Publications by authors named "Chandy C John"

205 Publications

Improving the diagnosis of severe malaria in African children using platelet counts and plasma HRP2 concentrations.

Sci Transl Med 2022 Jul 20;14(654):eabn5040. Epub 2022 Jul 20.

Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

Severe malaria caused by is difficult to diagnose accurately in children in high-transmission settings. Using data from 2649 pediatric and adult patients enrolled in four studies of severe illness in three countries (Bangladesh, Kenya, and Uganda), we fitted Bayesian latent class models using two diagnostic markers: the platelet count and the plasma concentration of histidine-rich protein 2 (HRP2). In severely ill patients with clinical features consistent with severe malaria, the combination of a platelet count of ≤150,000/μl and a plasma HRP2 concentration of ≥1000 ng/ml had an estimated sensitivity of 74% and specificity of 93% in identifying severe falciparum malaria. Compared with misdiagnosed children, pediatric patients with true severe malaria had higher parasite densities, lower hematocrits, lower rates of invasive bacterial disease, and a lower prevalence of both sickle cell trait and sickle cell anemia. We estimate that one-third of the children enrolled into clinical studies of severe malaria in high-transmission settings in Africa had another cause of their severe illness.
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http://dx.doi.org/10.1126/scitranslmed.abn5040DOI Listing
July 2022

What can twins teach us about malaria epidemiology?

Authors:
Chandy C John

J Infect Dis 2022 Jul 18. Epub 2022 Jul 18.

Indiana University School of Medicine.

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http://dx.doi.org/10.1093/infdis/jiac297DOI Listing
July 2022

Elevated Plasma Soluble ST2 Levels are Associated With Neuronal Injury and Neurocognitive Impairment in Children With Cerebral Malaria.

Pathog Immun 2022 23;7(1):60-80. Epub 2022 Jun 23.

Ryan White Center for Pediatric Infectious Disease and Global Health, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.

Background: Murine experimental cerebral malaria studies suggest both protective and deleterious central nervous system effects from alterations in the interleukin-33 (IL-33)/ST2 pathway.

Methods: We assessed whether soluble ST2 (sST2) was associated with neuronal injury or cognitive impairment in a cohort of Ugandan children with cerebral malaria (CM, n=224) or severe malarial anemia (SMA, n=193).

Results: Plasma concentrations of sST2 were higher in children with CM than in children with SMA or in asymptomatic community children. Cerebrospinal fluid (CSF) sST2 levels were elevated in children with CM compared with North American children. Elevated plasma and CSF ST2 levels in children with CM correlated with increased endothelial activation and increased plasma and CSF levels of tau, a marker of neuronal injury. In children with CM who were ≥5 years of age at the time of their malaria episode, but not in children <5 years of age, elevated risk factor-adjusted plasma levels of sST2 were associated with worse scores for overall cognitive ability and attention over a 2-year follow-up.

Conclusions: The study findings suggest that sST2 may contribute to neuronal injury and long-term neurocognitive impairment in older children with CM.
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http://dx.doi.org/10.20411/pai.v7i1.499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9254869PMC
June 2022

Blackwater fever and acute kidney injury in children hospitalized with an acute febrile illness: pathophysiology and prognostic significance.

BMC Med 2022 07 1;20(1):221. Epub 2022 Jul 1.

Sandra Rotman Centre for Global Health, Toronto General Hospital, University Health Network and University of Toronto, Toronto, ON, M5G1L7, Canada.

Background: Acute kidney injury (AKI) and blackwater fever (BWF) are related but distinct renal complications of acute febrile illness in East Africa. The pathogenesis and prognostic significance of BWF and AKI are not well understood.

Methods: A prospective observational cohort study was conducted to evaluate the association between BWF and AKI in children hospitalized with an acute febrile illness. Secondary objectives were to examine the association of AKI and BWF with (i) host response biomarkers and (ii) mortality. AKI was defined using the Kidney Disease: Improving Global Outcomes criteria and BWF was based on parental report of tea-colored urine. Host markers of immune and endothelial activation were quantified on admission plasma samples. The relationships between BWF and AKI and clinical and biologic factors were evaluated using multivariable regression.

Results: We evaluated BWF and AKI in 999 children with acute febrile illness (mean age 1.7 years (standard deviation 1.06), 55.7% male). At enrollment, 8.2% of children had a history of BWF, 49.5% had AKI, and 11.1% had severe AKI. A history of BWF was independently associated with 2.18-fold increased odds of AKI (95% CI 1.15 to 4.16). When examining host response, severe AKI was associated with increased immune and endothelial activation (increased CHI3L1, sTNFR1, sTREM-1, IL-8, Angpt-2, sFlt-1) while BWF was predominantly associated with endothelial activation (increased Angpt-2 and sFlt-1, decreased Angpt-1). The presence of severe AKI, not BWF, was associated with increased risk of in-hospital death (RR, 2.17 95% CI 1.01 to 4.64) adjusting for age, sex, and disease severity.

