Browsing by Author "Ayodo, George"
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Item A Psychometric Evaluation of the NIH Toolbox Fluid Cognition Tests Adapted for Swahili and Dholuo Languages in Kenyan Children and Adolescents(Cambridge University Press, 2023) McHenry, Megan S.; Roose, Anna; Abuonji, Emily; Nyalumbe, Mark; Ayuku, David; Ayodo, George; Tran, Tuan M.; Kaat, Aaron J.; Pediatrics, School of MedicineObjective: Our objective was to evaluate the psychometric properties of the culturally adapted NIH Toolbox African Languages® when used in Swahili and Dholuo-speaking children in western Kenya. Method: Swahili-speaking participants were recruited from Eldoret and Dholuo-speaking participants from Ajigo; all were <14 years of age and enrolled in primary school. Participants completed a demographics questionnaire and five fluid cognition tests of the NIH Toolbox® African Languages program, including Flanker, Dimensional Change Card Sort (DCCS), Picture Sequence Memory, Pattern Comparison, and List Sorting tests. Statistical analyses examined aspects of reliability, including internal consistency (in both languages) and test-retest reliability (in Dholuo only). Results: Participants included 479 children (n = 239, Swahili-speaking; n = 240, Dholuo-speaking). Generally, the tests had acceptable psychometric properties for research use within Swahili- and Dholuo-speaking populations (mean age = 10.5; SD = 2.3). Issues related to shape identification and accuracy over speed limited the utility of DCCS for many participants, with approximately 25% of children unable to match based on shape. These cultural differences affected outcomes of reliability testing among the Dholuo-speaking cohort, where accuracy improved across all five tests, including speed. Conclusions: There is preliminary evidence that the NIH Toolbox ® African Languages potentially offers a valid assessment of development and performance using tests of fluid cognition in Swahili and Dholuo among research settings. With piloting underway across other diverse settings, future research should gather additional evidence on the clinical utility and acceptability of these tests, specifically through the establishment of norming data among Kenyan regions and evaluating these psychometric properties.Item 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 MedicineImmune 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.Item Antibody Profiles to P. falciparum Antigens Over Time Characterize Acute and Long-Term Malaria Exposure in an Area of Low and Unstable Transmission(American Society of Tropical Medicine and Hygiene, 2020-12) Ondigo, Bartholomew N.; Hamre, Karen E.S.; Frosch, Anne E.P.; Ayodo, George; White, Michael T.; John, Chandy C.; Pediatrics, School of MedicinePrevalence and levels of antibodies to multiple Plasmodium falciparum antigens show promise as tools for estimating malaria exposure. In a highland area of Kenya with unstable transmission, we assessed the presence and levels of antibodies to 12 pre-erythrocytic and blood-stage P. falciparum antigens by multiplex cytometric bead assay or ELISA in 604 individuals in August 2007, with follow-up testing in this cohort in April 2008, April 2009, and May 2010. Four hundred individuals were tested at all four time points. During this period, the only substantial malaria incidence occurred from April to August 2009. Antibody prevalence in adults was high at all time points (> 70%) for apical membrane antigen 1, erythrocyte-binding antigen 175, erythrocyte-binding protein-2, glutamate rich protein (GLURP)-R2, merozoite surface protein (MSP) 1 (19), MSP-1 (42), and liver-stage antigen-1; moderate (30-70%) for GLURP-R0, MSP-3, and thrombospondin-related adhesive protein; and low (< 30%) for SE and circumsporozoite protein (CSP). Changes in community-wide malaria exposure were best reflected in decreasing antibody levels overtime for highly immunogenic antigens, and in antibody seroprevalence overtime for the less-immunogenic antigens. Over the 3 years, antibody levels to all antigens except CSP and schizont extract (SE) decreased in an age-dependent manner. Prevalence and levels of antibodies to all antigens except CSP and SE increased with age. Increases in antibody prevalence and levels to CSP and SE coincided with increases in community-wide malaria incidence. Antibody levels to multiple P. falciparum antigens decrease in the absence of consistent transmission. Multiplex assays that assess both the presence and level of antibodies to multiple pre-erythrocytic and blood-stage P. falciparum antigens may provide the most useful estimates of past and recent malaria transmission in areas of unstable transmission and could be useful tools in malaria control and elimination campaigns.Item Decrease in Numbers of Naive and Resting B Cells in HIV-Infected Kenyan Adults Leads to a Proportional Increase in Total and Plasmodium falciparum-Specific Atypical Memory B Cells(American Association of Immunologists, 2017-06-15) Frosch, Anne E.; Odumade, Oludare A.; Taylor, Justin