Impact of malaria in pregnancy and intermittent preventive treatment of malaria in pregnancy on the risk of malaria in infants

Background: Placental malaria (PM) has been associated with an increased risk of malaria during infancy in observational studies suggesting that effective intermittent preventive treatment of malaria in pregnancy (IPTp) may reduce the risk of malaria in infants. However, there are no randomised controlled trials that have shown that improved IPTp leads to less malaria during infancy. To address this knowledge gap, this thesis aimed to: 1) compare the incidence of malaria in infants during the first year of life among infants born to mothers with PM detected by histology and infants born to mothers without PM; 2) compare the incidence of malaria during the first year of life among infants born to mothers randomised to receive monthly IPTp with sulfadoxine-pyrimethamine (SP) versus those born to mothers randomised to receive monthly IPTp with dihydroartemisinin-piperaquine (DP); and 3) evaluate the effect of PM and IPTp on cord blood levels of IgG antibodies to Plasmodium falciparum malaria antigens in infants born to mothers enrolled in the trial. Methods: Infants born to HIV-uninfected pregnant mothers who participated in a double-blind, randomised trial of monthly IPTp with SP or DP in Busia, Uganda were followed from birth to 12 months of age. The primary outcome was the incidence of malaria measured by passive surveillance during the first year of life. PM was categorised as: 1) no PM (no parasites or pigment), 2) active PM (presence of parasites), 3) mild-moderate past PM (>0-20% high powered fields [HPFs] with pigment), and 4) severe past PM (>20% HPFs with pigment). Cord blood IgG antibody levels to P. falciparum antigens: apical membrane antigen-1 (AMA1), erythrocyte binding antigen-140 (EBA140), EBA175, EBA181, glutamate-rich protein (GLURP), merozoite surface protein-1 (MSP1), reticulocyte-binding protein homologue-2 (Rh2), Rh4, and Rh5 were measured using a multiplex antibody bead assay. Results: Between December 9, 2016 and December 7, 2017, 678 infants were born into the cohort, including 339 to mothers receiving IPTp-DP and 339 to mothers receiving IPTp-SP. A total of 581 infants (85.7%) were followed to 12 months of age. There were 1131 malaria episodes diagnosed in infants during follow-up. Compared to infants born to mothers with no PM, the incidence of malaria was higher among infants born to mothers with active PM (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.00-1.71, p=0.05) and those born to mothers with severe past PM (aIRR 1.28, 95% CI 0.89-1.83, p=0.18), but the differences were not statistically significant. When the analysis was stratified by infant sex, the incidence of malaria was higher in male infants born to mothers with severe past PM than in those born to mothers with no PM (aIRR 2.17, 95% CI 1.45-3.25, p<0.001), but not in female infants (aIRR 0.74, 95% CI 0.46-1.20, p=0.22). The association between IPTp and malaria incidence in infants was modified by infant sex. Compared to IPTp-SP, IPTp-DP was associated with a lower incidence of malaria among male infants (IRR 0·75, 95% CI 0·58-0·98, p=0·03), but not female infants (IRR 0.99, 95% CI 0.79-1.24, p=0.93). There was no significant difference in the cord blood levels of IgG antibodies to Plasmodium falciparum among infants born to mothers with active PM, mild-moderate past PM, or severe past PM compared to infants born to mothers with no PM, and among infants born to mothers who received IPTp-DP compared to those born to mothers who received IPTp-SP. Conclusion: Severe past PM was associated with a higher incidence of malaria among male infants. IPTp-DP was associated with a lower incidence of malaria among male infants compared to IPTp-SP. PM and IPTp did not affect cord blood P. falciparum IgG antibody levels. These findings suggest that severe past PM may negatively impact antimalarial immunity in male infants and that highly effective IPTp may be protective among male infants

Case Report: Birth Outcome and Neurodevelopment in Placental Malaria Discordant Twins.

