Browsing by Author "Co, Katrina"
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Item Association of Plasma Tau With Mortality and Long-term Neurocognitive Impairment in Survivors of Pediatric Cerebral Malaria and Severe Malarial Anemia(American Medical Association, 2021-12) Datta, Dibyadyuti; Bangirana, Paul; Opoka, Robert O.; Conroy, Andrea L.; Co, Katrina; Bond, Caitlin; Zhao, Yi; Kawata, Keisuke; Saykin, Andrew J.; John, Chandy C.; Biostatistics and Health Data Science, School of MedicineImportance: Cerebral malaria (CM) and severe malarial anemia (SMA) are associated with persistent neurocognitive impairment (NCI) among children in Africa. Identifying blood biomarkers of acute brain injury that are associated with future NCI could allow early interventions to prevent or reduce NCI in survivors of severe malaria. Objective: To investigate whether acutely elevated tau levels are associated with future NCI in children after CM or SMA. Design, setting, and participants: This prospective cohort study was conducted at Mulago National Referral Hospital in Kampala, Uganda, from March 2008 to October 2015. Children aged 1.5 to 12 years with CM (n = 182) or SMA (n = 162) as well as community children (CC; n = 123) were enrolled in the study. Data analysis was conducted from January 2020 to May 2021. Exposure: CM or SMA. Main outcomes and measures: Enrollment plasma tau levels were measured using single-molecule array detection technology. Overall cognition (primary) and attention and memory (secondary) z scores were measured at 1 week and 6, 12, and 24 months after discharge using tools validated in Ugandan children younger than 5 years or 5 years and older. Results: A total of 467 children were enrolled. In the CM group, 75 (41%) were girls, and the mean (SD) age was 4.02 (1.92) years. In the SMA group, 59 (36%) were girls, and the mean (SD) age was 3.45 (1.60) years. In the CC group, 65 (53%) were girls, and the mean (SD) age was 3.94 (1.92) years. Elevated plasma tau levels (>95th percentile in CC group; >6.43 pg/mL) were observed in 100 children (55%) with CM and 69 children (43%) with SMA (P < .001). In children with CM who were younger than 5 years, elevated plasma tau levels were associated with increased mortality (odds ratio [OR], 3.06; 95% CI, 1.01-9.26; P = .048). In children with CM who were younger than 5 years at both CM episode and follow-up neurocognitive testing, plasma tau levels (log10 transformed) were associated with worse overall cognition scores over 24-month follow-up (β = -0.80; 95% CI, -1.32 to -0.27; P = .003). In children with CM who were younger than 5 years at CM episode and 5 years or older at follow-up neurocognitive testing, plasma tau was associated with worse scores in attention (β = -1.08; 95% CI, -1.79 to -0.38; P = .003) and working memory (β = -1.39; 95% CI, -2.18 to -0.60; P = .001). Conclusions and relevance: In this study, plasma tau, a marker of injury to neuronal axons, was elevated in children with CM or SMA and was associated with mortality and persistent NCI in children with CM younger than 5 years.Item Evaluating kidney function using a point-of-care creatinine test in Ugandan children with severe malaria: a prospective cohort study(BMC, 2021-11-06) Batte, Anthony; Murphy, Kristin J.; Namazzi, Ruth; Co, Katrina; Opoka, Robert O.; Ssenkusu, John M.; John, Chandy C.; Conroy, Andrea L.; Pediatrics, School of MedicineBackground: Acute kidney injury (AKI) disproportionately affects individuals in low-and middle-income countries (LMIC). However, LMIC-particularly countries in sub-Saharan Africa- are under-represented in global AKI research. A critical barrier in diagnosing AKI is access to reliable serum creatinine results. We evaluated the utility of a point-of-care test to measure creatinine and diagnose AKI in Ugandan children with malaria. Methods: Paired admission creatinine was assessed in 539 Ugandan children 6 months to 4 years of age hospitalized with severe malaria based on blood smear or rapid diagnostic test. Creatinine levels were measured using isotope dilution mass spectrometry (IDMS)-traceable methods. The reference creatinine was measured using the modified Jaffe method by a certified laboratory and the point-of-care testing was conducted using an i-STAT blood analyzer (i-STAT1, with and without adjustment for the partial pressure of carbon dioxide). AKI was defined and staged using the Kidney Disease: Improving Global Outcomes criteria. Results: The mean age of children was 2.1 years, and 21.6% of children were stunted. Mortality was 7.6% in-hospital. Over the entire range of measured creatinine values (<0.20mg/dL-8.4mg/dL), the correlation between the reference creatinine and adjusted and unadjusted point-of-care creatinine was high with R2 values of 0.95 and 0.93 respectively; however, the correlation was significantly lower in children with creatinine values <1mg/dL (R2 of 0.44 between the reference and adjusted and