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- ItemRestrictedDifferential diagnosis for malaria and trypanosomes in areas where the diseases co-exist(Kamuzu University of Health Sciences, 2021-01-13) Makuluni, MarinaType of study: This is a cross-section study to investigate the co-infection of trypanosome and malaria parasites in areas where trypanosomiasis is endemic in Malawi. Problem: Malaria is ubiquitous, treatment of Human African Trypanosomiasis (HAT) tends to be delayed as the first diagnostic measure for any patient presenting with these symptoms gets malaria treatment first (Darby et al., 2008). Malaria in Malawi is mainly caused by Plasmodium falciparum and diagnosis requires a Malaria Rapid Diagnostic Test (mRDT) at the point of care which is an antibody/antigen test and microscopy of stained blood films is sometimes used. There are two main mRDT in use in Malawi, one developed based on Plasmodium histidine-rich protein (HRP) 2 (pHRP-2) antigen and the other based on Plasmodium lactate dehydrogenase (LDH) (pLDH) antigen both of which mainly target P. falciparum. HAT in Malawi is caused by T.brucei rhodesiense and standard of care diagnosis requires microscopy of stained blood smears although not sensitive when parasitemia is low (Manful et al., 2010). Published reports have revealed that Trypanosome parasite hide underneath the skin of some individuals although there may be no circulating parasites in the blood as one way of invading host adaptive immunity. The parasites may reside underneath the skin for years without being detected in blood circulation. This complicates the diagnosis of HAT as such individuals are diagnosed as microscopically negative for HAT disease and often sent home on antimalaria treatment without further diagnosis. Main objective: To investigate differential diagnosis of Malaria and Trypanosomiasis in Rumphi and Nkhokakota Specific Objectives: 1. To assess the magnitude of HAT patients that are missed out when using microscopy for diagnosis in comparison with a diagnostic HAT PCR. 2. To identify individuals co-infected with Malaria and Trypanosomes 3. To determine whether HAT positive individuals detected are infected with cutaneous trypanosomes. 4. To Identify differences in T.b. rhodesiense parasite gene expression when isolated in skin and or blood. Methodology: Patients that were pre-screened by medical personnel at the hospital for febrile symptoms and sent for Malaria test at the laboratory will be recruited for a period of two weeks to meet our sample size of 123 participants for both Nkhotakota and Rumphi district hospitals. Venous blood specimen will be collected from each participant for further laboratory analysis. Firstly, the blood will be parasites will be sent for treatment immediately following standard treatment guidelines for each disease used to screen for Malaria parasites using Malaria Rapid Diagnostic (RDT) test. Microscopy will be used to confirm individuals who are Malaria RDT positive. Lastly, the other part of the blood will be used for microscopic examination for diagnosis of HAT disease at the district hospital Blood samples that are microscopic negative for HAT will further be tested using a diagnostic HAT PCR at the College of Medicine to rule out any HAT cases that might be missed by the low sensitivity microscopic examination. Individuals that are HAT positive by either microscopy or PCR will be requested to have a small skin snip for further laboratory examination to identify cutaneous Trypanosomes. All participants who are positive for either Malaria or Trypanosome Expected Findings/Dissemination Study This study is expecting to identify the HAT cases that are missed during diagnosis in the two HAT endemic district hospitals of Malawi. The study will also help identify factors that influence mis-diagnosis of HAT in endemic areas of Malawi. Findings from this study will be disseminated at COMREC, College of Medicine Neglected Tropical Disease Research group, Trypanogen Project, Peer reviewed journals and research conferences.
- ItemRestrictedEfficacy, safety and pharmacokinetic exposure of artemether lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in HIV infected Malawian children on antiretroviral treatment(Kamuzu University of Health Sciences, 2021-03-17) Mbeye, NyanyiweType of research study: A prospective observational study will recruit and follow up two groups of children aged between 6 months and 16 years diagnosed with uncomplicated malaria in Lilongwe district. One group will be HIV infected and on antiretroviral treatment and another one will be HIV uninfected. The problem: There is paucity of consolidated evidence to guide optimisation of the current arsenal of drugs that are used to fight malaria in individuals co-infected with HIV especially in key at-risk subpopulations such as children. Potential drug-drug interactions between antimalarial drugs and antiretroviral therapy (ART) raise concern in the control of malaria in children who are co-infected with HIV. Artemether-lumefantrine (AL) is a commonly used artemisinin-based combination therapy (ACT) in most malaria programmatic settings but there is limited understanding of its efficacy in malaria and HIV co-infected children in light of the potential drug-drug interactions between ACTs and ART. WHO recommends countries to evaluate efficacy of their first-line antimalarial drugs at least once every two years. Since these studies are done in HIV negative children, there is an important need to assess the efficacy of first-line antimalarial drugs in HIV infected children on ART as well. Objective: This study aims to evaluate the efficacy and safety of artemether lumefantrine (AL) for the treatment of uncomplicated P. falciparum malaria in HIV infected and HIV uninfected children in Lilongwe, Malawi. Methodology: A prospective observational study of antimalarial efficacy will be conducted in a total of 71 HIV-malaria coinfected children on ART and 141 HIV uninfected children with confirmed malaria who meet the inclusion criteria. Once enrolled, participants will be given AL for treatment and followed up for 28 days. The follow up will consist of fixed schedule of visits (at Day 1,2,3,7,14,21 and 28) with corresponding clinical and laboratory examinations. The proportion of participants experiencing therapeutic failure during the follow-up period will be used to estimate the efficacy of AL. PCR analysis will be used to distinguish between recrudescence and reinfection. On day 7, post treatment initiation, a blood sample will be collected to quantify lumefantrine concentrations, as a predictor of overall lumefantrine exposure. These concentrations will be correlated with AL treatment efficacy. The design has adapted some procedures of the recommended WHO methods for surveillance of antimalarial drug efficacy. Expected findings and their dissemination: This study is designed to generate the information required to assess whether AL is efficacious in HIV infected children on ART. It is anticipated that the study results will improve the management of malaria in HIV infected children on antiretroviral drugs in areas affected by both HIV and malaria. This study will also provide information on the pharmacokinetics of AL and its efficacy that would contribute to the development of appropriate approaches/options for optimal effectiveness of the treatment. The findings of this study will be published in peer-reviewed journals and shared with all relevant stakeholders.