Conclusions: BWF is associated with severe AKI in children hospitalized with a severe febrile illness. Increased awareness of AKI in the setting of BWF, and improved access to AKI diagnostics, is needed to reduce disease progression and in-hospital mortality in this high-risk group of children through early implementation of kidney-protective measures.
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http://dx.doi.org/10.1186/s12916-022-02410-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9248152PMC
July 2022

Level and Duration of IgG and Neutralizing Antibodies to SARS-CoV-2 in Children with Symptomatic or Asymptomatic SARS-CoV-2 Infection.

Immunohorizons 2022 06 24;6(6):408-415. Epub 2022 Jun 24.

Ryan White Center for Pediatric Infectious Diseases and Global Health, Indiana University, Indianapolis, IN; and

There 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, = 8; adults, = 16), 2) symptomatic, PCR, or untested (children, = 27), 3) asymptomatic exposed (children, = 13), and 4) asymptomatic, no known exposure (children, = 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%; = 0.32) in contrast to adults (81.3 to 50.0%; = 0.03). Among children with nAb ( = 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.
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http://dx.doi.org/10.4049/immunohorizons.2200029DOI Listing
June 2022

Neutrophil gelatinase-associated lipocalin is elevated in children with acute kidney injury and sickle cell anemia, and predicts mortality.

Kidney Int 2022 Jun 17. Epub 2022 Jun 17.

Department of Pediatrics, Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, Indianapolis, Indiana, USA. Electronic address:

Urine neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury that has been adapted to a urine dipstick test. However, there is limited data on its use in low-and-middle-income countries where diagnosis of acute kidney injury remains a challenge. To study this, we prospectively enrolled 250 children with sickle cell anemia aged two to 18 years encompassing 185 children hospitalized with a vaso-occlusive pain crisis and a reference group of 65 children attending the sickle cell clinic for routine care follow up. Kidney injury was defined using serial creatinine measures and a modified-Kidney Disease Improving Global Outcome definition for sickle cell anemia. Urine NGAL was measured using the NGAL dipstick and a laboratory reference. The mean age of children enrolled was 8.9 years and 42.8% were female. Among hospitalized children, 36.2% had kidney injury and 3.2% died. Measured urine NGAL levels by the dipstick were strongly correlated with the standard enzyme-linked immunosorbent assay for urine NGAL (hospitalized children, 0.71; routine care reference, 0.88). NGAL levels were elevated in kidney injury and significantly increased across injury stages. Hospitalized children with a high-risk dipstick test (300ng/mL and more) had a 2.47-fold relative risk of kidney injury (95% confidence interval 1.68 to 3.61) and 7.28 increased risk of death (95% confidence interval 1.10 to 26.81) adjusting for age and sex. Thus, urine NGAL levels were found to be significantly elevated in children with sickle cell anemia and acute kidney injury and may predict mortality.
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http://dx.doi.org/10.1016/j.kint.2022.05.020DOI Listing
June 2022

Impact of oxidative stress on risk of death and readmission in African children with severe malaria: a prospective observational study.

J Infect Dis 2022 Jun 9. Epub 2022 Jun 9.

Department of Pediatrics, Ryan White Center for Pediatric Infectious Diseases and Global Health, Indiana University School of Medicine, Indianapolis, IN, United States.

Background: 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 < 0.001) and lower superoxide dismutase (SOD) activity than CC (p < 0.02). Children with CM had a higher risk of death with increasing HO-1 concentration (odds ratio (OR) [95% confidence interval, (CI)], 6.07 [1.17-31.31], p = 0.03), but a lower risk of death with increasing SOD activity (OR [95% CI], 0.02 [0.001-0.70], p = 0.03). There were no associations between oxidative stress biomarkers on admission and risk of readmission within 6 months of enrolment.

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. Registered at clinicaltrials.gov as NCT01093989.
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http://dx.doi.org/10.1093/infdis/jiac234DOI Listing
June 2022

Acute kidney injury interacts with coma, acidosis, and impaired perfusion to significantly increase risk of death in children with severe malaria.

Clin Infect Dis 2022 Mar 29. Epub 2022 Mar 29.

Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA.

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 to 48 months 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, acute kidney injury (AKI), elevated BUN and hyperkalemia were associated with increased mortality (all p<0.001). AKI interacted with each risk factor to increase mortality (p<0.001 for interaction). Children with clinical indications for dialysis (14.4% of all children) had an increased risk of death compared to those with no indications for dialysis (odds ratio [95% confidence interval], 6.56 [3.41, 12.59]).

Conclusion And Recommendation: 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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http://dx.doi.org/10.1093/cid/ciac229DOI Listing
March 2022

Acute kidney injury in hospitalized children with sickle cell anemia.

BMC Nephrol 2022 03 18;23(1):110. Epub 2022 Mar 18.

Department of Pediatrics, Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, Indianapolis, IN, USA.

Background: Children with sickle cell anemia (SCA) are at increased risk of acute kidney injury (AKI) that may lead to death or chronic kidney disease. This study evaluated AKI prevalence and risk factors in children with SCA hospitalized with a vaso-occlusive crisis (VOC) in a low-resource setting. Further, we evaluated whether modifications to the Kidney Disease: Improving Global Outcomes (KDIGO) definition would influence clinical outcomes of AKI in children with SCA hospitalized with a VOC.