Maternal infection during pregnancy can have lasting effects on neurodevelopment, but the impact of malaria in pregnancy on child neurodevelopment is unknown. We present a case of a 24-year-old gravida three woman enrolled at 14 weeks 6 days of gestation in a clinical trial evaluating malaria prevention strategies in pregnancy. She had two blood samples test positive for Plasmodium falciparum using loop-mediated isothermal amplification before 20 weeks of gestation. At 31 weeks 4 days of gestation, the woman presented with preterm premature rupture of membranes, and the twins were delivered by cesarean section. Twin A was 1,920 g and Twin B was 1,320 g. Both placentas tested negative for malaria by microscopy, but the placenta of Twin B had evidence of past malaria by histology. The twins' development was assessed using the Bayley Scales of Infant and Toddler Development-Third Edition. At 1 year chronologic age, Twin B had lower scores across all domains (composite scores: cognitive, Twin A [100], Twin B [70]; motor, Twin A [88], Twin B [73]; language, Twin A [109], Twin B [86]). This effect persisted at 2 years chronologic age (composite scores: cognitive, Twin A [80], Twin B [60]; motor, Twin A [76], Twin B [67]; language, Twin A [77], Twin B [59]). Infant health was similar over the first 2 years of life. We report differences in neurodevelopmental outcomes in placental malaria-discordant dizygotic twins. Additional research is needed to evaluate the impact of placental malaria on neurodevelopmental complications. Trial registration number: ClinicalTrials.gov number, NCT02163447. Registered: June 2014, https://clinicaltrials.gov/ct2/show/NCT02163447

ADOPTION OF SOIL CONSERVATION THROUGH COLLECTIVE ACTIONS IN SOUTHWESTERN UGANDA

In developing countries, access to and use of renewable natural resources are essential for rural livelihoods to thrive. Hence, cooperation in the management of natural resources is increasingly an important strategy that can enhance long-term socio-ecological resilience. In most cases, collective actions have widely been recognised as an alternative institutional arrangement to centralised governance for the management of natural resources, but their success largely depends on factors that are specific to localities where they are implemented. In this study, factors that influence adoption and extent of adoption of natural resource conservation activities were identified using two case studies: Bubaare and Bufundi Innovation Platforms in Uganda. The drivers of adoption of community natural resource management strategies are analysed using an Ordered Logit Model while extent of adoption is analysed using a truncated regression model. The education level of a household head, membership in collective action group, and perception of plot slope and relevance of bye-laws were factors associated with likelihood of adoption. Value of livestock, membership in collective action group, access to credit and off-farm income were found to positively influence the level of investment. Thus, collective action increases opportunities for adoption; hence farmers should be supported to work collectively.Dans les pays en voie de d\ue9veloppement, l\u2019acc\ue8s et l\u2019utilisation des ressources naturelles sont essentiels pour la suivie en mileu rural et pour y prosp\ue9rer. Ainsi, la coop\ue9ration dans la gestion des ressources naturelles est de plus en plus une strat\ue9gie importante qui peut am\ue9liorer \ue0 long terme la coh\ue9sion socio-\ue9cologique. Dans beaucoup de cas; les actions collectives ont \ue9t\ue9 largement reconnues comme une alternative d\u2019organisation institutionnelle pour centraliser la gouvernance de la gestion des ressources naturelles, mais leur succ\ue8s d\ue9pend largement des facteurs qui sont sp\ue9cifiques aux milieux o\uf9 elles sont mise en oeuvre. Dans cette \ue9tude, les facteus qui influencent l\u2019adoption et le degr\ue9 d\u2019adoption des activit\ue9s de conservation des ressources naturelles \ue9taient identifi\ue9s en utilisant deux cas d\u2019\ue9tude: Les Plate-formes d\u2019Innovation de Bubaare et Bufundi en Ouganda. Les forces motrices d\u2019adoption des strategies de gestion des ressources naturelles communautaires sont analys\ue9es en utilsant un mod\ue8le Logit Ordonn\ue9 tandis que le degr\ue9 d\u2019adoption est analys\ue9 en utilisant un mod\ue8le de r\ue9gression tronqu\ue9. Le niveau d\u2019\ue9ducation du chef de m\ue9nage, l\u2019appartenance au groupe d\u2019action collective, et la perception de la pente de la parcelle et limportance des arr\ueat\ue9s \ue9taient les facteurs associ\ue9s au taux d\u2019adoption. La value du b\ue9tail, l\u2019appartenance au groupe d\u2019action collective, l\u2019acc\ue8s au cr\ue9dit et le revenu non- agricole \ue9taient les facteurs qui influencent positivement le niveau d\u2019investissement. Donc, les actions collectives augmentent les opportunit\ue9s pour l\u2019adoption; ainsi les producteurs devraient \ueatre encourag\ue9s \ue0 travailler de fa\ue7con collective

