic and meteorological data that already have been used for the study of infectiousdiseases. “Tele-epidemiology” has been defined as an integrated approach aiming atassociating medical, epidemiological or entomological ground data, with remotely-sensedenvironmental data, based on the in depth comprehension and measurement of the involvedphysical and biological mechanisms. In cities, it has already been possible to highlightassociations between mapped urban settings and malariometric indices, using satellite data atappropriate scales. Among travellers, in the objective to evaluate malaria risk or efficacy ofprophylactic devices, it would be useful to evaluate and predict transmission levels in thevisited places. The objective of the present thesis was to identify environmental factors thatcould be remotely-sensed and that could be used in the evaluation of malaria risk amongtravellers on one hand and in urban settings on the other hand.First, remotely-sensed data have been used to evaluate levels of exposure to malaria risk ofmilitaries, in the scope of a study on their risk factors for clinical malaria. Results haveshowed that, even when taking into account age and compliance to chemoprophylaxis asconfusion factors, the environment was the factor the most strongly associated to clinicalmalaria risk.In parallel, an extensive entomological study has been conducted during five years in Dakarand allowed demonstrating a strong spatial and temporal heterogeneity of malariatransmission in the city. Collected information were centralized in a georeferenced database(GIS - Geographic Information System) containing all entomological, environmental,meteorological, biological and physical data collected on the field or by remote sensing.Finally, modelling of entomological risk in the capital city of Senegal was undertaken, basedon data collected on the ground and environmental data issued from satellites. A first stepshowed the evolution of malaria transmission risk areas and allowed declaring that thefraction of human population that was at high risk for transmission decreased between 1996and 2007. A second step led to the development of 1) a map of the breeding sites with aproductivity indicator in Dakar city, 2) a map of aggressive adult Anopheles densities, and 3)a dynamic aspect was added to those maps, taking into account the variations of theirmeteorological determinants.The results of the work undertaken in this thesis demonstrated that remotely-sensedinformation, associated with a large amount of ground data, allow to adjust predictive models and to draw entomological risk maps, in urban settings or for moving populations

Introduction: Early detection and case management remain the main strategies in malaria control programme (MCP) in a low endemic area such as in Java Island, Indonesia. These strategies require an understanding of the community’s care-seeking behaviour in relation to the various health services. Since most malaria cases in Java are diagnosed at home by the village malaria workers (VMWs), this study aimed to examine the user-provider interface in early detection and case management of malaria, particularly the interaction between the clinical malaria patients and the VMWs. Methods: The number of blood slides examined and the laboratory results over a 20-year period were retrieved from the routine malaria surveillance system. The population at risk of malaria and the rainfall data were obtained from secondary sources. In addition, age, sex, malaria species, types of drugs, drug and dosage and time lapse between slides taken and examined were recorded from the malaria registers at the three endemic health centres from 1994-1998. The quality of diagnosis was examined by re-reading 153 slides at the Faculty of Medicine, Gadjah Mada University. Prior to using rapid assessment procedures (RAP), we proposed 11 criteria and applied these to 15 published RAP studies in health. For each of the papers, two authors assessed the adequacy of information provided independently. Using the criteria as a guideline for developing a protocol, a RAP study of malaria was thereafter carried out. Data were retrieved from 38 free-listings, 28 in-depth interviews, seven focus group discussions and unstructured observation. A qualitative thematic content analysis was applied. Finally, based on the RAP results, a one-year longitudinal study of care-seeking behaviour of all clinical malaria cases treated by the VMWs was conducted in Mlonggo II area. Age, sex, daily actions and date of consultations were recorded by all VMWs in a diary that covered prior all contacts between the patients and the VMWs. Also, 24 interactions between the VMWs and the patients were audiotaped. Results: The incidence of malaria during the 1990s fluctuated, albeit at the lower level than that of the 1980s, and it reached a peak (3.5/1000 population) during an outbreak in 1996-97. There was no clear association between the El Nino phenomenon and incidence of malaria. The incidence was almost twice as high in children &lt;15 years than in adults (15+ years). In &lt;5 year old children the risk of P. vivax malaria was higher than the risk of P. falciparum. Comparisons between active and passive case detection (ACD and PCD) showed that almost 60% of 10, 493 confirmed malaria cases in Jepara were identified from ACD. ACD also detected significantly higher percentage of P. falciparum gametocyte infections than PCD (14.7% vs. 5.7%). The duration between slides taken to examination was however longer for ACD than for PCD (2.3 vs. 1.1 days). Applying the criteria to the published RAP studies, it was found that information was limited to address subjectivity, staff and ethics criteria. In Jepara, malaria (known as katisen or panas tis) was considered a common but minor illness. This was also reflected by the most common action taken by the patients, i.e. not doing anything. However, when the illness was perceived as important, the community had a good access to different health care providers. Eighty seven percent of cases had been treated by the VMWs on day four of the illness period. On day two, the proportion not treated was significantly higher in male than in female cases (60.7% and 54.6%; p 0.01) and in those &lt;15 years of age compared with those 15+ years (71.3% and 56.9%; p&lt;0.001). Insufficient understanding of malaria signs and symptoms likely leads to delay in illness recognition and treatment. Interactions between the VMWs and the patients were mostly focused on medical tasks, and low compliance with treatment was a common concern of the VMWs in the interaction. Conclusion: El Nino phenomenon was not associated with an epidemic in Jepara. A possible association between age and the risk of P. vivax malaria needs further investigation. In this decentralised health care system, ACD should be continued in a focus endemic area and therefore, efforts to retain the VMWs should be considered. This research showed similar findings between the RAP study and the longitudinal study. A consistent gap was found between the common understanding and the biomedical description of malaria. The performance of the VMWs supports the MCP through early contact with clinical malaria patients. Visits of VMWs within four days of symptom recognition appear to be the ideal situation for both the programme and the community. If case management continues to be the main strategy in MCP in this low endemic area, the emic perspective of the people must be well integrated to improve home treatment. Likewise, simple interventions to strengthen the role of VMWs in home management should be conducted.

ASIC 200: Global Issues in the Arts and Sciences.