Browsing by Author "Bangirana, Paul"

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    Acute kidney injury in Ugandan children with severe malaria is associated with long-term behavioral problems
    (Public Library of Science, 2019-12-17) Hickson, Meredith R.; Conroy, Andrea L.; Bangirana, Paul; Opoka, Robert O.; Idro, Richard; Ssenkusu, John M.; John, Chandy C.; Pediatrics, School of Medicine
    Background Acute kidney injury (AKI) is a risk factor for neurocognitive impairment in severe malaria (SM), but the impact of AKI on long-term behavioral outcomes following SM is unknown. Methods We conducted a prospective study on behavioral outcomes of Ugandan children 1.5 to 12 years of age with two forms of severe malaria, cerebral malaria (CM, n = 226) or severe malarial anemia (SMA, n = 214), and healthy community children (CC, n = 173). AKI was defined as a 50% increase in creatinine from estimated baseline. Behavior and executive function were assessed at baseline and 6, 12, and 24 months later using the Child Behavior Checklist and Behavior Rating Inventory of Executive Function, respectively. Age-adjusted z-scores were computed for each domain based on CC scores. The association between AKI and behavioral outcomes was evaluated across all time points using linear mixed effect models, adjusting for sociodemographic variables and disease severity. Results AKI was present in 33.2% of children with CM or SMA at baseline. Children ≥6 years of age with CM or SMA who had AKI on admission had worse scores in socio-emotional function in externalizing behaviors (Beta (95% CI), 0.52 (0.20, 0.85), p = 0.001), global executive function (0.48 (0.15, 0.82), p = 0.005) and behavioral regulation (0.66 (0.32, 1.01), p = 0.0002) than children without AKI. There were no behavioral differences associated with AKI in children <6 years of age. Conclusions AKI is associated with long-term behavioral problems in children ≥6 years of age with CM or SMA, irrespective of age at study enrollment.
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    Acute Kidney Injury Interacts With Coma, Acidosis, and Impaired Perfusion to Significantly Increase Risk of Death in Children With Severe Malaria
    (Oxford University Press, 2022) Namazzi, Ruth; Opoka, Robert; Datta, Dibyadyuti; Bangirana, Paul; Batte, Anthony; Berrens, Zachary; Goings, Michael J.; Schwaderer, Andrew L.; Conroy, Andrea L.; John, Chandy C.; Pediatrics, School of Medicine
    Background: Mortality in severe malaria remains high in children treated with intravenous artesunate. Acute kidney injury (AKI) is a common complication of severe malaria, but the interactions between AKI and other complications on the risk of mortality in severe malaria are not well characterized. Methods: Between 2014 and 2017, 600 children aged 6-48 months to 4 years hospitalized with severe malaria were enrolled in a prospective clinical cohort study evaluating clinical predictors of mortality in children with severe malaria. Results: The mean age of children in this cohort was 2.1 years (standard deviation, 0.9 years) and 338 children (56.3%) were male. Mortality was 7.3%, and 52.3% of deaths occurred within 12 hours of admission. Coma, acidosis, impaired perfusion, AKI, elevated blood urea nitrogen (BUN), and hyperkalemia were associated with increased mortality (all P < .001). AKI interacted with each risk factor to increase mortality (P < .001 for interaction). Children with clinical indications for dialysis (14.4% of all children) had an increased risk of death compared with those with no indications for dialysis (odds ratio, 6.56; 95% confidence interval, 3.41-12.59). Conclusions: AKI interacts with coma, acidosis, or impaired perfusion to significantly increase the risk of death in severe malaria. Among children with AKI, those who have hyperkalemia or elevated BUN have a higher risk of death. A better understanding of the causes of these complications of severe malaria, and development and implementation of measures to prevent and treat them, such as dialysis, are needed to reduce mortality in severe malaria.