unadjusted i-STAT creatinine). The prevalence of AKI was 45.5% using the reference creatinine, and 27.1 and 32.3% using the unadjusted and adjusted point-of-care creatinine values, respectively. There was a step-wise increase in mortality across AKI stages, and all methods were strongly associated with mortality (p<0.0001 for all). AKI defined using the reference creatinine measure was the most sensitive to predict mortality with a sensitivity of 85.4% compared to 70.7 and 63.4% with the adjusted and unadjusted point-of-care creatinine values, respectively. Conclusions: Point-of-care assessment of creatinine in lean Ugandan children <4 years of age underestimated creatinine and AKI compared to the clinical reference. Additional studies are needed to evaluate other biomarkers of AKI in LMIC to ensure equitable access to AKI diagnostics globally.Item Impact of Oxidative Stress on Risk of Death and Readmission in African Children With Severe Malaria: A Prospective Observational Study(Oxford University Press, 2022) Blatt, Daniel B.; Hanisch, Benjamin; Co, Katrina; Datta, Dibyadyuti; Bond, Caitlin; Opoka, Robert O.; Cusick, Sarah E.; Michelow, Ian C.; John, Chandy C.; Pediatrics, School of MedicineBackground: We hypothesized that oxidative stress in Ugandan children with severe malaria is associated with mortality. Methods: We evaluated biomarkers of oxidative stress in children with cerebral malaria (CM, n = 77) or severe malarial anemia (SMA, n = 79), who were enrolled in a randomized clinical trial of immediate vs delayed iron therapy, compared with community children (CC, n = 83). Associations between admission biomarkers and risk of death during hospitalization or risk of readmission within 6 months were analyzed. Results: Nine children with CM and none with SMA died during hospitalization. Children with CM or SMA had higher levels of heme oxygenase-1 (HO-1) (P < .001) and lower superoxide dismutase (SOD) activity than CC (P < .02). Children with CM had a higher risk of death with increasing HO-1 concentration (odds ratio [OR], 6.07 [95% confidence interval {CI}, 1.17-31.31]; P = .03) but a lower risk of death with increasing SOD activity (OR, 0.02 [95% CI, .001-.70]; P = .03). There were no associations between oxidative stress biomarkers on admission and risk of readmission within 6 months of enrollment. Conclusions: Children with CM or SMA develop oxidative stress in response to severe malaria. Oxidative stress is associated with higher mortality in children with CM but not with SMA.Item Investigating Differences in Nutritional Parameters in Ugandan Children with Plasmodium falciparum Severe Malaria(2020-07) Brown, Lucy; Co, Katrina; Bond, Caitlin; Opoka, Robert; Datta, Dibya; John, ChandyBackground: The past two decades have witnessed a 60% decline in global malaria mortality. However, two thirds of all malaria deaths continue to occur among children <5 years, with a majority in the WHO African Region. Malnutrition is an important risk factor for malaria. Wasting, Stunting and Underweight are crucial indicators of malnutrition, and are associated with increased mortality in children <5. Annually, 14 million children <5 are classified as wasted and 59 million children are classified as stunted. Objective: The objective of this study is to look at nutritional parameters, weight-for-age (WAZ), height-for-age (HAZ), and weight-for-height (WHZ), and how they differ over time in children <5 with severe malaria (SM) from the Ugandan cities Mulago and Jinja and the outcomes of mortality and nutritional parameters, underweight, stunting, and wasting. Methods: We defined underweight, stunting, and wasting as 2SD below the WAZ, HAZ, and WHZ means. We evaluated Z-scores and mortality status from children <5 years enrolled in a prospective cohort study (NDI, Neurodevelopmental Impairment in Children with Severe Malaria) at enrollment and 12-month follow-up between two sites. Results: WAZ, HAZ and WHZ at baseline were significantly lower among SM groups than in CC (p<0.01), and the SM group maintained significantly lower WHZ (p<0.01) and HAZ (p<0.001) at 12-month follow-up. Among the children who died, there were no significant differences of nutritional markers in Mulago, but in Jinja there was found to be a significant association between mortality and low WAZ (p<0.05) and underweight (p<0.05). Of children classified as underweight in Jinja, 37.5% of them died compared to 15.9% who survived; additionally, the odds ratio for decreased WAZ and mortality was 0.58 (p<0.05). Conclusion: Underweight, stunting, and wasting may be risk factors for SM, and underweight may exacerbate poor mortality outcomes in rural areas like Jinja. While underweight is worsened among children with SM at 1 month and normalizes by 12 months, stunting remains persistently low at 12 months. Nutritional interventions must be aimed at maintaining linear growth throughout the first year of SM in children <5 to reduce the