A dissertation submitted to the Faculty of Medicine, Universlty of the Witwatersrand, in partial fulfilment of the requirements for the degree of Master of Medicine in the branch of Haematology. / Despite the efforts, for more than twenty years, to control malaria, the incidence of this disease still appears to be escalating globally. At the Chris Hani/Baragwanath Hospital, data analysis of malaria admissions between January 1994 to December 1996 showed an increasing trend from year to year. The main objective of the study was to try and provide some insight into this increasing rate of malaria at the ChrisHani/Baragwanath Hospital. The study was structured into two main parts: a retrospective analysis which concentrated on malaria admissions between and including January 1994 and March 1994, and a prospective analysis interviewing and examining all the malaria cases that were diagnosed between and including January 1995 and March 1995. Both aspects of the study assessed the patients socioeconomically, haematologically and immunologically. A detailed travel,medical and drug history was taken through the aid of a questionnaire. Two hundred and sixty-three patients (175 male and 88 female), of which 35% (91/263) were children (< 13 years old), were diagnosed with malaria. The clinical and laboratory presentations were consistent with other studies. The prevalence of complicated disease however was less than what has been described in the literature; cerebral malaria (as defined by Warrell, 1982) was documented in 1% of patients, hypoglycaemia (glucose < 2.2 mmol/l) and renal failure (creatinine > 265 umol/l) accounted for 5% and 3% of the cases respectively. In contrast to this 32% had features of liver dysfunction, however it appeared that haemolysis was the main contributing factor to the liver derangement. The most common infecting species was Plasmodium falciparum, alone (91.3% of the patients) or part of a mixed infection with either P. vivax or P.ovale (3.8% of patients). More than 88% of the infections were contracted in other African, mainly southern African countries, the most important of which was neighbouring Mozambique (58%). About 11% were contracted in endemic areas of South Africa i.e Northern Province, Mpumalanga and Kwazulu Natal. Twelve percent of cases (24/203) gave a history of previous malaria, The underlying immune status of these patients was analyzed using the Indirect Fluorescence Antibody Test (IFAT) and compared with the total study group. The test did not reveal any striking differences between the two groups. The previously exposed patients however did demonstrate a much lower parasitaemia, with 71% (17/24) of cases presenting with a parasite density <_;1%. These results may indicate the ability of these patients to clear their parasitaemias earlier due to previous sensitization, with the subsequent establishment of a low grade chronic infection. Seven of 88 women admitted had a documented pregnancy at the time of diagnosis. Foetal death was recorded in 517 cases which confirms the poor prognosis in pregnancy associated malaria infection, reported by other authors. Fifteen patients (13 adults and 2 children) required admission into the intensive care unit. Indications included high parasite loads, > 5% (67%) and renal failure, creatinine> 265 umol/l (33%). Standard chemotherapy was administered to all the patients with the most frequently used being quinine (94% of cases), alone or in combination with other drugs. The use of prophylactic agents for the prevention ofmalaria was restricted to twelve patients (8%), with the majority of individuals being ignorant about( malaria and therefore being unaware that any medication along with other preventative measures, were necessary prior to entering , and while staying in an endemic region. It was also apparent that the correct dosage was not adhered to as none of the patients completed their antimalarial course after returning from the malaria area. The most commonly used prophylactic drugs were chloroquine, alone or in combination with proguanil and pyrimethamine plus dapsone (Maloprim), The latter is no longer recommended routinely as a prophylactic agent. Following univariate analysis using Fisher's exact test and the student t-test, and a multivariate: nalysis (using a logistic regression model), hyperparasitaemia (p=O.0070) and renal failure (p=O.0016) were identified as significant predictors of poor outcome. Significant differences were also demonstrated in the mean WCC and the mean HB levels between the survivors versus the patients that died, indicating that a significantly elevated WCC and an anaemia at presentation, may be important risk factors towards the establishment of severe/complicated infection. The overall mortality rate was 3%. Climatic data (which was limited to the Johannesburg area), together with evidence that the malaria bearing Anopheles vector does not exist in Gauteng suggests that the conditions in the city may not be suitable for local transmission of malaria during the summer. It therefore appears that all efforts need to be channeled into the education of our travelers who visit malaria endemic regions and upon returning succumb to 'imported' malaria. Perhaps the education of the traveler alone is not sufficient, and medical personnel who diagnose the condition and who prescribe prophylactic agents need to revise their knowledge of this life threatening infection, so that their advice and drug therapies are optimal and effective. Lastly the pharmaceutical companies that manufacture these drugs might be persuaded to make their products more affordable for those individuals who are most at risk. We need to utilize our limited options to the fullest until such a time as the ultimate challenge is realised - an effective malaria vaccine. / Andrew Chakane 2018