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    Acute kidney injury is associated with impaired cognition and chronic kidney disease in a prospective cohort of children with severe malaria
    (Springer Nature, 2019-05-21) Conroy, Andrea L.; Opoka, Robert O.; Bangirana, Paul; Idro, Richard; Ssenkusu, John M.; Datta, Dibyadyuti; Hodges, James S.; Morgan, Catherine; John, Chandy C.; Pediatrics, School of Medicine
    BACKGROUND: Acute kidney injury (AKI) is a recognized complication of pediatric severe malaria, but its long-term consequences are unknown. METHODS: Ugandan children with cerebral malaria (CM, n = 260) and severe malaria anemia (SMA, n = 219) or community children (CC, n = 173) between 1.5 and 12 years of age were enrolled in a prospective cohort study. Kidney Disease: Improving Global Outcomes (KDIGO) criteria were used to retrospectively define AKI and chronic kidney disease (CKD). Cognitive testing was conducted using the Mullen Scales of Early Learning in children < 5 and Kaufman Assessment Battery for Children (K-ABC) second edition in children ≥ 5 years of age. RESULTS: The prevalence of AKI was 35.1%, ranging from 25.1% in SMA to 43.5% in CM. In-hospital mortality was 11.9% in AKI compared to 4.2% in children without AKI (p = 0.001), and post-discharge mortality was 4.7% in AKI compared to 1.3% in children without AKI (p = 0.030) corresponding to an all-cause adjusted hazard ratio of 2.30 (95% CI 1.21, 4.35). AKI was a risk factor for short- and long-term neurocognitive impairment. At 1 week post-discharge, the frequency of neurocognitive impairment was 37.3% in AKI compared to 13.5% in children without AKI (adjusted odds ratio (aOR) 2.31 [95% CI 1.32, 4.04]); at 1-year follow-up, it was 13.3% in AKI compared to 3.4% in children without AKI (aOR 2.48 [95% CI 1.01, 6.10]), and at 2-year follow-up, it was 13.0% in AKI compared to 3.4% in children without AKI (aOR 3.03 [95% CI 1.22, 7.58]). AKI was a risk factor for CKD at 1-year follow-up: 7.6% of children with severe malaria-associated AKI had CKD at follow-up compared to 2.8% of children without AKI (p = 0.038) corresponding to an OR of 2.81 (95% CI 1.02, 7.73). The presenting etiology of AKI was consistent with prerenal azotemia, and lactate dehydrogenase as a marker of intravascular hemolysis was an independent risk factor for AKI in CM and SMA (p < 0.0001). In CM, AKI was associated with the presence and severity of retinopathy (p < 0.05) and increased cerebrospinal fluid albumin suggestive of blood-brain barrier disruption. CONCLUSIONS: AKI is a risk factor for long-term neurocognitive impairment and CKD in pediatric severe malaria.
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    Acute kidney injury, persistent kidney disease, and post-discharge morbidity and mortality in severe malaria in children: A prospective cohort study
    (Elsevier, 2022-02-12) Namazzi, Ruth; Batte, Anthony; Opoka, Robert O.; Bangirana, Paul; Schwaderer, Andrew L.; Berrens, Zachary; Datta, Dibyadyuti; Goings, Michael; Ssenkusu, John M.; Goldstein, Stuart L.; John, Chandy C.; Conroy, Andrea L.; Pediatrics, School of Medicine
    Background: Globally, 85% of acute kidney injury (AKI) cases occur in low-and-middle-income countries. There is limited information on persistent kidney disease (acute kidney disease [AKD]) following severe malaria-associated AKI. Methods: Between March 28, 2014, and April 18, 2017, 598 children with severe malaria and 118 community children were enrolled in a two-site prospective cohort study in Uganda and followed up for 12 months. The Kidney Disease: Improving Global Outcomes (KDIGO) criteria were used to define AKI (primary exposure) and AKD at 1-month follow-up (primary outcome). Plasma neutrophil gelatinase-associated lipocalin (NGAL) was assessed as a structural biomarker of AKI. Findings: The prevalence of AKI was 45·3% with 21·5% of children having unresolved AKI at 24 h. AKI was more common in Eastern Uganda. In-hospital mortality increased across AKI stages from 1·8% in children without AKI to 26·5% with Stage 3 AKI (p < 0·0001). Children with a high-risk plasma NGAL test were more likely to have unresolved AKI (OR, 7·00 95% CI 4·16 to 11·76) and die in hospital (OR, 6·02 95% CI 2·83 to 12·81). AKD prevalence was 15·6% at 1-month follow-up with most AKD occurring in Eastern Uganda. Risk factors for AKD included severe/unresolved AKI, blackwater fever, and a high-risk NGAL test (adjusted p < 0·05). Paracetamol use during hospitalization was associated with reduced AKD (p < 0·0001). Survivors with AKD post-AKI had higher post-discharge mortality (17·5%) compared with children without AKD (3·7%). Interpretation: Children with severe malaria-associated AKI are at risk of AKD and post-discharge mortality.