Methods: We prospectively enrolled 185 children from 2 - 18 years of age with SCA (Hemoglobin SS) hospitalized with a VOC at a tertiary hospital in Uganda. Kidney function was assessed on admission, 24-48 h of hospitalization, and day 7 or discharge. Creatinine was measured enzymatically using an isotype-dilution mass spectrometry traceable method. AKI was defined using the original-KDIGO definition as ≥ 1.5-fold change in creatinine within seven days or an absolute change of ≥ 0.3 mg/dl within 48 h. The SCA modified-KDIGO (sKDIGO) definition excluded children with a 1.5-fold change in creatinine from 0.2 mg/dL to 0.3 mg/dL.

Results: Using KDIGO, 90/185 (48.7%) children had AKI with 61/185 (33.0%) AKI cases present on admission, and 29/124 (23.4%) cases of incident AKI. Overall, 23 children with AKI had a 1.5-fold increase in creatinine from 0.2 mg/dL to 0.3 m/dL. Using the sKDIGO-definition, 67/185 (36.2%) children had AKI with 43/185 (23.2%) cases on admission, and 24/142 (16.9%) cases of incident AKI. The sKDIGO definition, but not the original-KDIGO definition, was associated with increased mortality (0.9% vs. 7.5%, p = 0.024). Using logistic regression, AKI risk factors included age (aOR, 1.10, 95% CI 1.10, 1.20), hypovolemia (aOR, 2.98, 95% CI 1.08, 8.23), tender hepatomegaly (aOR, 2.46, 95% CI 1.05, 5.81), and infection (aOR, 2.63, 95% CI 1.19, 5.81) (p < 0.05).

Conclusion: These results demonstrate that AKI is a common complication in children with SCA admitted with VOC. The sKDIGO definition of AKI in children with SCA was a better predictor of clinical outcomes in children. There is need for promotion of targeted interventions to ensure early identification and treatment of AKI in children with SCA.
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http://dx.doi.org/10.1186/s12882-022-02731-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8933904PMC
March 2022

Emerging infections and pandemics: The critical importance of global health equity action.

Mol Ther 2022 05 17;30(5):1793-1796. Epub 2022 Mar 17.

Ryan White Center for Pediatric Infectious Diseases and Global Health, Indiana University School of Medicine, 1044 W Walnut Street, R4-402D, Indianapolis, IN 46202, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ymthe.2022.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8929681PMC
May 2022

Acute kidney injury, persistent kidney disease, and post-discharge morbidity and mortality in severe malaria in children: A prospective cohort study.

EClinicalMedicine 2022 Feb 12;44:101292. Epub 2022 Feb 12.

Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, 1044 W. Walnut St., Indianapolis, IN, USA.

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 ( < 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  < 0·05). Paracetamol use during hospitalization was associated with reduced AKD ( < 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.

Funding: This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke (R01NS055349 to CCJ) and the Fogarty International Center (D43 TW010928 to CCJ), and a Ralph W. and Grace M. Showalter Young Investigator Award to ALC.
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http://dx.doi.org/10.1016/j.eclinm.2022.101292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8850340PMC
February 2022

Malaria.

JAMA 2022 02;327(6):597

Indiana University School of Medicine, Indianapolis.

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http://dx.doi.org/10.1001/jama.2021.21468DOI Listing
February 2022

Identification of Key Determinants of Cerebral Malaria Development and Inhibition Pathways.

mBio 2022 Jan 25:e0370821. Epub 2022 Jan 25.

Johns Hopkins Bloomberg School of Public Health, Department of Molecular Microbiology and Immunology and Malaria Research Institute, Baltimore, Maryland, USA.

Cerebral malaria (CM), coma caused by Plasmodium falciparum-infected red blood cells (iRBCs), is the deadliest complication of malaria. The mechanisms that lead to CM development are incompletely understood. Here we report on the identification of activation and inhibition pathways leading to mouse CM with supporting evidence from the analysis of human specimens. We find that CM suppression can be induced by vascular injury when sporozoites exit the circulation to infect the liver and that CM suppression is mediated by the release of soluble factors into the circulation. Among these factors is insulin like growth factor 1 (IGF1), administration of which inhibits CM development in mice. Liver infection by sporozoites is a required step for infection of the organism. We found that alternate pathways of sporozoite liver infection differentially influence cerebral malaria (CM) development. CM is one of the primary causes of death following malaria infection. To date, CM research has focused on how CM phenotypes develop but no successful therapeutic treatment or prognostic biomarkers are available. Here we show for the first time that sporozoite liver invasion can trigger CM-inhibitory immune responses. Importantly, we identified a number of early-stage prognostic CM inhibitory biomarkers, many of which had never been associated with CM development. Serological markers identified using a mouse model are directly relevant to human CM.
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http://dx.doi.org/10.1128/mbio.03708-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8787489PMC
January 2022

Association of Plasma Tau With Mortality and Long-term Neurocognitive Impairment in Survivors of Pediatric Cerebral Malaria and Severe Malarial Anemia.