Despite the efforts, for more than twenty years, to control malaria, the incidence of this disease still appeal's to be escalating globally. At the Chris Hani/Baragwanath Hospital, data analysis of malaria admissions between January 1994 to December 1996 showed an increasing trend from year to year. The main objective of the study was to try and provide some insight into this increasing rate of malaria at the Chris Hani/Baragwanath Hospital. The study was structured into two main parts: a retrospective analysis which concentrated on malaria admissions between and including January 1994 and March 15)94, and a prospective analysis interviewing and examining all the malaria cases that were diagnosed between and including January 1995 and March 1995. Both aspects of the study assessed the patients socioeconomically, haematologicaliy and immunologicailly. A detailed travel,medicai and drug history was taken through the aid of a questionnaire. Two hundred and sixty-three patients (175 male and 88 female), of which 35% (91/263) were children (< 13 years old), were diagnosed with malaria. The clinical and laboratory presentations were consistent with other studies. The prevalence of complicated disease however was less than what has been described in the literature; cerebral malaria (as defined by Warrell, 1982) was documented in 1% of patients, hypoglycaemia (glucose < 2.2 mmol/1) and renal failure (creatinine > 265 pnol/1) accounted for 5% and 3% of the cases respectively. In contrast to this 32% had features of liver dysfunction, however it appeared that haemolysis was the main contributing factor to the liver derangement. The most common infecting species was Plasmodium falciparum, alone (91.3% of the patients) or part of a mixed infection with either P.vivax or P.ovale (3.8% of patients). More than 88% of the infections were contracted in other African, mainly southern African countries, the most important of which was neighbouring Mozambique (58%). About 11% were contracted in endemic areas of South Africa i.e Northern Province, Mpumalanga and Kwazulu Natal. Twelve percent of cases (24/203) gave a history of previous malaria. The underlying immune status of these patients was analyzed using the Indirect Fluorescence Antibody Test (IFAT) and compared with the total study group. The test did not reveal any striking differences between the two groups. The previously exposed patients however did demonstrate a much lower parasitaemia, with 71% (17/24) of cases presenting with a parasite density <1% . These results may indicate the ability of these patients to clear their parasitaemias earlier due to previous sensitization, with the subsequent establishment of a low grade chronic infection. Seven of 88 women admitted had a documented pregnancy at the time of diagnosis. Foetal death was recorded in 5/7 cases which confirms the poor prognosis in pregnancy associated malaria infection, reported b / other authors. Fifteen patients (13 adults and 2 children) required admission into the intensive care unit. Indications included high parasite loads, > 5% (67%) and renal failure, creatinine > 265 p.mol/1 (33%). Standard chemotherapy was administered to all the patients with the most frequently used being quinine (94% of cases), alone or in combination with other drugs. The use of prophylactic agents for the prevention of malaria was restricted to twelve patients (8%), with the majority of individuals being ignorant about malaria and therefore being unaware that any medication along with other preventative measures, were necessary prior to entering , and while staying in an endemic region. It was also apparent that the correct dosage was not adhered to as none of the patients completed their antimalarial course after returning from the malaria area. The most commonly used prophylactic drugs were chloroquine, alone or in combination with proguanil and pyrimethamine plus dapsone (Maloprim). The latter is no longer recommended routinely as a prophylactic agent. Following univariate analysis using Fisher’s exact test and the student t-test, and a multivariate analysis (using a logistic regression model), hyperparasitaemia (p=0.0070) and renal failure (p=0.0016) were identified as significant predictors of poor outcome. Significant differences were also demonstrated in the mean WCC and the mean HB levels between the survivors versus the patients that died, indicating that a significantly elevated WCC and an anaemia at presentation, may be important risk factors towards the establishment of severe/complicated infection. The overall mortality rate was 3%. Climatic data (which was limited to the Johannesburg area), together with evidence that the malaria bearing Anopheles vector does not exist in Gauteng suggests that the conditions in the city may not be suitable for local transmission of malaria during the summer. It therefore appears that all efforts need to be channeled into the education of our travelers who visit malaria endemic regions and upon returning succumb to ‘imported’ malaria. Perhaps the education of the traveler alone is not sufficient, and medical personnel who diagnose the condition and who prescribe prophylactic agents need to revise their knowledge o f this life threatening infection, so that their advice and drug therapies are optimal and effective. Lastly the pharmaceutical companies that manufacture these drugs might be persuaded to make their products more affordable for those individuals who are most at risk. We need to utilize our limited options to the fullest until such a time as the ultimate challenge is realised - an effective malaria vaccine.