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    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 Medicine
    Importance: 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.
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    Association of severe malaria with cognitive and behavioural outcomes in low- and middle-income countries: a meta-analysis and systematic review
    (BMC, 2023-08-03) Ssemata, Andrew Sentoogo; Nakitende, Ann Jacquelline; Kizito, Simon; Thomas, Melissa R.; Islam, Sumaiya; Bangirana, Paul; Nakasujja, Noeline; Yang, Ziyi; Yu, Yunpeng; Tran, Tuan M.; John, Chandy C.; McHenry, Megan S.; Social and Behavioral Sciences, School of Public Health
    Background: Malaria affects 24 million children globally, resulting in nearly 500,000 child deaths annually in low- and middle-income countries (LMICs). Recent studies have provided evidence that severe malaria infection results in sustained impairment in cognition and behaviour among young children; however, a formal meta-analysis has not been published. The objective was to assess the association between severe malaria infection with cognitive and behavioural outcomes among children living in LMICs. Methods: Six online bibliographic databases were searched and reviewed in November 2022. Studies included involved children < 18 years of age living in LMICs with active or past severe malaria infection and measured cognitive and/or behaviour outcomes. The quality of studies was assessed. Definitions of severe malaria included cerebral malaria, severe malarial anaemia, and author-defined severe malaria. Results from all studies were qualitatively summarized. For studies with relevant data on attention, learning, memory, language, internalizing behaviour and externalizing behaviour, results were pooled and a meta-analysis was performed. A random-effects model was used across included cohorts, yielding a standardized mean difference between the severe malaria group and control group. Results: Out of 3,803 initial records meeting the search criteria, 24 studies were included in the review, with data from 14 studies eligible for meta-analysis inclusion. Studies across sub-Saharan Africa assessed 11 cohorts of children from pre-school to school age. Of all the studies, composite measures of cognition were the most affected areas of development. Overall, attention, memory, and behavioural problems were domains most commonly found to have lower scores in children with severe malaria. Meta-analysis revealed that children with severe malaria had worse scores compared to children without malaria in attention (standardized mean difference (SMD) -0.68, 95% CI -1.26 to -0.10), memory (SMD -0.52, 95% CI -0.99 to -0.06), and externalizing behavioural problems (SMD 0.45, 95% CI 0.13-0.78). Conclusion: Severe malaria is associated with worse neuropsychological outcomes for children living in LMICs, specifically in attention, memory, and externalizing behaviours. More research is needed to identify the long-term implications of these findings. Further interventions are needed to prevent cognitive and behavioural problems after severe malaria infection.
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    Autoantibody levels are associated with acute kidney injury, anemia and post-discharge morbidity and mortality in Ugandan children with severe malaria
    (Nature Research, 2019-10-17) Rivera-Correa, Juan; Conroy, Andrea L.; Opoka, Robert O.; Batte, Anthony; Namazzi, Ruth; Ouma, Benson; Bangirana, Paul; Idro, Richard; Schwaderer, Andrew L.; John, Chandy C.; Rodriguez, Ana; Pediatrics, School of Medicine
    Autoantibodies targeting host antigens contribute to autoimmune disorders, frequently occur during and after infections and have been proposed to contribute to malaria-induced anemia. We measured anti-phosphatidylserine (PS) and anti-DNA antibody levels in 382 Ugandan children prospectively recruited in a study of severe malaria (SM). High antibody levels were defined as antibody levels greater than the mean plus 3 standard deviations of community children (CC). We observed increases in median levels of anti-PS and anti-DNA antibodies in children with SM compared to CC (p < 0.0001 for both). Children with severe malarial anemia were more likely to have high anti-PS antibodies than children with cerebral malaria (16.4% vs. 7.4%), p = 0.02. Increases in anti-PS and anti-DNA antibodies were associated with decreased hemoglobin (p < 0.05). A one-unit increase in anti-DNA antibodies was associated with a 2.99 (95% CI, 1.68, 5.31) increase odds of acute kidney injury (AKI) (p < 0.0001). Elevated anti-PS and anti-DNA antibodies were associated with post-discharge mortality (p = 0.031 and p = 0.042, respectively). Children with high anti-PS antibodies were more likely to have multiple hospital readmissions compared to children with normal anti-PS antibody levels (p < 0.05). SM is associated with increased autoantibodies against PS and DNA. Autoantibodies were associated with anemia, AKI, post-discharge mortality, and hospital readmission.
