Dataset Information

Quantifying Heterogeneous Malaria Exposure and Clinical Protection in a Cohort of Ugandan Children.

ABSTRACT:

Background

Plasmodium falciparum malaria remains a leading cause of childhood morbidity and mortality. There are important gaps in our understanding of the factors driving the development of antimalaria immunity as a function of age and exposure.

Methods

We used data from a cohort of 93 children participating in a clinical trial in Tororo, Uganda, an area of very high exposure to P. falciparum We jointly quantified individual heterogeneity in the risk of infection and the development of immunity against infection and clinical disease.

Results

Results showed significant heterogeneity in the hazard of infection and independent effects of age and cumulative number of infections on the risk of infection and disease. The risk of developing clinical malaria upon infection decreased on average by 6% (95% confidence interval [CI], 0%-12%) for each additional year of age and by 2% (95% CI, 1%-3%) for each additional prior infection. Children randomly assigned to receive dihydroartemisinin-piperaquine for treatment appeared to develop immunity more slowly than those receiving artemether-lumefantrine.

Conclusions

Heterogeneity in P. falciparum exposure and immunity can be independently evaluated using detailed longitudinal studies. Improved understanding of the factors driving immunity will provide key information to anticipate the impact of malaria-control interventions and to understand the mechanisms of clinical immunity.

SUBMITTER: Rodriguez-Barraquer I

PROVIDER: S-EPMC5021229 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Publications

Quantifying Heterogeneous Malaria Exposure and Clinical Protection in a Cohort of Ugandan Children.

Rodriguez-Barraquer Isabel I Arinaitwe Emmanuel E Jagannathan Prasanna P Boyle Michelle J MJ Tappero Jordan J Muhindo Mary M Kamya Moses R MR Dorsey Grant G Drakeley Chris C Ssewanyana Isaac I Smith David L DL Greenhouse Bryan B

The Journal of infectious diseases 20160801 7

<h4>Background</h4>Plasmodium falciparum malaria remains a leading cause of childhood morbidity and mortality. There are important gaps in our understanding of the factors driving the development of antimalaria immunity as a function of age and exposure.<h4>Methods</h4>We used data from a cohort of 93 children participating in a clinical trial in Tororo, Uganda, an area of very high exposure to P. falciparum We jointly quantified individual heterogeneity in the risk of infection and the developm ...[more]

PMID: 27481862

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Project description:Human immunodeficiency virus (HIV) protease inhibitors show activity against Plasmodium falciparum in vitro. We hypothesized that the incidence of malaria in HIV-infected children would be lower among children receiving lopinavir-ritonavir-based antiretroviral therapy (ART) than among those receiving nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based ART.We conducted an open-label trial in which HIV-infected children 2 months to 5 years of age who were eligible for ART or were currently receiving NNRTI-based ART were randomly assigned to either lopinavir-ritonavir-based ART or NNRTI-based ART and were followed for 6 months to 2 years. Cases of uncomplicated malaria were treated with artemether-lumefantrine. The primary end point was the incidence of malaria.We enrolled 176 children, of whom 170 received the study regimen: 86 received NNRTI-based ART, and 84 lopinavir-ritonavir-based ART. The incidence of malaria was lower among children receiving the lopinavir-ritonavir-based regimen than among those receiving the NNRTI-based regimen (1.32 vs. 2.25 episodes per person-year; incidence-rate ratio, 0.59; 95% confidence interval [CI], 0.36 to 0.97; P=0.04), as was the risk of a recurrence of malaria after treatment with artemether-lumefantrine (28.1% vs. 54.2%; hazard ratio, 0.41; 95% CI, 0.22 to 0.76; P=0.004). The median lumefantrine level on day 7 after treatment for malaria was significantly higher in the lopinavir-ritonavir group than in the NNRTI group. In the lopinavir-ritonavir group, lumefantrine levels exceeding 300 ng per milliliter on day 7 were associated with a reduction of more than 85% in the 63-day risk of recurrent malaria. A greater number of serious adverse events occurred in the lopinavir-ritonavir group than in the NNRTI group (5.6% vs. 2.3%, P=0.16). Pruritus occurred significantly more frequently in the lopinavir-ritonavir group, and elevated alanine aminotransferase levels significantly more frequently in the NNRTI group.Lopinavir-ritonavir-based ART as compared with NNRTI-based ART reduced the incidence of malaria by 41%, with the lower incidence attributable largely to a significant reduction in the recurrence of malaria after treatment with artemether-lumefantrine. Lopinavir-ritonavir-based ART was accompanied by an increase in serious adverse events. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT00978068.).

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Project description:Background Acute kidney injury (AKI) is increasingly recognized as a consequential clinical complication in children with severe malaria. However, approaches to estimate baseline creatinine (bSCr) are not standardized in this unique patient population. Prior to wide-spread utilization, bSCr estimation methods need to be evaluated in many populations, particularly in children from low-income countries. Methods We evaluated six methods to estimate bSCr in Ugandan children aged 6?months to 12?years of age in two cohorts of children with severe malaria (n?=?1078) and healthy community children (n?=?289). Using isotope dilution mass spectrometry (IDMS)-traceable creatinine measures from community children, we evaluated the bias, accuracy and precision of estimating bSCr using height-dependent and height-independent estimated glomerular filtration (eGFR) equations to back-calculate bSCr or estimating bSCr directly using published or population-specific norms. Results We compared methods to estimate bSCr in healthy community children against the IDMS-traceable SCr measure. The Pottel-age based equation, assuming a normal GFR of 120?mL/min per 1.73m2, was the more accurate method with minimal bias when compared to the Schwartz height-based equation. Using the different bSCr estimates, we demonstrated the prevalence of KDIGO-defined AKI in children with severe malaria ranged from 15.6–43.4%. The lowest estimate was derived using population upper levels of normal and the highest estimate was derived using the mean GFR of the community children (137?mL/min per 1.73m2) to back-calculate the bSCr. Irrespective of approach, AKI was strongly associated with mortality with a step-wise increase in mortality across AKI stages (p?<?0.0001 for all). AKI defined using the Pottel-age based equation to estimate bSCr showed the strongest relationship with mortality with a risk ratio of 5.13 (95% CI 3.03–8.68) adjusting for child age and sex. Conclusions We recommend using height-independent age-based approaches to estimate bSCr in hospitalized children in sub-Saharan Africa due to challenges in accurate height measurements and undernutrition which may impact bSCr estimates. In this population the Pottel-age based GFR estimating equation obtained comparable bSCr estimates to population-based estimates in healthy children.

Dataset Information

Quantifying Heterogeneous Malaria Exposure and Clinical Protection in a Cohort of Ugandan Children.

Background

Methods

Results

Conclusions

Publications

Quantifying Heterogeneous Malaria Exposure and Clinical Protection in a Cohort of Ugandan Children.

Similar Datasets

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