No description available.

No description available.

Malaria remains one of the most devastating vector-borne parasitic diseases in tropical and subtropical regions. Approximately 40% of the world’s population lives in malaria endemic areas mostly in developing countries. The estimated global incidence is about 225 million cases and 80% of these cases occur in sub-Saharan Africa. The approximated global deaths due to malaria every year is about 700,000 people and 90% occur in Africa. In South Africa, parts of Mpumalanga, Limpopo and KwaZulu-Natal have endemic malaria. The incidence of malaria in South Africa by province is 56, 2 cases per 100,000 population at risk; 31,1 cases per 100,000 population at risk and 3,3 cases per 100,000 population at risk for Mpumalanga; Limpopo and KwaZulu-Natal, respectively. Approximately 80% of the cases are imported from malaria endemic countries and diagnosed in the South African health facilities. It is therefore important that these cases are disentangled from local cases using environmental or climatic conditions as proxy measures especially in light of South Africa eradication goal. Methodology Secondary data used in this study were obtained from Mpumalanga Department of Health, South African Weather Services, Statistics South Africa and Global Climatic Research Units. These data were analysed from 2001 to 2010 to determine the correlation between surrounding climatic or environmental conditions and malaria incidence in Mpumalanga Province. The Pearson correlation was used to assess for significant correlations between malaria incidence and environmental or climatic conditions. A negative binomial regression model was used to identify and quantify factors significantly association with malaria risk. The Kulldorff spatial and space-time scan statistic was used to detect significant clustering of malaria cases in space and space-time. Results The incidence of malaria has decreased significantly since 2001 to 2010 in Mpumalanga Province. The decline has been observed from 1,304 cases per 100,000 population at risk in 2001 to less than 200 cases per 100,000 population at risk in 2010. About 96% of malaria cases were reported from Ehlanzeni District and less than 4% were reported from Gert Sibande and Nkangala Districts. The temperature, rainfall and humidity were statistically significant in all months from all years (p<0.05). The temperature, rainfall and humidity had a significant positive correlation with malaria cases. An excess of 1,752 and 104 malaria cases were detected in May and June over time when using weather stations data. When using remote sensed data, an excess of 1,131; 3,036; 4,009; 994 and 235 cases were observed from March, April, May, June and July, respectively. Discussion and conclusion The significant positive correlations between malaria cases and temperature, rainfall and humidity suggested that for an increase in each unit factor, malaria cases also increases. The excess number of cases observed especially during the winter season, suggested the likelihood of the importation of those cases. These results were in accordance with results from previous studies.

Plasmodium vivax is the most geographically widespread of the human malarias and is capable of causing severe debilitating disease. The parasite’s unique biology poses challenges to control of the disease and the understanding of its epidemiology. It is less researched and well understood than the more deadly P. falciparum. In this thesis, spatial relapse patterns and models of endemicity and clinical disease were applied to generate robust estimates of the P. vivax burden to address a key knowledge gap in malaria epidemiology. First, a review of the distribution of the parasite, its vectors and populations at risk found nearly one third of the global population living at risk, and more potential vectors than P. falciparum. In spite of low observed endemicity, the public health impact of P. vivax is likely to have been seriously underestimated in the past. To accurately define the burden of P. vivax it was necessary to improve understanding of one of the parasite’s most unique and challenging aspects, its ability to relapse. A meta-analysis of individual records of relapse showed that relapse periodicity varied systematically by geographic region and could be categorized by nine global regions. The nine regions were applied to a model to quantify the relationship between prevalence of infection and incidence of clinical disease. As relapse would have an influence on both measures, separate relationships were drawn for each relapse zone. The prevalence-incidence model was used to translate maps of predicted endemicity into measures of clinical burden. The evidence-base of P. vivax prevalence was poor in some regions and therefore a burden estimate based on surveillance reports was also derived. Reported cases must be adjusted for parameters such as under-reporting and treatment-seeking behaviours. A model used to fill gaps in treatment-seeking data available from national household surveys was developed to allow burden to be estimated using both cartographic modelling and surveillance reporting methods. To improve fidelity, the results of the two approaches were combined to enumerate P. vivax burden globally. The results and conclusions of these studies are discussed with recommendations for how these findings influence our understanding of P. vivax epidemiology and implications for future control and elimination efforts.