JAMA Netw Open 2021 12 1;4(12):e2138515. Epub 2021 Dec 1.

Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, Indianapolis.

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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http://dx.doi.org/10.1001/jamanetworkopen.2021.38515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8665370PMC
December 2021

The Impact of Undernutrition on Cognition in Children with Severe Malaria and Community Children: A Prospective 2-Year Cohort Study.

J Trop Pediatr 2021 10;67(5)

Department of Pediatrics, Ryan White Center for Pediatric Infectious Diseases and Global Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Background: The frequency of recovery from undernutrition after an episode of severe malaria, and the relationship between undernutrition during severe malaria and clinical and cognitive outcomes are not well characterized.

Methods: We evaluated undernutrition and cognition in children in Kampala, Uganda 18 months to 5 years of age with cerebral malaria (CM), severe malarial anemia (SMA) or community children (CC). The Mullen Scales of Early Learning was used to measure cognition. Undernutrition, defined as 2 SDs below median for weight-for-age (underweight), height-for-age (stunting) or weight-for-height (wasting), was compared with mortality, hospital readmission and cognition over 24-month follow-up.

Results: At enrollment, wasting was more common in CM (16.7%) or SMA (15.9%) than CC (4.7%) (both p < 0.0001), and being underweight was more common in SMA (27.0%) than CC (12.8%; p = 0.001), while prevalence of stunting was similar in all three groups. By 6-month follow-up, prevalence of wasting or being underweight did not differ significantly between children with severe malaria and CC. Undernutrition at enrollment was not associated with mortality or hospital readmission, but children who were underweight or stunted at baseline had lower cognitive z-scores than those who were not {underweight, mean difference [95% confidence interval (CI)] -0.98 (-1.66, -0.31), -0.72 (-1.16, -0.27) and -0.61 (-1.08, -0.13); and stunted, -0.70 (-1.25, -0.15), -0.73 (-1.16, -0.31) and -0.61 (-0.96, -0.27), for CM, SMA and CC, respectively}.

Conclusion: In children with severe malaria, wasting and being underweight return to population levels after treatment. However, being stunted or underweight at enrollment was associated with worse long-term cognition in both CC and children with severe malaria.
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http://dx.doi.org/10.1093/tropej/fmab091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8578678PMC
October 2021

Evaluating kidney function using a point-of-care creatinine test in Ugandan children with severe malaria: a prospective cohort study.

BMC Nephrol 2021 11 6;22(1):369. Epub 2021 Nov 6.

Department of Pediatrics, Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, 1044 W. Walnut St., Indianapolis, IN, 46202, USA.

Background: 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 R values of 0.95 and 0.93 respectively; however, the correlation was significantly lower in children with creatinine values <1mg/dL (R 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.
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http://dx.doi.org/10.1186/s12882-021-02573-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8572470PMC
November 2021

Towards the use of a smartphone imaging-based tool for point-of-care detection of asymptomatic low-density malaria parasitaemia.

Malar J 2021 Sep 25;20(1):380. Epub 2021 Sep 25.

Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, 47907, USA.

Background: 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.
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http://dx.doi.org/10.1186/s12936-021-03894-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466697PMC
September 2021

The prevalence and density of asymptomatic Plasmodium falciparum infections among children and adults in three communities of western Kenya.

Malar J 2021 Sep 17;20(1):371. Epub 2021 Sep 17.

Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.

Background: Further reductions in malaria incidence as more countries approach malaria elimination require the identification and treatment of asymptomatic individuals who carry mosquito-infective Plasmodium gametocytes that are responsible for furthering malaria transmission. Assessing the relationship between total parasitaemia and gametocytaemia in field surveys can provide insight as to whether detection of low-density, asymptomatic Plasmodium falciparum infections with sensitive molecular methods can adequately detect the majority of infected individuals who are potentially capable of onward transmission.

Methods: In a cross-sectional survey of 1354 healthy children and adults in three communities in western Kenya across a gradient of malaria transmission (Ajigo, Webuye, and Kapsisywa-Kipsamoite), asymptomatic P. falciparum infections were screened by rapid diagnostic tests, blood smear, and quantitative PCR of dried blood spots targeting the varATS gene in genomic DNA. A multiplex quantitative reverse-transcriptase PCR assay targeting female and male gametocyte genes (pfs25, pfs230p), a gene with a transcriptional pattern restricted to asexual blood stages (piesp2), and human GAPDH was also developed to determine total parasite and gametocyte densities among parasitaemic individuals.

Results: The prevalence of varATS-detectable asymptomatic infections was greatest in Ajigo (42%), followed by Webuye (10%). Only two infections were detected in Kapsisywa. No infections were detected in Kipsamoite. Across all communities, children aged 11-15 years account for the greatest proportion total and sub-microscopic asymptomatic infections. In younger age groups, the majority of infections were detectable by microscopy, while 68% of asymptomatically infected adults (> 21 years old) had sub-microscopic parasitaemia. Piesp2-derived parasite densities correlated poorly with microscopy-determined parasite densities in patent infections relative to varATS-based detection. In general, both male and female gametocytaemia increased with increasing varATS-derived total parasitaemia. A substantial proportion (41.7%) of individuals with potential for onward transmission had qPCR-estimated parasite densities below the limit of microscopic detection, but above the detectable limit of varATS qPCR.