- ItemRestrictedMalaria breath biomarkers across the spectrum of malaria disease severity(2022-05-12) John, Audrey Odom; Seydel, KarlType of study: Observational cohort study The Problem: The need for rapid, accurate, affordable, and non-invasive diagnostic methods for malaria remains urgent, particularly in peripheral health centers. Methodology: The study population of interest will be children aged 4-8 years drawn from two ongoing COMREC-approved studies at Queen Elizabeth Central Hospital in Blantyre. Fifty children in the ongoing “Treatment of brain swelling in pediatric cerebral malaria” study (P. 09/16/2024, PI: Taylor) with cerebral malaria will be matched with fifty children with asymptomatic parasitemia from the “Malaria pathogenesis: Progression cohort and extremes, case control study” (P.11/18/2530, PI: Seydel). Fifty children with no evidence of malaria infection in the “Malaria pathogenesis” study will be used as uninfected controls. After obtaining informed consent from their primary caretaker, a brief medical history and demographic information will be collected. For children with cerebral malaria (CM), breath will be collected through a mask with two one-way valves – allowing for inspiration through one valve and exhalation through a separate valve. Asymptomatic children and children confirmed to not have malaria by qPCR (controls) will provide exhaled breath gas samples after 5 minutes of sitting or lying quietly. A full breath will be exhaled into a small plastic device attached to an inflatable plastic bag. Once the exhaled breath is collected, the sample will be filter concentrated into a sorbet trap that absorbs nonpolar organic molecules. These samples can then be stored refrigerated and shipped at 4-6°C. A finger prick blood sample will be taken on a filter paper at the same time to be used for PCR quantification of asexual parasites and gametocytes. A nasopharyngeal swab will be taken from the children with CM to test for viral and bacterial respiratory pathogens. Following sample collection, children with CM will receive routine medical care for their malaria, including usual antimalarial therapy as warranted. The asymptomatic children will be tested for malaria with a mRDT and treated with standard anti-malarial therapy (LA) if found to be positive. The children with no evidence of malaria will also be tested by mRDT and treated with LA if found to be positive. The breath samples will be analyzed for VOCs by thermal desorption (TD) mass spectrometry. The mass spectrometry resource facility at Children’s Hospital of Philadelphia (CHOP) has successfully detected VOCs emitted by cultured malaria parasites (1) and in breath of Malawian children (2) and will again be engaged to seek these compounds in the breath from patient specimens. Objectives: To develop a novel non-invasive, rapid, accurate, reusable, and affordable malaria diagnostic method capable of detecting P. falciparum even at sub-mRDT parasitemias. This will be achieved through two specific aims:12-May-2022 Breath malaria biomarkers COMREC submission Version 1.2, 26 Feb 2022 Page 5 of 22 5 a) To collect and analyze breath from fifty children with asymptomatic malaria and fifty children without malaria infection to determine the possible presence of biomarkers able to distinguish these populations b) To collect and analyze breath from fifty children with cerebral malaria and simultaneously evaluate these children for the presence of respiratory pathogens, allowing us to characterize the possible role of respiratory pathogens in altering the malaria breathprint. Expected Findings: We hypothesize that VOCs will be detected in the breath of children with malaria even at the very low levels of parasite infection seen in many asymptomatically infected children. Furthermore, we hypothesize that co-infection with respiratory pathogens will shift the VOC profile – but that an underlying ‘breathprint’ can be identified that is malaria specific. These core VOCs can then be explored as novel biomarkers of malaria infection that could be used to screen for asymptomatic infection serving as the basis for future non-invasive malaria diagnostic devices. It is the hope that, in addition to being non-invasive, these devices could be portable, reusable, affordable, and accurate so that they could be used in rural health facilities and communities to identify the population of children who are asymptomatically infected and thus serving as a transmission reservoir. Dissemination: Results will be disseminated to the medical community through peer- reviewed publications and presentations at relevant scientific conferences. Results will also be shared with KUHeS at the annual Research Dissemination Conference. We will also report our findings and publications to COMREC