A Thesis Submitted to the Faculty of Health Sciences, University of the Witwatersrand in partial fulfilment of the requirements for the Degree of Master of Science in Epidemiology Major Area-Subject: Biostatistics and Epidemiology November 2014 / Background: Malaria is a serious public health challenge in sub-Saharan Africa with children under five being the most vulnerable, and a child dies every 30 seconds from it. Therefore, it is important to investigate malaria’s direct and indirect determinants in specific sub-Saharan populations as well as identifying malaria hotspots in order to have informed and targeted preventative interventions. Rationale: Given the extent and seriousness of malaria in Southern Africa, understanding fully the factors associated with malaria is important in successfully fighting it. Therefore, understanding the determinants of malaria in children under five is important in working towards eliminating malaria in sub-Saharan populations. Objectives: This study’s objectives were:  To describe demographic, behavioral and environmental determinants (factors) associated with malaria episodes in under fives in households in Malawi in the year 2012  To investigate the determinants of malaria episodes in children under five years in Malawi in 2012  To compare spatial distribution of malaria episodes in households in Malawi in 2012. Methods: This study was a secondary data analysis based on data from the Malawi 2012 Malaria Indicator Survey (MIS) obtained from Demographic and Health Survey (DHS) program website. The outcome variable was positive blood smear result for malaria in children less than five years, after an initial positive rapid malaria diagnostic test done at the homestead. We controlled for confounders after propensity score matching in order to reduce selection bias. Cases and controls were matched based on their propensity scores. Statistical modelling was done using logistic regression as well as generalized structural equation modeling (G-SEM) to model direct and indirect effects on the outcome. Poisson regression was done to determine associations between the outcome (positive blood smear malaria result) and selected explanatory variables at household level and we then introduced a structured and unstructured random effect to measure spatial effects if any of malaria morbidity in children under the age of five. Results: The matched data had 1 325 children with 367 (24.3%) having blood smear positive malaria. Female children made up approximately 53% of the total study participants. Child related variables (age, haemoglobin and position in household) as well as wealth index were significant (directly and indirectly) with p values <0.001. Socio-economic status (SES) [Odds ratio (OR) = 0.96, 95% Confidence interval (CI) = 0.92, 0.99] and primary level of education [OR = 0.50, 95%CI = 0.32, 0.77] were important determinants. The spatially structured effects accounted for more than 90% of random effects as these had a mean of 1.32 (95% Credible Interval (CI) =0.37, 2.50) whilst spatially unstructured had a mean of 0.10(CI=9.0x10-4, 0.38). The spatially adjusted significant variables on malaria morbidity were; type of place of residence (Urban or Rural) [posterior odds ratio (POR) =2.06; CI = 1.27, 3.34], not owning land [RR=1.77; CI= 1.19, 2.64], not staying in a slum [RR=0.52; CI= 0.33, 0.83] and enhanced vegetation index [RR=0.02; CI= 0.00, 1.08]. A trend was observed on usage of insecticide treated mosquito nets [POR=0.80; CI= 0.63, 1.03]. Conclusion: Socio-economic status (directly and indirectly) and education are important factors that influence malaria control. The study showed malaria as a disease of poverty with significant results in slum, type of place of residence as well as ownership of land. It is important that these factors be taken into consideration when planning malaria control programs in order to have effective programs. Direct and indirect effect modelling can also provide an alternative modelling technique that incorporates indirect effects that might not be of significance when modeled directly. This will help in improving malaria control. Enhanced vegetation index was also an important factor in malaria morbidity but precipitation and temperature suitability index were not significant factors.