Conclusions: This assessment of parasitaemia and gametocytaemia in three communities with different transmission intensities revealed evidence of a substantial sub-patent infectious reservoir among asymptomatic carriers of P. falciparum. Experimental studies are needed to definitively determine whether the low-density infections in communities such as Ajigo and Webuye contribute significantly to malaria transmission.
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http://dx.doi.org/10.1186/s12936-021-03905-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447531PMC
September 2021

Decreased parasite burden and altered host response in children with sickle cell anemia and severe anemia with malaria.

Blood Adv 2021 11;5(22):4710-4720

Ryan White Center for Pediatric Infectious Diseases and Global Health, School of Medicine, Indiana University, Indianapolis, IN.

Plasmodium falciparum malaria causes morbidity and mortality in African children with sickle cell anemia (SCA), but comparisons of host responses to P falciparum between children with SCA (homozygous sickle cell disease/hemoglobin SS [HbSS]) and normal hemoglobin genotype/hemoglobin AA (HbAA) are limited. We assessed parasite biomass and plasma markers of inflammation and endothelial activation in children with HbAA (n = 208) or HbSS (n = 22) who presented with severe anemia and P falciparum parasitemia to Mulago Hospital in Kampala, Uganda. Genotyping was performed at study completion. No child had known SCA at enrollment. Children with HbSS did not differ from children with HbAA in peripheral parasite density, but had significantly lower sequestered parasite biomass. Children with HbSS had greater leukocytosis but significantly lower concentrations of several plasma inflammatory cytokines, including tumor necrosis factor α (TNF-α). In contrast, children with HbSS had threefold greater concentrations of angiopoietin-2 (Angpt-2), a marker of endothelial dysregulation associated with mortality in severe malaria. Lower TNF-α concentrations were associated with increased risk of postdischarge mortality or readmission, whereas higher Angpt-2 concentrations were associated with increased risk of recurrent clinical malaria. Children with SCA have decreased parasite sequestration and inflammation but increased endothelial dysregulation during severe anemia with P falciparum parasitemia, which may ameliorate acute infectious complications but predispose to harmful long-term sequelae.
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http://dx.doi.org/10.1182/bloodadvances.2021004704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759120PMC
November 2021

Children are the key to the Endgame: A case for routine pediatric COVID vaccination.

Vaccine 2021 09 12;39(38):5333-5336. Epub 2021 Aug 12.

New York-Presbyterian/Weill Cornell Medical Center, Department of Pediatrics, 525 E 68th St, New York, NY 10065, United States. Electronic address:

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http://dx.doi.org/10.1016/j.vaccine.2021.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358829PMC
September 2021

Parenteral artemisinins are associated with reduced mortality and neurologic deficits and improved long-term behavioral outcomes in children with severe malaria.

BMC Med 2021 07 28;19(1):168. Epub 2021 Jul 28.

Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, R4 402C 1044 West Walnut St, Indianapolis, IN, 46202, USA.

Background: In 2011, the World Health Organization recommended injectable artesunate as the first-line therapy for severe malaria (SM) due to its superiority in reducing mortality compared to quinine. There are limited data on long-term clinical and neurobehavioral outcomes after artemisinin use for treatment of SM.

Methods: From 2008 to 2013, 502 Ugandan children with two common forms of SM, cerebral malaria and severe malarial anemia, were enrolled in a prospective observational study assessing long-term neurobehavioral and cognitive outcomes following SM. Children were evaluated a week after hospital discharge, and 6, 12, and 24 months of follow-up, and returned to hospital for any illness. In this study, we evaluated the impact of artemisinin derivatives on survival, post-discharge hospital readmission or death, and neurocognitive and behavioral outcomes over 2 years of follow-up.

Results: 346 children received quinine and 156 received parenteral artemisinin therapy (artemether or artesunate). After adjustment for disease severity, artemisinin derivatives were associated with a 78% reduction in in-hospital mortality (adjusted odds ratio, 0.22; 95% CI, 0.07-0.67). Among cerebral malaria survivors, children treated with artemisinin derivatives also had reduced neurologic deficits at discharge (quinine, 41.7%; artemisinin derivatives, 23.7%, p=0.007). Over a 2-year follow-up, artemisinin derivatives as compared to quinine were associated with better adjusted scores (negative scores better) in internalizing behavior and executive function in children irrespective of the age at severe malaria episode. After adjusting for multiple comparisons, artemisinin derivatives were associated with better adjusted scores in behavior and executive function in children <6 years of age at severe malaria exposure following adjustment for child age, sex, socioeconomic status, enrichment in the home environment, and the incidence of hospitalizations over follow-up. Children receiving artesunate had the greatest reduction in mortality and benefit in behavioral outcomes and had reduced inflammation at 1-month follow-up compared to children treated with quinine.