Increasing incidence of malaria in children despite insecticide-treated bed nets and prompt anti-malarial therapy in Tororo, Uganda.

BACKGROUND: The burden of malaria has decreased in parts of Africa following the scaling up of control interventions. However, similar data are limited from high transmission settings. METHODS: A cohort of 100 children, aged six weeks to 10 months of age, were enrolled in an area of high malaria transmission intensity and followed through 48 months of age. Children were given a long-lasting insecticide-treated bed net (LLIN) at enrolment and received all care, including monthly blood smears and treatment with artemisinin-based combination therapy (ACT) for uncomplicated malaria, at a dedicated clinic. The incidence of malaria was estimated by passive surveillance and associations between malaria incidence and age, calendar time and season were measured using generalized estimating equations. RESULTS: Reported compliance with LLINs was 98% based on monthly routine evaluations. A total of 1,633 episodes of malaria were observed, with a median incidence of 5.3 per person-year (PPY). There were only six cases of complicated malaria, all single convulsions. Malaria incidence peaked at 6.5 PPY at 23 months of age before declining to 3.5 PPY at 48 months. After adjusting for age and season, the risk of malaria increased by 52% from 2008 to 2011 (RR 1.52, 95% CI 1.10-2.09). Asymptomatic parasitaemia was uncommon (monthly prevalence <10%) and rarely observed prior to 24 months of age. CONCLUSIONS: In Tororo, despite provision of LLINs and prompt treatment with ACT, the incidence of malaria is very high and appears to be rising. Additional malaria control interventions in high transmission settings are likely needed. TRIAL REGISTRATION: Current Controlled Trials Identifier NCT00527800

Impact of Antimalarial Treatment and Chemoprevention on the Drug Sensitivity of Malaria Parasites Isolated from Ugandan Children

Changing treatment practices may be selecting for changes in the drug sensitivity of malaria parasites. We characterized ex vivo drug sensitivity and parasite polymorphisms associated with sensitivity in 459 Plasmodium falciparum samples obtained from subjects enrolled in two clinical trials in Tororo, Uganda, from 2010 to 2013. Sensitivities to chloroquine and monodesethylamodiaquine varied widely; sensitivities to quinine, dihydroartemisinin, lumefantrine, and piperaquine were generally good. Associations between ex vivo drug sensitivity and parasite polymorphisms included decreased chloroquine and monodesethylamodiaquine sensitivity and increased lumefantrine and piperaquine sensitivity with pfcrt 76T, as well as increased lumefantrine sensitivity with pfmdr1 86Y, Y184, and 1246Y. Over time, ex vivo sensitivity decreased for lumefantrine and piperaquine and increased for chloroquine, the prevalences of pfcrt K76 and pfmdr1 N86 and D1246 increased, and the prevalences of pfdhfr and pfdhps polymorphisms associated with antifolate resistance were unchanged. In recurrent infections, recent prior treatment with artemether-lumefantrine was associated with decreased ex vivo lumefantrine sensitivity and increased prevalence of pfcrt K76 and pfmdr1 N86, 184F, and D1246. In children assigned chemoprevention with monthly dihydroartemisinin-piperaquine with documented circulating piperaquine, breakthrough infections had increased the prevalence of pfmdr1 86Y and 1246Y compared to untreated controls. The noted impacts of therapy and chemoprevention on parasite polymorphisms remained significant in multivariate analysis correcting for calendar time. Overall, changes in parasite sensitivity were consistent with altered selective pressures due to changing treatment practices in Uganda. These changes may threaten the antimalarial treatment and preventive efficacies of artemether-lumefantrine and dihydroartemisinin-piperaquine, respectively

Perceptions, attitudes, and willingness of healthcare and frontline workers to participate in an Ebola vaccine trial in Uganda.