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    Blood biomarkers of neuronal injury in paediatric cerebral malaria and severe malarial anaemia
    (Oxford University Press, 2023-11-27) Datta, Dibyadyuti; Gopinadhan, Adnan; Soto, Alejandro; Bangirana, Paul; Opoka, Robert O.; Conroy, Andrea L.; Saykin, Andrew J.; Kawata, Keisuke; John, Chandy C.; Pediatrics, School of Medicine
    Persistent neurodisability is a known complication in paediatric survivors of cerebral malaria and severe malarial anaemia. Tau, ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein have proven utility as biomarkers that predict adverse neurologic outcomes in adult and paediatric disorders. In paediatric severe malaria, elevated tau is associated with mortality and neurocognitive complications. We aimed to investigate whether a multi-analyte panel including ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein can serve as biomarkers of brain injury associated with mortality and neurodisability in cerebral malaria and severe malarial anaemia. In a prospective cohort study of Ugandan children, 18 months to 12 years of age with cerebral malaria (n = 182), severe malarial anaemia (n = 158), and asymptomatic community children (n = 118), we measured admission blood levels of ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein. We investigated differences in biomarker levels, associations with mortality, blood–brain barrier integrity, neurodeficits and cognitive Z-scores in survivors up to 24-month follow-up. Admission ubiquitin C-terminal hydrolase-L1 levels were elevated >95th percentile of community children in 71 and 51%, and neurofilament-light chain levels were elevated >95th percentile of community children in 40 and 37% of children with cerebral malaria and severe malarial anaemia, respectively. Glial fibrillary acidic protein was not elevated in disease groups compared with controls. In cerebral malaria, elevated neurofilament-light chain was observed in 16 children who died in hospital compared with 166 survivors (P = 0.01); elevations in ubiquitin C-terminal hydrolase-L1 levels were associated with degree of blood–brain barrier disruption (P = 0.01); and the % predictive value for neurodeficits over follow-up (discharge, 6-, 12-, and 24 months) increased for ubiquitin C-terminal hydrolase-L1 (60, 67, 72, and 83), but not neurofilament-light chain (65, 68, 60, and 67). In cerebral malaria, elevated ubiquitin C-terminal hydrolase-L1 was associated with worse memory scores in children <5 years at malaria episode who crossed to over 5 years old during follow-up cognitive testing [β −1.13 (95% confidence interval −2.05, −0.21), P = 0.02], and elevated neurofilament-light chain was associated with worse attention in children ≥5 years at malaria episode and cognitive testing [β −1.08 (95% confidence interval −2.05, −1.05), P = 0.03]. In severe malarial anaemia, elevated ubiquitin C-terminal hydrolase-L1 was associated with worse attention in children <5 years at malaria episode and cognitive testing [β −0.42 (95% confidence interval −0.76, −0.07), P = 0.02]. Ubiquitin C-terminal hydrolase-L1 and neurofilament-light chain levels are elevated in paediatric cerebral malaria and severe malarial anaemia. In cerebral malaria, elevated neurofilament-light chain is associated with mortality whereas elevated ubiquitin C-terminal hydrolase-L1 is associated with blood–brain barrier dysfunction and neurodeficits over follow-up. In cerebral malaria, both markers are associated with worse cognition, while in severe malarial anaemia, only ubiquitin C-terminal hydrolase-L1 is associated with worse cognition.