Conclusions: Treatment of severe malaria with artemisinin derivatives, particularly artesunate, results in reduced in-hospital mortality and neurologic deficits in children of all ages, reduced inflammation following recovery, and better long-term behavioral outcomes. These findings suggest artesunate has long-term beneficial effects in children surviving severe malaria.
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http://dx.doi.org/10.1186/s12916-021-02033-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317420PMC
July 2021

Multiplexed and High-Throughput Label-Free Detection of RNA/Spike Protein/IgG/IgM Biomarkers of SARS-CoV-2 Infection Utilizing Nanoplasmonic Biosensors.

Anal Chem 2021 06 14;93(25):8754-8763. Epub 2021 Jun 14.

Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, 402 N Blackford Street, Indianapolis, Indiana 46202, United States.

To tackle the COVID-19 outbreak, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is an unmet need for highly accurate diagnostic tests at all stages of infection with rapid results and high specificity. Here, we present a label-free nanoplasmonic biosensor-based, multiplex screening test for COVID-19 that can quantitatively detect 10 different biomarkers (6 viral nucleic acid genes, 2 spike protein subunits, and 2 antibodies) with a limit of detection in the aM range, all within one biosensor platform. Our newly developed nanoplasmonic biosensors demonstrate high specificity, which is of the upmost importance to avoid false responses. As a proof of concept, we show that our detection approach has the potential to quantify both IgG and IgM antibodies directly from COVID-19-positive patient plasma samples in a single instrument run, demonstrating the high-throughput capability of our detection approach. Most importantly, our assay provides receiving operating characteristics, areas under the curve of 0.997 and 0.999 for IgG and IgM, respectively. The calculated -value determined through the Mann-Whitney nonparametric test is <0.0001 for both antibodies when the test of COVID-19-positive patients ( = 80) is compared with that of healthy individuals ( = 72). Additionally, the screening test provides a calculated sensitivity (true positive rate) of 100% (80/80), a specificity (true negative rate) >96% (77/80), a positive predictive value of 98% at 5% prevalence, and a negative predictive value of 100% at 5% prevalence. We believe that our very sensitive, multiplex, high-throughput testing approach has potential applications in COVID-19 diagnostics, particularly in determining virus progression and infection severity for clinicians for an appropriate treatment, and will also prove to be a very effective diagnostic test when applied to diseases beyond the COVID-19 pandemic.
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http://dx.doi.org/10.1021/acs.analchem.0c05300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230954PMC
June 2021

Time to Reflect on Global Health Agenda in Kenya: A Tribute to our Academic and Biomedical Research Mentors.

J Health Care Poor Underserved 2021 ;32(2):xvi-xxi

We submit this column to present a brief biography, a tribute to three departed global health mentors who were instrumental in our careers and for the growth of biomedical research in Kenya. We briefly discuss their educational backgrounds and put forth a set of qualities, values, personal supportive experiences, and achievements that nurtured our careers as scientists. The mentors are Prof. Ayub Opiyo Ofulla, Dr. John F. Kennedy Vulule, and Dr. Peter Odada Sumba. We appeal to the community of researchers in biomedical sciences, global health, and epidemiology who study a particular disease or health risk (conducting interventional and observational research) to mentor, teach, and serve as role models for upcoming scholars. There is a need for a positive and supportive attitude to create a universal environment to nurture the next generation of researchers transcending race, color, nationality, ethnicity, culture, faith, gender identities, sexual orientation, age, ability, and background.
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http://dx.doi.org/10.1353/hpu.2021.0085DOI Listing
September 2021

Use of the creating opportunities for parent empowerment programme to decrease mental health problems in Ugandan children surviving severe malaria: a randomized controlled trial.

Malar J 2021 Jun 13;20(1):267. Epub 2021 Jun 13.

Department of Pediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda.

Background: Severe malaria is associated with long-term mental health problems in Ugandan children. This study investigated the effect of a behavioural intervention for caregivers of children admitted with severe malaria, on the children's mental health outcomes 6 months after discharge.

Methods: This randomized controlled trial was conducted at Naguru Hospital in Kampala, Uganda from January 2018 to July 2019. Caregiver and child dyads were randomly assigned to either a psycho-educational arm providing information about hospital procedures during admission (control group), or to a behavioural arm providing information about the child's possible emotions and behaviour during and after admission, and providing age appropriate games for the caregiver and child (intervention group). Pre- and post-intervention assessments for caregiver anxiety and depression (Hopkins Symptom Checklist) and child mental health problems (Strength and Difficulties Questionnaire and the Child Behaviour Checklist) were done during admission and 6 months after discharge, respectively. T-tests, analysis of covariance, Chi-Square, and generalized estimating equations were used to compare outcomes between the two treatment arms.

Results: There were 120 caregiver-child dyads recruited at baseline with children aged 1.45 to 4.89 years (mean age 2.85 years, SD = 1.01). The intervention and control groups had similar sociodemographic, clinical and behavioural characteristics at baseline. Caregiver depression at baseline, mother's education and female child were associated with behavioural problems in the child at baseline (p < 0.05). At 6 months follow-up, there was no difference in the frequency of behavioural problems between the groups (6.8% vs. 10% in intervention vs control groups, respectively, p = 0.72). Caregiver depression and anxiety scores between the treatment arms did not differ at 6 months follow-up.

