Browsing by Author "John, Chandy C."

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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 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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    Adherence to clinical guidelines is associated with reduced inpatient mortality among children with severe anemia in Ugandan hospitals
    (PLOS, 2019-01-25) Opoka, Robert O.; Ssemata, Andrew S.; Oyang, William; Nambuya, Harriet; John, Chandy C.; Karamagi, Charles; Tumwine, James K.; Pediatrics, School of Medicine
    BACKGROUND: In resource limited settings, there is variability in the level of adherence to clinical guidelines in the inpatient management of children with common conditions like severe anemia. However, there is limited data on the effect of adherence to clinical guidelines on inpatient mortality in children managed for severe anemia. METHODS: We analyzed data from an uncontrolled before and after in-service training intervention to improve quality of care in Lira and Jinja regional referral hospitals in Uganda. Inpatient records of children aged 0 to 5 years managed as cases of 'severe anemia (SA)' were reviewed to ascertain adherence to clinical guidelines and compare inpatient deaths in SA children managed versus those not managed according to clinical guidelines. Logistic regression analysis was conducted to evaluate the relationship between clinical care factors and inpatient deaths amongst patients managed for SA. RESULTS: A total of 1,131 children were assigned a clinical diagnosis of 'severe anemia' in the two hospitals. There was improvement in the level of care after the in-service training intervention with more children being managed according to clinical guidelines compared to the period before, 218/510 (42.7%) vs 158/621 (25.4%) (p < 0.001). Overall, children managed according to clinical guidelines had reduced risk of inpatient mortality compared to those not managed according to clinical guidelines, [OR 0.28, (95%, CI 0.14, 0.55), p = 0.001]. Clinical care factors associated with decreased risk of inpatient death included, having pre-transfusion hemoglobin done to confirm diagnosis [OR 0.5; 95% CI 0.29, 0.87], a co-morbid diagnosis of severe malaria [OR 0.4; 95% CI 0.25, 0.76], and being reviewed after admission by a clinician [OR 0.3; 95% CI 0.18, 0.59], while a co-morbid diagnosis of severe acute malnutrition was associated with increased risk of inpatient death [OR 4.2; 95% CI 2.15, 8.22]. CONCLUSION: Children with suspected SA who are managed according to clinical guidelines have lower in-hospital mortality than those not managed according to the guidelines. Efforts to reduce inpatient mortality in SA children in resource-limited settings should focus on training and supporting health workers to adhere to clinical guidelines.
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    Adipose tissue parasite sequestration drives leptin production in mice and correlates with human cerebral malaria
    (American Association for the Advancement of Science, 2021-03-24) Mejia, Pedro; Treviño-Villarreal, J. Humberto; De Niz, Mariana; Meibalan, Elamaran; Longchamp, Alban; Reynolds, Justin S.; Turnbull, Lindsey B.; Opoka, Robert O.; Roussilhon, Christian; Spielmann, Tobias; Ozaki, C. Keith; Heussler, Volker T.; Seydel, Karl B.; Taylor, Terrie E.; John, Chandy C.; Milner, Danny A.; Marti, Matthias; Mitchell, James R.; Medicine, School of Medicine
    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 Plasmodium falciparum 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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    Admission EEG findings in diverse paediatric cerebral malaria populations predict outcomes
    (BMC, 2018-05-22) Postels, Douglas G.; Wu, Xiaoting; Li, Chenxi; Kaplan, Peter W.; Seydel, Karl B.; Taylor, Terrie E.; Kousa, Youssef A.; Idro, Richard; Opoka, Robert; John, Chandy C.; Birbeck, Gretchen L.; Medicine, School of Medicine
    Electroencephalography at hospital presentation may offer important insights regarding prognosis that can inform understanding of cerebral malaria (CM) pathophysiology and potentially guide patient selection and risk stratification for future clinical trials. Electroencephalogram (EEG) findings in children with CM in Uganda and Malawi were compared and associations between admission EEG findings and outcome across this diverse population were assessed. Demographic, clinical and admission EEG data from Ugandan and Malawian children admitted from 2009 to 2012 with CM were gathered, and survivors assessed for neurological abnormalities at discharge. RESULTS: 281 children were enrolled (Uganda n = 122, Malawi n = 159). The Malawian population was comprised only of retinopathy positive children (versus 72.5% retinopathy positive in Uganda) and were older (4.2 versus 3.7 years; p = 0.046), had a higher HIV prevalence (9.0 versus 2.8%; p = 0.042), and worse hyperlactataemia (7.4 versus 5.2 mmol/L; p < 0.001) on admission compared to the Ugandan children. EEG findings differed between the two groups in terms of average voltage and frequencies, reactivity, asymmetry, and the presence/absence of sleep architecture. In univariate analyses pooling EEG and outcomes data for both sites, higher average and maximum voltages, faster dominant frequencies, and retained reactivity were associated with survival (all p < 0.05). Focal slowing was associated with death (OR 2.93; 95% CI 1.77-7.30) and a lower average voltage was associated with neurological morbidity in survivors (p = 0.0032). CONCLUSIONS: Despite substantial demographic and clinical heterogeneity between subjects in Malawi and Uganda as well as different EEG readers at each site, EEG findings on admission predicted mortality and morbidity. For CM clinical trials aimed at decreasing mortality or morbidity, EEG may be valuable for risk stratification and/or subject selection.