Nearly half of the world's population lives in tropical and temperate climates where they may be at risk from one or more vector borne diseases. Approximately 2.1 billion people, living in more than 100 countries are at risk from malaria. While the malaria situation has improved in some places, the overall prevalence in Africa, Asia and the Americas continues to deteriorate. This has led nations, institutions, organisations and agencies including the World Health Organisation to call for development of new and innovative approaches to its surveillance and control. In nature, maintenance of malaria transmission involves a complex interaction between the mosquito vector, the human host, the disease organism, and both the internal and external environments. An understanding of this complex relationship is the key to the prevention, control and eventual eradication of malaria. Malaria prevention and control programmes do not only have to be based on sound knowledge of how these factors interrelate, but also on an application of the political will of the concerned authorities. This study attempts to identify some determinants of malaria and to characterise it in epidemiological zones in Zambia. The study aims at contributing to the body of knowledge that would support implementation of an evidence-based national malaria programme. This study has come at an opportune time when there is renewed focus on malaria prevention and control globally. It is hoped that these aspects of the malaria programme in Zambia will not have to be rewritten in the foreseeable future, instead will be improved upon in order to progress to the delivery of quality assured malaria services as close to the family as possible based on the principles of community-health partnerships. The study is presented in a series of chapters; each developed as a follow up to the previous one and forms a bridge to the next. In this way, it enables the reader to build a relatively complete picture of the malaria situation in the country. However, some repetitions could not be avoided with regard to descriptions of study sites. In the chapters dealing with health systems and quantification of malaria risk, the country (Zambia) is taken as the study site. The remaining sections are based on specific sites, selected on the basis of their representing different aspects of the malaria situation in the country. Mapping of households and other referral points provided the basis upon which a Malaria Information System would in future be built. One of the two study sites was special because most of the previously conducted malaria research in Zambia has been conducted at this site. While the other was not only new in terms of malaria research, it also represented locations in the high rainfall zone in Zambia. The introductory chapter sets out the general principles of Geographical Information System (GIS), malariology, entomology, and health systems. The chapter reviews the current global burden of malaria including its implications for economic development of endemic subSaharan African countries, and discusses progress made in the light of drug and insecticide resistance and the changing global weather patterns. This section examines the position of the African continent in relation to the global malaria eradication era and the possible reasons why it was excluded from the global malaria eradication campaign of 1956-1969. It goes on to analyse new obstacles being faced in rejuvenating global interest in malaria programmes, starting with Primary Health Care through to the principles of Roll Back Malaria (RBM). It also emphasizes special Africa-specific initiatives related to malaria, such as the MARA/ARMA collaboration which (through the use of GIS) is providing a basis for evidence-based decision making. The fist chapter deals with the historical aspects of malaria control in Zambia. It traces how malaria was successfully controlled over a period of 46 years. It starts with a rural set up where copper mineral deposits were discovered. From there it traces the history of malaria control spanning almost eight decades to the present day. It outlines the major milestones in both the malaria programme and in the political history of the country; from a British protectorate , through Federation to the present day nation, Zambia. The chapter demonstrates how malaria can be controlled in an intense transmission situation, using a combination of simple and relatively cost-effective interventions. It also demonstrates that political will is an essential element to disease control. The second chapter examines the role of health systems in the delivery of quality, efficient and cost-effective services to the population. It examines the adequacy of health services in the light of time-limited Roll Back Malaria goals, according to the Abuja Declaration of 2000. This chapter analyses the capacity of the local health system to deliver on its health vision of taking quality assured health services (Malaria services) as close to the family as possible. Together, these goals are examined in terms of population accessing the facilities within 30 minutes' walking distance. Chapter three focuses on identifying factors that facilitate or hinder households acquiring and using Insecticide Treated Nets (ITNs) in the same locality. Specifically, distance of households to some reference points is examined. Also the effects of social, economic and educational status of heads of households are analysed. Together all parameters are analysed statistically to isolate the important reasons why some homes acquire ITNs while others do not. The study concludes with an analysis of the importance of ITN s in averting malaria among users. Some anecdotal evidence resented on the value of ITN s in reducing malaria incidence in the general population is presented. GIS is employed in the fourth chapter to produce a malaria endemicity risk map for the country. It employs population Plasmodjum faldparum infection rates. It proposes stratification and compares it with existing expert opinions and the climate-based Fuzzy Logic predictive model. The resultant malaria risk map is verified against existing maps and expert opinions. The chapter then discusses application for local decision making on policy and action. Chapter number five is dedicated to identifying and studying the bionomics of malaria vectors at two sites. It reviews existing literature on this subject, from 1929 to date. It identifies possible malaria vectors, their behaviour and ecology at two sites representing two extreme situations of malaria endemicity in the country. The combination of Anopheles vector densities and their reliance on temperature and rainfall are analysed and the implications discussed. The chapter also looks at possible ways forward for the country in the light of the paucity of information in this respect. P. faldparum infection rates are estimated together with their entomological inoculation rates and possible implications for malaria transmission potential. The final section (chapter six), highlights the major lessons and their implications for global goals and local health policies. It also outlines the way forward chapter by chapter. / Thesis (Ph.D.)-University of Natal, Durban, 2003.