J.; Ireland, Kathleen; Ayodo, George; Ondigo, Bartholomew; Narum, David L.; Vulule, John; John, Chandy C.; Medicine, School of MedicineHuman immunodeficiency virus type 1 (HIV-1) infection is associated with B cell activation and exhaustion, and hypergammaglobulinemia. How these changes influence B cell responses to coinfections such as malaria is poorly understood. To address this, we compared B cell phenotypes and Abs specific for the Plasmodium falciparum vaccine candidate apical membrane Ag-1 (AMA1) in HIV-infected and uninfected adults living in Kenya. Surprisingly, HIV-1 infection was not associated with a difference in serum AMA1-specific Ab levels. HIV-infected individuals had a higher proportion of total atypical and total activated memory B cells (MBCs). Using an AMA1 tetramer to detect AMA1-specific B cells, HIV-infected individuals were also shown to have a higher proportion of AMA1-specific atypical MBCs. However, this proportional increase resulted in large part from a loss in the number of naive and resting MBCs rather than an increase in the number of atypical and activated cells. The loss of resting MBCs and naive B cells was mirrored in a population of cells specific for an Ag to which these individuals were unlikely to have been chronically exposed. Together, the data show that changes in P. falciparum Ag-specific B cell subsets in HIV-infected individuals mirror those in the overall B cell population, and suggest that the increased proportion of atypical MBC phenotypes found in HIV-1-infected individuals results from the loss of naive and resting MBCs.Item Evaluation of an ultrasensitive HRP2-based rapid diagnostic test for detection of asymptomatic Plasmodium falciparum parasitaemia among children in western Kenya(BMC, 2022-11-16) Turnbull, Lindsey B.; Ayodo, George; Knight, Veronicah; John, Chandy C.; McHenry, Megan S.; Tran, Tuan M.; Medicine, School of MedicineBackground Accurate detection of asymptomatic malaria parasitaemia in children living in high transmission areas is important for malaria control and reduction programmes that employ screen-and-treat surveillance strategies. Relative to microscopy and conventional rapid diagnostic tests (RDTs), ultrasensitive RDTs (us-RDTs) have demonstrated reduced limits of detection with increased sensitivity to detect parasitaemia in symptomatic individuals. In this study, the performance of the NxTek™ Eliminate Malaria P.f test was compared with traditional microscopy and quantitative polymerase chain reaction (qPCR) testing methods of detection for P. falciparum parasitaemia among asymptomatic children aged 7–14 years living in an area of high malaria transmission intensity in western Kenya. Methods In October 2020, 240 healthy children without any reported malaria symptoms were screened for the presence of P. falciparum parasitaemia; 120 children were randomly selected to participate in a follow-up visit at 6–10 weeks. Malaria parasitaemia was assessed by blood-smear microscopy, us-RDT, and qPCR of a conserved var gene sequence from genomic DNA extracted from dried blood spots. Sensitivity, specificity, and predictive values were calculated for field diagnostic methods using qPCR as the gold standard. Comparison of detectable parasite density distributions and area under the curve were also calculated to determine the effectiveness of the us-RDT in detecting asymptomatic infections with low parasite densities. Results The us-RDT detected significantly more asymptomatic P. falciparum infections than microscopy (42.5% vs. 32.2%, P = 0.002). The positive predictive value was higher for microscopy (92.2%) than for us-RDT (82.4%). However, false negative rates were high for microscopy and us-RDT, with negative predictive values of 53.7% and 54.6%, respectively. While us-RDT detected significantly more infections than microscopy overall, the density distribution of detectable infections did not differ (P = 0.21), and qPCR detected significantly more low-density infections than both field methods (P < 0.001, for both comparisons). Conclusions Us-RDT is more sensitive than microscopy for detecting asymptomatic malaria parasitaemia in children. Though the detectable parasite density distributions by us-RDT in our specific study did not significantly differ from microscopy, the additional sensitivity of the us-RDT resulted in more identified asymptomatic infections in this important group of the population and makes the use of the us-RDT advisable compared to other currently available malaria field detection methods.Item HIV infection drives IgM and IgG3 subclass bias in Plasmodium falciparum-specific and total immunoglobulin concentration in Western Kenya(BioMed Central, 2019-08-30) Odhiambo, Eliud O.; Datta, Dibyadyuti; Guyah, Bernard; Ayodo, George; Ondigo, Bartholomew N.; Abong’o, Benard O.; John, Chandy C.; Frosch, Anne E. P.; Pediatrics, School of MedicineBACKGROUND: HIV infection is associated with more frequent and severe episodes of malaria and may be the result of altered malaria-specific B cell responses. However, it is poorly understood how HIV and