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    Asymptomatic Malaria and Other Infections in Children Adopted from Ethiopia, United States, 2006-2011
    (Centers For Disease Control and Prevention, 2015-07) Adebo, Senait M.; Eckerle, Judith K.; Andrews, Mary E.; Howard, Cynthia R.; John, Chandy C.; Department of Pediatrics, IU School of Medicine
    We screened 52 children adopted from Ethiopia for malaria because they had previously lived in a disease-endemic region or had past or current hepatomegaly or splenomegaly. Seven (13.5%) children had asymptomatic malaria parasitemia by microscopy (n = 2) or PCR (n = 5). Our findings suggest that adoptees at risk for asymptomatic malaria should be screened, preferably by PCR.
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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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    The Benjamin H. Kean Travel Fellowship in Tropical Medicine: Assessment of Impact at 15 Years
    (American Society of Tropical Medicine and Hygiene, 2017-09-07) Carman, Aubri S.; John, Chandy C.; Pediatrics, School of Medicine
    Abstract. The Benjamin H. Kean Fellowship in Tropical Medicine is an American Society of Tropical Medicine and Hygiene initiative that provides medical students with funding for international clinical or research experiences lasting at least 1 month. Of the 175 Kean fellows from 1998 to 2013, 140 had current available e-mails, and 70 of the 140 (50%) responded to a survey about their fellowship experience. Alumni indicated that the Kean Fellowship had a high impact on their career plans with regard to preparation for (N = 65, 94.2%) and inspiration to pursue (N = 59, 88.1%) a career in tropical medicine and global health. Continued involvement in tropical medicine and global health was common: 52 alumni (74.3%) were currently working in tropical medicine or global health, 49 (71.0%) had done so in the interim between the Kean fellowship and their current position; and 17 of 19 Kean fellows (89.4%) who had completed all medical training and were now in professional practice continued to work in tropical medicine and global health. Alumni had been highly productive academically, publishing a total of 831 PubMed-indexed manuscripts, almost all on tropical medicine or global health topics, in the period between their fellowship year and 2013. Alumni reported strengths of the fellowship including funding, networking, and flexibility, and suggested that more networking and career mentoring would enhance the program. The Benjamin H. Kean fellowship program has been highly successful at inspiring and fostering ongoing work by trainees in tropical medicine and global health.
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    Blackwater Fever in Ugandan Children With Severe Anemia is Associated With Poor Postdischarge Outcomes: A Prospective Cohort Study
    (Oxford University Press, 2019-07-12) Opoka, Robert O.; Waiswa, Ali; Harriet, Nambuya; John, Chandy C.; Tumwine, James K.; Karamagi, Charles; Medicine, School of Medicine
    Background: Blackwater fever (BWF), one of the complications of severe malaria, has recently re-emerged as a cause of severe anemia (SA) in African children. However, postdischarge morbidity in children with BWF has previously not been described. Methods: This was a descriptive cohort study in which children, aged 0-5 years, admitted to Jinja Regional Referral Hospital with acute episodes of SA (hemoglobin ≤5.0 g/dL) were followed up for 6 months after hospitalization. Incidence of readmissions or deaths during the follow-up period was compared between SA children with BWF and those without BWF. Results: A total of 279 children with SA including those with BWF (n = 92) and no BWF (n = 187) were followed for the duration of the study. Overall, 128 (45.9%) of the study participants were readmitted at least once while 22 (7.9%) died during the follow-up period. After adjusting for age, sex, nutritional status, and parasitemia, SA children with BWF had higher risk of readmissions (hazard ratio [HR], 1.68; 95% confidence interval [CI], 1.1-2.5) and a greater risk of death (HR. 3.37; 95% CI, 1.3-8.5) compared with those without BWF. Malaria and recurrence of SA were the most common reasons for readmissions. Conclusions: There is a high rate of readmissions and deaths in the immediate 6 months after initial hospitalization among SA children in the Jinja hospital. SA children with BWF had increased risk of readmissions and deaths in the postdischarge period. Postdischarge malaria chemoprophylaxis should be considered for SA children living in malaria endemic areas.