Conclusion: This behavioural intervention for caregivers and their children admitted with severe malaria had no effect on the child's mental health outcomes at 6 months. Further studies need to develop interventions for mental health problems after severe malaria in children with longer follow-up time. Trail registration ClinicalTrials.gov Identifier: NCT03432039.
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http://dx.doi.org/10.1186/s12936-021-03795-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201864PMC
June 2021

Dynamic modulation of spleen germinal center reactions by gut bacteria during Plasmodium infection.

Cell Rep 2021 05;35(6):109094

Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, USA; Ryan White Center for Pediatric Infectious Diseases and Global Health, Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address:

Gut microbiota educate the local and distal immune system in early life to imprint long-term immunological outcomes while maintaining the capacity to dynamically modulate the local mucosal immune system throughout life. It is unknown whether gut microbiota provide signals that dynamically regulate distal immune responses following an extra-gastrointestinal infection. We show here that gut bacteria composition correlated with the severity of malaria in children. Using the murine model of malaria, we demonstrate that parasite burden and spleen germinal center reactions are malleable to dynamic cues provided by gut bacteria. Whereas antibiotic-induced changes in gut bacteria have been associated with immunopathology or impairment of immunity, the data demonstrate that antibiotic-induced changes in gut bacteria can enhance immunity to Plasmodium. This effect is not universal but depends on baseline gut bacteria composition. These data demonstrate the dynamic communications that exist among gut bacteria, the gut-distal immune system, and control of Plasmodium infection.
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http://dx.doi.org/10.1016/j.celrep.2021.109094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141963PMC
May 2021

Adipose tissue parasite sequestration drives leptin production in mice and correlates with human cerebral malaria.

Sci Adv 2021 03 24;7(13). Epub 2021 Mar 24.

Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.

Circulating levels of the adipokine leptin are linked to neuropathology in experimental cerebral malaria (ECM), but its source and regulation mechanism remain unknown. Here, we show that sequestration of infected red blood cells (iRBCs) in white adipose tissue (WAT) microvasculature increased local vascular permeability and leptin production. Mice infected with parasite strains that fail to sequester in WAT displayed reduced leptin production and protection from ECM. WAT sequestration and leptin induction were lost in CD36KO mice; however, ECM susceptibility revealed sexual dimorphism. Adipocyte leptin was regulated by the mechanistic target of rapamycin complex 1 (mTORC1) and blocked by rapamycin. In humans, although infection did not increase circulating leptin levels, iRBC sequestration, tissue leptin production, and mTORC1 activity were positively correlated with CM in pediatric postmortem WAT. These data identify WAT sequestration as a trigger for leptin production with potential implications for pathogenesis of malaria infection, prognosis, and treatment.
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http://dx.doi.org/10.1126/sciadv.abe2484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990332PMC
March 2021

Identifying Risk Factors That Distinguish Symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infection From Common Upper Respiratory Infections in Children.

Cureus 2021 Feb 10;13(2):e13266. Epub 2021 Feb 10.

Department of Pediatrics, Indiana University School of Medicine, Indianapolis, USA.

Background Demographic and clinical risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children presenting with respiratory viral symptoms are not well defined. An understanding of risk factors for SARS-CoV-2 infection can help prioritize testing. Methodology We evaluated potential demographic and clinical factors in children who had respiratory viral symptoms and were tested by polymerase chain reaction (PCR) for SARS-CoV-2 and other respiratory viral infections. Results Among the 263 symptomatic children tested for routine seasonal respiratory viruses by PCR, 18 (6.8%) tested positive for SARS-CoV-2. Overall, 22.2% of SARS-CoV-2-infected children and 37.1% of SARS-CoV-2-uninfected children had infection with one or more non-SARS-CoV-2 pathogens (p = 0.31). Higher proportions of children with compared to without SARS-CoV-2 infection were male (77.8 vs. 51.8%, p = 0.05), Hispanic (44.4% vs. 9.8%, p < 0.001), or had the symptoms of fatigue (22.2% vs. 2.5%, p = 0.003) or anosmia/ageusia (11.1% vs. 0%, p = 0.004). History of hypoxic-ischemic encephalopathy (HIE) and obesity were more common in children with versus without SARS-CoV-2 infection (11.1% vs. 1.2%, p = 0.04, and 11.1% vs. 0%, p = 0.004, respectively). In a multivariate analysis, Hispanic ethnicity, symptoms of fatigue or anosmia/ageusia, and presence of obesity (as noted on physical examination) or HIE were independently associated with SARS-CoV-2 infection. Numbers in each category were small, and these preliminary associations require confirmation in future studies. Conclusions In this area of the United States, infection with other viruses did not rule out infection with SARS-CoV-2. Additionally, children with respiratory viral symptoms who were of Hispanic ethnicity, had symptoms of weakness/fatigue, or had obesity or HIE were at an increased risk for SARS-CoV-2 infection. Future studies should assess if these factors are associated with risk in populations in other areas of the United States.
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http://dx.doi.org/10.7759/cureus.13266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948314PMC
February 2021

Plasma angiopoietin-2 is associated with age-related deficits in cognitive sub-scales in Ugandan children following severe malaria.

