Browsing by Author "Hodges, James S."

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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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    Antibody Correlates of Protection from Clinical Plasmodium falciparum Malaria in an Area of Low and Unstable Malaria Transmission
    (American Society of Tropical Medicine and Hygiene, 2020-12) Hamre, Karen E.S.; Ondigo, Bartholomew N.; Hodges, James S.; Dutta, Sheetij; Theisen, Michael; Ayodo, George; John, Chandy C.; Pediatrics, School of Medicine
    Immune correlates of protection against clinical malaria are difficult to ascertain in low-transmission areas because of the limited number of malaria cases. We collected blood samples from 5,753 individuals in a Kenyan highland area, ascertained malaria incidence in this population over the next 6 years, and then compared antibody responses to 11 Plasmodium falciparum vaccine candidate antigens in individuals who did versus did not develop clinical malaria in a nested case-control study (154 cases and 462 controls). Individuals were matched by age and village. Antigens tested included circumsporozoite protein (CSP), liver-stage antigen (LSA)-1, apical membrane antigen-1 FVO and 3D7 strains, erythrocyte-binding antigen-175, erythrocyte-binding protein-2, merozoite surface protein (MSP)-1 FVO and 3D7 strains, MSP-3, and glutamate-rich protein (GLURP) N-terminal non-repetitive (R0) and C-terminal repetitive (R2) regions. After adjustment for potential confounding factors, the presence of antibodies to LSA-1, GLURP-R2, or GLURP-R0 was associated with decreased odds of developing clinical malaria (odds ratio [OR], [95% CI] 0.56 [0.36-0.89], 0.56 [0.36-0.87], and 0.77 [0.43-1.02], respectively). Levels of antibodies to LSA-1, GLURP-R2, and CSP were associated with decreased odds of developing clinical malaria (OR [95% CI]; 0.61 [0.41-0.89], 0.60 [0.43-0.84], and 0.49 [0.24-0.99], for every 10-fold increase in antibody levels, respectively). The presence of antibodies to CSP, GLURP-R0, GLURP-R2, and LSA-1 combined best-predicted protection from clinical malaria. Antibodies to CSP, GLURP-R0, GLURP-R2, and LSA-1 are associated with protection against clinical malaria in a low-transmission setting. Vaccines containing these antigens should be evaluated in low malaria transmission areas.
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    The endothelial protein C receptor rs867186-GG genotype is associated with increased soluble EPCR and could mediate protection against severe malaria
    (Nature Publishing Group, 2016-06-03) Shabani, Estela; Opoka, Robert O.; Bangirana, Paul; Park, Gregory S.; Vercellotti, Gregory M.; Guan, Weihua; Hodges, James S.; Lavstsen, Thomas; John, Chandy C.; Department of Pediatrics, IU School of Medicine
    The endothelial protein C receptor (EPCR) appears to play an important role in Plasmodium falciparum endothelial cell binding in severe malaria (SM). Despite consistent findings of elevated soluble EPCR (sEPCR) in other infectious diseases, field studies to date have provided conflicting data about the role of EPCR in SM. To better define this role, we performed genotyping for the rs867186-G variant, associated with increased sEPCR levels, and measured sEPCR levels in two prospective studies of Ugandan children designed to understand immunologic and genetic factors associated with neurocognitive deficits in SM including 551 SM children, 71 uncomplicated malaria (UM) and 172 healthy community children (CC). The rs867186-GG genotype was more frequent in CC (4.1%) than SM (0.6%, P = 0.002). The rs867186-G variant was associated with increased sEPCR levels and sEPCR was lower in children with SM than CC (P < 0.001). Among SM children, those who had a second SM episode showed a trend toward lower plasma sEPCR both at initial admission and at 6-month follow-up compared to those without repeated SM (P = 0.06 for both). The study findings support a role for sEPCR in severe malaria pathogenesis and emphasize a distinct role of sEPCR in malaria as compared to other infectious diseases.
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    Lack of Consistent Malaria Incidence Hotspots in a Highland Kenyan Area During a 10-Year Period of Very Low and Unstable Transmission
    (American Society of Tropical Medicine and Hygiene, 2020-12) Hamre, Karen E.S.; Hodges, James S.; Ayodo, George; John, Chandy C.; Pediatrics, School of Medicine
    The use of spatial data in malaria elimination strategies is important to understand whether targeted interventions against malaria can be used, particularly in areas with limited resources. We previously documented consistent areas of increased malaria incidence in the epidemic-prone area of Kipsamoite in highland Kenya from 2001 to 2004. In this area and a neighboring subcounty (Kapsisiywa), malaria incidence decreased substantially in 2005, going from peak incidence of 31.7 per 1,000 persons in June 2004 to peak incidence of 7.4 per 1,000 persons in May 2005. Subsequently, the use of indoor residual spraying and artemisinin combination therapy malaria treatment led to a possible interruption of malaria transmission for a 13-month period from 2007 to 2008, after which the incidence returned to very low levels until an epidemic in April-July 2013. In the present study, we used novel kernel density estimation methods to determine whether areas of increased malaria incidence were consistent in six periods of peak incidence from 2003 to 2013, and to assess patterns of incidence in the period before versus. after the period of possible interruption. Areas of highest incidence differed during peak malaria transmission periods over the years 2003-2013, and differed before and after the potential malaria interruption. In this epidemic-prone region with very low malaria transmission, consistent malaria "hotspots" identified in a time of higher transmission are no longer present. Ongoing assessment of spatial malaria epidemiology to identify and target current areas of elevated malaria risk may be important in campaigns to control or eliminate malaria in epidemic-prone areas.
