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- 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