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    Case Report: Birth Outcome and Neurodevelopment in Placental Malaria Discordant Twins
    (ASTMH, 2019-03) Conroy, Andrea L.; Bangirana, Paul; Muhindo, Mary K.; Kakuru, Abel; Jagannathan, Prasanna; Opoka, Robert O.; Liechty, Edward A.; Nakalembe, Miriam; Kamya, Moses R.; Dorsey, Grant; John, Chandy C.; Pediatrics, School of Medicine
    Maternal infection during pregnancy can have lasting effects on neurodevelopment, but the impact of malaria in pregnancy on child neurodevelopment is unknown. We present a case of a 24-year-old gravida three woman enrolled at 14 weeks 6 days of gestation in a clinical trial evaluating malaria prevention strategies in pregnancy. She had two blood samples test positive for Plasmodium falciparum using loop-mediated isothermal amplification before 20 weeks of gestation. At 31 weeks 4 days of gestation, the woman presented with preterm premature rupture of membranes, and the twins were delivered by cesarean section. Twin A was 1,920 g and Twin B was 1,320 g. Both placentas tested negative for malaria by microscopy, but the placenta of Twin B had evidence of past malaria by histology. The twins' development was assessed using the Bayley Scales of Infant and Toddler Development-Third Edition. At 1 year chronologic age, Twin B had lower scores across all domains (composite scores: cognitive, Twin A [100], Twin B [70]; motor, Twin A [88], Twin B [73]; language, Twin A [109], Twin B [86]). This effect persisted at 2 years chronologic age (composite scores: cognitive, Twin A [80], Twin B [60]; motor, Twin A [76], Twin B [67]; language, Twin A [77], Twin B [59]). Infant health was similar over the first 2 years of life. We report differences in neurodevelopmental outcomes in placental malaria-discordant dizygotic twins. Additional research is needed to evaluate the impact of placental malaria on neurodevelopmental complications.
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    Cerebral malaria is associated with long-term mental health disorders: a cross sectional survey of a long-term cohort
    (Springer (Biomed Central Ltd.), 2016) Idro, Richard; Kakooza-Mwesige, Angelina; Asea, Benjamin; Ssebyala, Keron; Bangirana, Paul; Opoka, Robert O.; Lubowa, Samson K.; Semrud-Clikeman, Margaret; John, Chandy C.; Nalugya, Joyce; Department of Pediatrics, IU School of Medicine
    BACKGROUND: Cerebral malaria (CM) and severe malarial anaemia (SMA) are associated with neuro-developmental impairment in African children, but long-term mental health disorders in these children are not well defined. METHODS: A cohort of children previously exposed to CM (n = 173) or SMA (n = 99) had neurologic assessments performed and screening for behaviour difficulties using the Strengths and Difficulties Questionnaire (SDQ) a median of 21 months after the disease episode. These findings were compared to concurrently recruited community children (CC, n = 108). Participants with SDQ total difficulties score ≥ 17 had a mental health interview with the child and adolescent version of the Mini-International Neuropsychiatric Interview (MINI-KID) and a sample had brain magnetic resonance imaging (MRI). RESULTS: Fifty-five children had SDQ score ≥ 17. On the MINI-KID, these children were classified as having no difficulties (n = 18), behaviour difficulties only (n = 13) or a mental health disorder (n = 24). Behaviour difficulties were seen in similar frequencies in CM (3.5%), SMA (4.0%) and CC (2.8%). In contrast, mental health disorders were most frequent in CM (10.4%), followed by SMA (4.0%) and CC (1.8%). Externalizing disorders (conduct, oppositional defiance and attention deficit hyperactivity) were the most common mental health disorders. The median total coma duration was 72 (IQR 36.0-115.0) h in patients with mental health disorders compared to 48 (IQR 28.5-78.7) h in those without, p = 0.039. Independent risk factors for mental health disorder included neurologic deficit at discharge (OR 4.09 (95% CI 1.60, 10.5) and seizure recurrences during hospitalization, (OR 2.80, 95% CI 1.13, 6.97). Brain MRI findings consistent with small vessel ischaemic neural injury was seen in over half of these children. CONCLUSIONS: Cerebral malaria may predispose children to mental health disorders, possibly as a consequence of ischaemic neural injury. There is urgent need for programmes of follow-up, diagnosis and interventions for these children.