- ItemRestrictedMalaria disease severity and correlation with Plasmodium falciparum gametocyte burden and sex ratio in children treated at health facilities in Blantyre, Malawi(Kamuzu University of Health Sciences, 2021-01-11) Gama, Syze ChogaType of study This is a Retrospective Cohort study which will use previously collected samples from the paediatrics malaria research ward at Queen Elizabeth Central Hospital (QECH) and Gateway clinic of Blantyre District Health Office. The Problem Malaria continues to be an endemic public health problem in Malawi causing an estimated six million cases annually. According to the Demographic Health Survey of 2010, it still remains the leading cause of morbidity and mortality in under -five children and pregnant women. Over 95% of the malaria cases are caused by Plasmodium falciparum(1). People presenting with the disease are often diagnosed microscopically for the presence of ring stages (asexual stage) of the parasite and receive anti- malarial treatment if found positive. The gametocyte (sexual stage) is responsible for production and transmission of the from human to the mosquito vector. Despite not being tracked in microscopy diagnosis, the number of gametocytes and ratio of female to male gametocytes, determines the transmissibility of malaria. Malaria disease severity is determined by the clinical evidence of vital organ dysfunction and thus understanding the association of malaria disease severity and gametocyte burden and sex ratio will assist in determining the children who might take transmissible parasites back to the community even after taking anti-malaria treatment. This knowledge will help to tackle this vast reservoir of transmission between the human host and the mosquito vector. Objectives To determine the correlation between malaria disease severity and Plasmodium falciparum gametocyte burden and sex ratio in children treated at health facilities in Blantyre, Malawi. Methodology This is a Retrospective cohort study which will use blood samples (Dried Blood Spots) collected in the malaria pathogenesis study at malaria research ward at QECH and Gateway clinic. Laboratory analysis of these samples will be done using quantitative Polymerase Chain Reaction (qPCR) technique.The Mann-Whitney test will be used to test if there will be any statistical significance in the difference of gametocyte sex ratio between the two groups. The mean, median and the inter-quartile range in each group will be analyzed for gametocyte burden and they will be compared. Expected findings and dissemination This study will look at the correlation between malaria severity and P. falciparum gametocytes burden and sex ratio in children treated in health facilities in Blantyre. The final findings will be documented in a report which will be sent to the hospital management, COMREC as well as policy makers. Oral presentation of the results will be done to the hospital management, and at the COM research dissemination conference. The results will also be published in a peer review journal.
- ItemRestrictedThe prevalence of Plasmodium falciparum histidine rich protein 2 and histidine rich protein 3 genetic deletions and its association with malaria severity among Malawian children aged 1 to 12 years.(Kamuzu University of Health Sciences, 2021-07-15) Mvula, Godfrey ZondwayoType of study: This is a quantitative cross-sectional study which will use samples from children diagnosed with malaria in the period from December 2018 to June, 2021.The patients will be categorized in three groups based on the malaria severity; asymptomatic cases, uncomplicated cases and severe malaria cases. The Problem The World Health Organization(WHO) recommended the use of Rapid Diagnostic Tests(RDTs) which target Histidine Rich Protein 2 and Histidine Rich Protein 3 gene (HRP 2/3) to detect malaria. Recent reports of the emerging spread of mutant parasites that fail to express Plasmodium HRP2/3 has complicated the usefulness of RDT’s as Plasmodium infections may be missed and contribute to poor management of malaria especially in vulnerable groups like children. Objective To determine the prevalence of Plasmodium falciparum (Pf) HRP2/3 genetic deletions and its association with malaria severity among Malawian children with a malaria. Methodology The proposed study will use cross-sectional study design to determine the prevalence of HRP2/3 genetic deletion and its association with malaria severity among children aged 1 to 12 years diagnosed with malaria at Queen Elizabeth Central hospital and Ntaja Health center. The Polymerase chain reaction(PCR) also known as PfHRP2/3 deletion assay will be used to determine presence or absence of Plasmodium falciparum strains carrying HRP deletion genes. The descriptive statistics will be used to describe the characteristics of children recruited in the study. The prevalence of PfHRP2/3 will also be presented with 95 percent confidence interval. The chisquared test will be performed to see the association of HRP2/3 deletion with each disease severity group. Furthermore, logistic regression analysis will be conducted to determine the association of malaria severity with the HRP2/3 gene deletion. Expected findings and dissemination We anticipate to find PfHRP2/3 deletion genes in Plasmodium falciparum that affects the performance of HRP2/3 based RDTs and its association with severity of malaria disease. The results will be shared with College of Medicine Research Ethics Committee(COMREC), policy makers, Blantyre Malaria Project(BMP) and publish in journal papers.