risk factor of underweight on poor mortality outcomes.Item Level and Duration of IgG and Neutralizing Antibodies to SARS-CoV-2 in Children with Symptomatic or Asymptomatic SARS-CoV-2 Infection(AAI, 2022-06-01) Khaitan, Alka; Datta, Dibyadyuti; Bond, Caitlin; Goings, Michael; Co, Katrina; Odhiambo, Eliud O.; Miller, Lucy; Zhang, Lin; Beasley, Stephanie; Poorbaugh, Josh; John, Chandy C.; Pediatrics, School of MedicineThere are conflicting data about level and duration of Abs to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children after symptomatic or asymptomatic infection. In this human population, we enrolled adults and children in a prospective 6-mo study in the following categories: 1) symptomatic, SARS-CoV-2 PCR+ (SP+; children, n = 8; adults, n = 16), 2) symptomatic, PCR−, or untested (children, n = 27), 3) asymptomatic exposed (children, n = 13), and 4) asymptomatic, no known exposure (children, n = 19). Neutralizing Abs (nAbs) and IgG Abs to SARS-CoV-2 Ags and spike protein variants were measured by multiplex serological assay. All SP+ children developed nAb, whereas 81% of SP+ adults developed nAb. Decline in the presence of nAb over 6 mo was not significant in symptomatic children (100 to 87.5%; p = 0.32) in contrast to adults (81.3 to 50.0%; p = 0.03). Among children with nAb (n = 22), nAb titers and change in titers over 6 mo were similar in symptomatic and asymptomatic children. In children and adults, nAb levels postinfection were 10-fold lower than those reported after SARS-CoV-2 mRNA vaccination. Levels of IgG Abs in children to SARS-CoV-2 Ags and spike protein variants were similar to those in adults. IgG levels to primary Ags decreased over time in children and adults, but levels to three spike variants decreased only in children. Children with asymptomatic or symptomatic SARS-CoV-2 infection develop nAbs that remain present longer than in adults but wane in titer over time and broad IgG Abs that also wane in level over time. However, nAb levels were lower postinfection than those reported after immunization.Item Prevalence of Asymptomatic SARS-CoV-2 Infection in Children and Adults in Marion County, Indiana(Cureus Inc., 2020-08-16) Wood, James; Datta, Dibyadyuti; Hudson, Brenda L; Co, Katrina; Tepner, Sarah; Hardwick, Emily; John, Chandy C.; Pediatrics, School of MedicineBackground and Objectives: Two community studies outside the US showed asymptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in adults, but not in children <10 years of age. In this study, we assessed the prevalence of asymptomatic SARS-CoV-2 infection in children and adults in Marion County, Indiana. Methods: Individuals living in Marion County with no symptoms of coronavirus 2019 disease (COVID-19) within seven days of enrollment were eligible for this cross-sectional household study. Study kits were delivered to the participant’s residence for self-swabbing, picked up by the study team, and tested by polymerase chain reaction (PCR) for SAR-CoV-2 infection. Results: Five hundred eleven nasal swabs were collected from 119 children and 392 adults ≥18 years of age. One participant (seven years of age) tested positive, for an overall study prevalence of 0.2% (95% CI 0, 0.6%). The participant had no known contact with a person with SARS-CoV-2 infection, and five family members tested negative for infection. The child and family members all tested negative for infection 10 and 20 days after the first test, and none developed symptoms of COVID-19 for 20 days after testing. Conclusions: Asymptomatic SARS-CoV-2 infection can occur in children <10 years with no known COVID-19 exposure. Large cohort studies should be conducted to determine prevalence of asymptomatic infection and risk of transmission from asymptomatic infection in children and adults over time.Item Towards the use of a smartphone imaging-based tool for point-of-care detection of asymptomatic low-density malaria parasitaemia(BMC, 2021-09-25) Colbert, Ashlee J.; Co, Katrina; Lima‑Cooper, Giselle; Lee, Dong Hoon; Clayton, Katherine N.; Wereley, Steven T.; John, Chandy C.; Linnes, Jacqueline C.; Kinzer‑Ursem, Tamara L.; Pediatrics, School of MedicineBackground: Globally, there are over 200 million cases of malaria annually and over 400,000 deaths. Early and accurate detection of low-density parasitaemia and asymptomatic individuals is key to achieving the World Health Organization (WHO) 2030 sustainable development goals of reducing malaria-related deaths by 90% and eradication in 35 countries. Current rapid diagnostic tests are neither sensitive nor specific enough to detect the low parasite concentrations in the blood of asymptomatic individuals. Methods: Here, an imaging-based sensing technique, particle diffusometry (PD), is combined with loop mediated isothermal amplification (LAMP) on a smartphone-enabled device to detect low levels of parasitaemia often associated with asymptomatic malaria. After amplification, PD quantifies