Malar J 2021 Jan 6;20(1):17. Epub 2021 Jan 6.

Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, Indianapolis, IN, USA.

Background: Elevated angiopoietin-2 (Angpt-2) concentrations are associated with worse overall neurocognitive function in severe malaria survivors, but the specific domains affected have not been elucidated.

Methods: Ugandan children with severe malaria underwent neurocognitive evaluation a week after hospital discharge and at 6, 12 and 24 months follow-up. The relationship between Angpt-2 concentrations and age-adjusted, cognitive sub-scale z-scores over time were evaluated using linear mixed effects models, adjusting for disease severity (coma, acute kidney injury, number of seizures in hospital) and sociodemographic factors (age, gender, height-for-age z-score, socio-economic status, enrichment in the home environment, parental education, and any preschool education of the child). The Mullen Scales of Early Learning was used in children < 5 years and the Kaufman Assessment Battery for Children 2nd edition was used in children ≥ 5 years of age. Angpt-2 levels were measured on admission plasma samples by enzyme-linked immunosorbent assay. Adjustment for multiple comparisons was conducted using the Benjamini-Hochberg Procedure of False Discovery Rate.

Results: Increased admission Angpt-2 concentration was associated with worse outcomes in all domains (fine and gross motor, visual reception, receptive and expressive language) in children < 5 years of age at the time of severe malaria episode, and worse simultaneous processing and learning in children < 5 years of age at the time of severe malaria who were tested when ≥ 5 years of age. No association was seen between Angpt-2 levels and cognitive outcomes in children ≥ 5 years at the time of severe malaria episode, but numbers of children and testing time points were lower for children ≥ 5 years at the time of severe malaria episode.

Conclusion: Elevated Angpt-2 concentration in children with severe malaria is associated with worse outcomes in multiple neurocognitive domains. The relationship between Angpt-2 and worse cognition is evident in children < 5 years of age at the time of severe malaria presentation and in selected domains in older years.
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http://dx.doi.org/10.1186/s12936-020-03545-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789657PMC
January 2021

Adults Are Not Big Children: What Brain Magnetic Resonance Imaging Findings Tell Us About Differences in Pediatric and Adult Cerebral Malaria.

Authors:
Chandy C John

Clin Infect Dis 2021 10;73(7):e2397-e2398

Ryan White Center for Pediatric Infectious Diseases and Global Health, Indiana University School of Medicine, Indianapolis, Indiana, USA.

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http://dx.doi.org/10.1093/cid/ciaa1659DOI Listing
October 2021

Socio-emotional and adaptive behaviour in children treated for severe anaemia at Lira Regional Referral Hospital, Uganda: a prospective cohort study.

Child Adolesc Psychiatry Ment Health 2020 Nov 26;14(1):45. Epub 2020 Nov 26.

Department of Psychiatry, Makerere University, College of Health Sciences, P.O. Box 7072, Kampala, Uganda.

Background: Severe anaemia is a global public health challenge commonly associated with morbidity and mortality among children < 5 years of age in Sub-Saharan Africa. However, less is known about the behavioural performance of children < 5 years surviving severe anaemia in low resource settings. We investigated social-emotional and adaptive behaviour in children < 5 years diagnosed with severe anaemia in Northern Uganda.

Methods: We conducted a hospital based prospective cohort study among children 6-42 months who were treated for severe anaemia (n = 171) at Lira Regional Referral Hospital, Uganda. Socio-emotional and adaptive behaviour were assessed 14 days post discharge using the Bayley Scales of Infant and Toddler Development, 3rd edition. Age-adjusted z-scores for each domain were calculated using scores from healthy community children (n = 88) from the same environment for each age category. Multiple linear regression was used to compare z-scores in the social-emotional and adaptive behaviour scales between the two groups after adjusting for weight-for-age z-score, social economic status, mother's education, father's education and father's employment on all the scales.

Results: Compared with healthy community controls, children with severe anaemia had poorer [adjusted mean scores (standard error)], socio-emotional [- 0.29, (0.05) vs. 0.01, (0.08), P = 0.002]; but not overall/ composite adaptive behaviour [- 0.10, (0.05) vs. - 0.01, (0.07), P = 0.343]. Within the adaptive behaviour subscales, children with SA displayed significantly poorer scores on the community use [adjusted mean score (standard error)], [- 0.63, (0.10) vs. - 0.01, (0.13), P < 0.001]; and leisure [- 0.35, (0.07) vs. - 0.02, (0.07), P = 0.036] skills.

Conclusion: This study suggests that severe anaemia in children < 5 years is associated with poor social-emotional scores in the short-term post clinical recovery in Northern Uganda. We recommend long-term follow-up to determine the course of these problems and appropriate interventions to reduce the behavioural burden among children < 5 years surviving severe anaemia in Uganda.
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http://dx.doi.org/10.1186/s13034-020-00352-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694894PMC
November 2020
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