the associated lymphopenia and immune activation affect malaria-specific antibody responses. METHODS: HIV infected and uninfected adults were recruited from Bondo subcounty hospital in Western Kenya at the time of HIV testing (antiretroviral and co-trimoxazole prophylaxis naïve). Total and Plasmodium falciparum apical membrane antigen-1 (AMA1) and glutamate rich protein-R0 (GLURP-R0) specific IgM, IgG and IgG subclass concentrations was measured in 129 and 52 of recruited HIV-infected and uninfected individuals, respectively. In addition, HIV-1 viral load (VL), CD4+ T cell count, and C-reactive protein (CRP) concentration was quantified in study participants. Antibody levels were compared based on HIV status and the associations of antibody concentration with HIV-1 VL, CD4+ count, and CRP levels was measured using Spearman correlation testing. RESULTS: Among study participants, concentrations of IgM, IgG1 and IgG3 antibodies to AMA1 and GLURP-R0 were higher in HIV infected individuals compared to uninfected individuals (all p < 0.001). The IgG3 to IgG1 ratio to both AMA1 and GLURP-R0 was also significantly higher in HIV-infected individuals (p = 0.02). In HIV-infected participants, HIV-1 VL and CRP were weakly correlated with AMA1 and GLURP-R0 specific IgM and IgG1 concentrations and total (not antigen specific) IgM, IgG, IgG1, and IgG3 concentrations (all p < 0.05), suggesting that these changes are related in part to viral load and inflammation. CONCLUSIONS: Overall, HIV infection leads to a total and malaria antigen-specific immunoglobulin production bias towards higher levels of IgM, IgG1, and IgG3, and HIV-1 viraemia and systemic inflammation are weakly correlated with these changes. Further assessments of antibody affinity and function and correlation with risk of clinical malaria, will help to better define the effects of HIV infection on clinical and biological immunity to malaria.Item 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 MedicineThe 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.Item 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 MedicineIn 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.Item The prevalence and density of asymptomatic Plasmodium falciparum infections among children and adults in three communities of western Kenya(BMC, 2021-09-17) Salgado, Christina; Ayodo, George; Macklin, Michael D.; Gould, Meetha P.; Nallandhighal, Srinivas; Odhiambo, Eliud O.; Obala, Andrew; Prudhomme O’Meara, Wendy; John, Chandy C.; Tran, Tuan M.; Medicine, School of MedicineBackground: 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.Item Subclinical Inflammation in Asymptomatic Schoolchildren With Plasmodium falciparum Parasitemia Correlates With Impaired Cognition(Oxford University Press, 2024) Johnson, Alexander E.; Upadhye, Aditi; Knight, Veronicah; Gaskin, Erik L.; Turnbull, Lindsey B.; Ayuku, David; Nyalumbe, Mark; Abuonji, Emily; John, Chandy C.; McHenry, Megan S.; Tran, Tuan M.; Ayodo, George; Medicine, School of MedicineBackground: Subclinical inflammation and cognitive deficits have been separately associated with asymptomatic Plasmodium falciparum infections in schoolchildren. However, whether parasite-induced inflammation is associated with worse cognition has not been addressed. We conducted a cross-sectional pilot study to better assess the effect of asymptomatic P. falciparum parasitemia and inflammation on cognition in Kenyan schoolchildren. Methods: We enrolled 240 children aged 7-14 years residing in high malaria transmission in Western Kenya. Children performed five fluid cognition tests from a culturally adapted NIH toolbox and provided blood samples for blood smears and laboratory testing. Parasite densities and plasma concentrations of 14 cytokines were determined by quantitative PCR and multiplex immunoassay, respectively. Linear regression models were used to determine the effects of parasitemia and plasma cytokine concentrations on each of the cognitive scores as well as a composite cognitive score while controlling for age, gender, maternal education, and an interaction between age and P. falciparum infection status. Results: Plasma concentrations of TNF, IL-6, IL-8, and IL-10 negatively correlated with the composite score and at least one of the individual cognitive tests. Parasite density in parasitemic children negatively correlated with the composite score and measures of cognitive flexibility and attention. In the adjusted model, parasite density and TNF, but not P. falciparum infection status, independently predicted lower cognitive composite scores. By mediation analysis, TNF significantly mediated ~29% of the negative effect of parasitemia on cognition. Conclusions: Among schoolchildren with PCR-confirmed asymptomatic P. falciparum infections, the negative effect of parasitemia on cognition could be mediated, in part, by subclinical inflammation. Additional studies are needed to validate our findings in settings of lower malaria transmission and address potential confounders that could affect both inflammation and cognitive performance.