the Brownian motion of fluorescent nanoparticles in the solution during a 30 s video taken on the phone. The resulting diffusion coefficient is used to detect the presence of Plasmodium DNA amplicons. The coefficients of known negative samples are compared to positive samples using a one-way ANOVA post-hoc Dunnett's test for confirmation of amplification. Results: As few as 3 parasite/µL of blood was detectable in 45 min without DNA extraction. Plasmodium falciparum parasites were detected from asymptomatic individuals' whole blood samples with 89% sensitivity and 100% specificity when compared to quantitative polymerase chain reaction (qPCR). Conclusions: PD-LAMP is of value for the detection of low density parasitaemia especially in areas where trained personnel may be scarce. The demonstration of this smartphone biosensor paired with the sensitivity of LAMP provides a proof of concept to achieve widespread asymptomatic malaria testing at the point of care.Item Underweight is Associated with Mortality Among Ugandan Children with Plasmodium falciparum Severe Malaria(2021-08) Brown, Lucy; Co, Katrina; Bond, Caitlin; Datta, Dibya; John, Chandy; Opoka, RobertBackground: The past two decades have witnessed a 60% decline in global malaria mortality. However, two thirds of all malaria deaths continue to occur among children <5 years, with a majority in the WHO African Region. Malnutrition is an important risk factor for malaria. Globally, wasting, stunting and being underweight are crucial indicators of malnutrition, and are associated with increased mortality in children <5. Those most vulnerable to malaria and malnutrition are children <5 living in Sub-Saharan Africa, particularly in rural areas often facing a higher burden of disease.Objective: The objective of this study was to assess the prevalence and persistence of nutritional abnormalities causing children to be underweight, stunted, or show signs of wasting, and the association of these abnormalities with in-hospital and post-discharge mortality, risk of repeat illness and long-term sequelae in Ugandan children with 5 different forms of severe malaria (SM) compared to community children (CC).Methods: We conducted a prospective observational study investigating neurocognitive outcomes at 12-months after severe malaria episode in 600 children with SM and 120 CC, aged 0.5-4 years, between 2014-2017 at 2 hospitals (Kampala and Jinja) in Uganda. Using age-adjusted scores from healthy CC, we calculated z-scores for weight-for-age (WAZ), height-for-age (HAZ), and weight-for-height (WHZ). We defined underweight, stunting, and wasting as 2SD below the WAZ, HAZ, and WHZ means. Results: At baseline, children with SM had significantly lower mean WAZ and HAZ compared to CC (-1.1 [1.1 SD] vs. -0.47 [1.1], p<0.001; -0.68 [1.1] vs. 0.30 [1.0], p<0.001, respectively), with no difference by site. By 12-month follow-up there were no significant differences in nutritional markers between SM and CC. During admission, 44 (7.3%) children with SM died. Higher baseline WAZ was associated with decreased risk of in-hospital death in children with SM across the two sites (OR [95% CI] = 0.70 [0.51, 0.95], p=0.02), with no significant interaction between WAZ and site. Baseline HAZ and WHZ were not significantly associated with in-hospital mortality (OR [95% CI]) = 0.84 [0.66, 1.06] and 0.77 [0.57, 1.02], respectively). During the post-discharge period, 23 (4.4%) children with SM and 1 (0.9%) CC died prior to 12-month follow-up. Nutritional marker z-scores were not significantly associated with risk of post-discharge mortality in children with SM, overall and by site. However, children in Kampala who were underweight had increased odds of post-discharge mortality compared to those who were normal weight (OR [95% CI] = 4.18 [1.36, 12.84], p=0.01). Among those who survived in Kampala, higher WAZ was associated with increased risk of returning to clinic for any cause within 12-month follow-up (HR [95% CI] = 1.16 [1.06, 1.28], p=0.002), but was not significant for malaria sick visits or readmission. HAZ and WHZ in Kampala and all nutritional markers in Jinja were not significantly associated with return sick visits or readmission. Conclusion: Underweight and stunting were worse in both sites among children with SM versus the controls at 1 month, and both of these nutritional parameters normalized by 12 months. In Kampala, low WAZ was associated with worse mortality outcomes after discharge, while high WAZ was associated with repeat clinic visits. In both sites, high WAZ was protective against in-hospital mortality. Chronic malnutrition and SM remain severe risk factors for mortality in Uganda. Weight status was found to have the most significant impact on mortality outcomes. The high incidence of mortality among children <5 with SM requires urgent intervention, and nutrition programs should be aimed at increasing weight, especially in the early months of disease.