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    A Mass Insecticide-Treated Bed Net Distribution Campaign Reduced Malaria Risk on an Individual but Not Population Level in a Highland Epidemic-Prone Area of Kenya
    (American Society of Tropical Medicine and Hygiene, 2020-12) Hamre, Karen E.S.; Ayodo, George; Hodges, James S.; John, Chandy C.; Pediatrics, School of Medicine
    In epidemic-prone areas of the western highlands, the Kenya Ministry of Health conducted campaigns of indoor residual spraying (IRS) of households, followed by mass distribution of insecticide-treated bed nets (ITNs), as part of the National Malaria Strategy. We previously reported that in the highland areas of Kipsamoite and Kapsisiywa, widespread IRS coverage in 2007, after lower but substantial coverage in 2005 and 2006, contributed to possible local interruption of malaria transmission between 2007 and 2008. Indoor residual spraying campaigns in the area ended in 2010, succeeded by a mass ITN distribution campaign in 2011 and 2012 targeting universal coverage. Insecticide-treated bed net use in the area increased from 17.1% pre-campaign in 2011 to 51.7% post-campaign in 2012, but decreased to 35.8% in 2013. The ITN campaign did not reduce malaria incidence in the population as a whole (odds ratio [OR] after ITN distribution versus before, 1.29, 95% CI: 1.00-1.66, P = 0.049). However, in 2011-2013, individuals who stated that they slept under ITNs as compared with those who did not had a decrease in malaria incidence that approached statistical significance (OR 0.74, 95% CI: 0.52-1.04, P = 0.08). Mass ITN distribution after previous annual IRS campaigns was insufficient to further reduce malaria transmission in this area of low and highly seasonal transmission possibly because of low ITN use despite the mass campaign.
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    Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): a trial for children with sickle cell anemia
    (ASH, 2017) Opoka, Robert O.; Ndugwa, Christopher M.; Latham, Teresa S.; Lane, Adam; Hume, Heather A.; Kasirye, Phillip; Hodges, James S.; Ware, Russell E.; John, Chandy C.; Pediatrics, School of Medicine
    Hydroxyurea treatment is recommended for children with sickle cell anemia (SCA) living in high-resource malaria-free regions, but its safety and efficacy in malaria-endemic sub-Saharan Africa, where the greatest sickle-cell burden exists, remain unknown. In vitro studies suggest hydroxyurea could increase malaria severity, and hydroxyurea-associated neutropenia could worsen infections. NOHARM (Novel use Of Hydroxyurea in an African Region with Malaria) was a randomized, double-blinded, placebo-controlled trial conducted in malaria-endemic Uganda, comparing hydroxyurea to placebo at 20 ± 2.5 mg/kg per day for 12 months. The primary outcome was incidence of clinical malaria. Secondary outcomes included SCA-related adverse events (AEs), clinical and laboratory effects, and hematological toxicities. Children received either hydroxyurea (N = 104) or placebo (N = 103). Malaria incidence did not differ between children on hydroxyurea (0.05 episodes per child per year; 95% confidence interval [0.02, 0.13]) vs placebo (0.07 episodes per child per year [0.03, 0.16]); the hydroxyurea/placebo malaria incidence rate ratio was 0.7 ([0.2, 2.7]; P = .61). Time to infection also did not differ significantly between treatment arms. A composite SCA-related clinical outcome (vaso-occlusive painful crisis, dactylitis, acute chest syndrome, splenic sequestration, or blood transfusion) was less frequent with hydroxyurea (45%) than placebo (69%; P = .001). Children receiving hydroxyurea had significantly increased hemoglobin concentration and fetal hemoglobin, with decreased leukocytes and reticulocytes. Serious AEs, sepsis episodes, and dose-limiting toxicities were similar between treatment arms. Three deaths occurred (2 hydroxyurea, 1 placebo, and none from malaria). Hydroxyurea treatment appears safe for children with SCA living in malaria-endemic sub-Saharan Africa, without increased severe malaria, infections, or AEs. Hydroxyurea provides SCA-related laboratory and clinical efficacy, but optimal dosing and monitoring regimens for Africa remain undefined. This trial was registered at www.clinicaltrials.gov as #NCT01976416.