Doctor of Philosophy / Department of Geography / Douglas G. Goodin / The malaria burden has decreased in Nepal between 1988 and 2013. However, there are challenges to completely eradicating the disease. Malaria patterns in a few endemic districts have not changed, and higher malaria case rates have been detected within districts which otherwise were categorized as low endemic areas. Underlying biophysical, socioeconomic, and behavioral factors influence malaria transmission and create region-specific patterns. This research employs various concepts, tools, and techniques to understand the geographic distribution of malaria in Nepal. In this research, malaria prevalence patterns were investigated at multiple spatial and temporal scales. The study identifies malaria hot spots, describes their characteristics and examines shifts in malaria hot spots between 1988 and 2013. Within that 26-year time span, 267,121 confirmed malaria cases were recorded. Thirty-nine of 75 districts were identified as malaria hot spots in Nepal. Based on the frequency, persistence and proportion of caseloads each year, the identified hotspots were grouped into five categories; stable, disappearing, emerging, reemerging, and intermittent. The research also investigated the relationship between climatic factors and malaria frequency, and found that temperature and precipitation during the monsoon and non-monsoon seasons played significant roles in determining the absence and presence of malaria and low and high frequency of malaria distribution at the district level. The dissertation also presents the findings of a study that investigated malaria–related knowledge, perceptions and practices among adults in Nepal, specifically knowledge about its signs, symptoms, consequences, and the availability and use of prevention tools. Although a significant portion of respondents had heard of malaria there was wide variation in their knowledge about specific information related to the disease. Locality, age, household size, education, and income were significantly associated with malaria–related knowledge.

This dissertation describes the development and application of a new mathematical model for simulating the progression of Plasmodium falciparum infections in individuals with no malarial acquired immunity. The model allows for stochastic simulation of asexual and sexual parasitemias as well as the onset of fever and human to mosquito infectivity on a daily time scale. The model components for the asexual and sexual stages were developed elsewhere but are here extended to allow for simulation of the full range of dynamics observed in a subset of malaria therapy patients. As a first application of the model, I calculate the human component of malarial R0, the basic reproductive number. I then compare this value to those from three other models and describe how this quantity can be used to model malaria transmission. The second application of the model incorporates the effects of drug treatment on progression of infection by utilizing modeled pharmacokinetic and pharmacodynamic properties of a variety of antimalarials. I utilize a stage specific proportional killing model for sexual stages, informed from recent in vitro data. The relationship of effect sizes to treatment coverage and type of treatment in both early and late treatment seeking settings is calculated. In the third chapter, I consider the economic and epidemiological ramifications of antimalarial and rapid diagnostic subsidization for malaria control. For the epidemiological modeling I utilize a semi-mechanistic model of the spread of drug resistance parameterized from historical malaria mortality data; for the economic model I consider the effect of rapid diagnostics on the intensive and extensive margins of antibiotics and antimalarials, as well as the benefits to improved targeting of both. I find that rapid diagnostic testing is justified given our baseline assumptions for areas with low proportions of malarious individuals among all treatment-seekers, but that caution is necessary before deployment worldwide. For antimalarial subsidization, we find that this is a cost-effective method for reducing mortality in developing countries, though efforts to delay the onset and slow the spread of resistance are urgently needed.