BACKGROUND: Understanding the knowledge, perception and attitudes towards Ebola vaccines is an important factor in ensuring future use of these vaccines. A qualitative methods study embedded in an Ebola vaccine immunogenicity and safety trial (NCT04028349) was conducted to explore the knowledge and perceptions of healthcare (HCWs) and frontline workers (FLWs), about Ebola vaccines and their willingness to participate or recommend participation in Uganda. METHOD: We carried out focus group discussions and semi-structured interviews before and after vaccination, with 70 HCWs and FLWs who consented to participate in the trial, and in the qualitative component, from August to September 2019. Data were analysed using thematic content analysis. RESULTS: Respondents showed good knowledge about Ebola and the vaccines in general, and had wide access to information through several channels, including the study team. On prevention, particular attention was given to effective communication within health facilities. Misconceptions were mainly around route of transmission, animal origin and types of vaccines. Previous fears were based on rumours circulating in the community, mainly about the presence of the virus in the vaccine, side effects and intention to harm (e.g. by "the whites"), ultimately insisting on transparency, trust and involvement of local leaders. Acceptability of participation was motivated by the need to protect self and others, and the willingness to advance research. Majority were willing to recommend participation to their community. CONCLUSIONS: Overall, information sharing leads to a better understanding and acceptance of vaccine trials and a positive vaccination experience can be a deciding factor in the acceptance of others. Particular attention should be paid to involving the community in addressing misconceptions and fears, while ensuring that participants have access to vaccination sites in terms of transport, and that they are properly accommodated at the study site including staying for a reasonable period of time

Population Pharmacokinetics and Pharmacodynamics of Lumefantrine in Young Ugandan Children Treated With Artemether-Lumefantrine for Uncomplicated Malaria.

BACKGROUND: The pharmacokinetics and pharmacodynamics of lumefantrine, a component of the most widely used treatment for malaria, artemether-lumefantrine, has not been adequately characterized in young children. METHODS: Capillary whole-blood lumefantrine concentration and treatment outcomes were determined in 105 Ugandan children, ages 6 months to 2 years, who were treated for 249 episodes of Plasmodium falciparum malaria with artemether-lumefantrine. RESULTS: Population pharmacokinetics for lumefantrine used a 2-compartment open model with first-order absorption. Age had a significant positive correlation with bioavailability in a model that included allometric scaling. Children not receiving trimethoprim-sulfamethoxazole with capillary whole blood concentrations 200 ng/mL (P = .0007). However, for children receiving trimethoprim-sulfamethoxazole, the risk of recurrent parasitemia did not differ significantly on the basis of this threshold. Day 3 concentrations were a stronger predictor of 28-day recurrence than day 7 concentrations. CONCLUSIONS: We demonstrate that age, in addition to weight, is a determinant of lumefantrine exposure, and in the absence of trimethoprim-sulfamethoxazole, lumefantrine exposure is a determinant of recurrent parasitemia. Exposure levels in children aged 6 months to 2 years was generally lower than levels published for older children and adults. Further refinement of artemether-lumefantrine dosing to improve exposure in infants and very young children may be warranted

The association between malnutrition and the incidence of malaria among young HIV-infected and -uninfected Ugandan children: a prospective study

BACKGROUND: In sub-Saharan Africa, malnutrition and malaria remain major causes of morbidity and mortality in young children. There are conflicting data as to whether malnutrition is associated with an increased or decreased risk of malaria. In addition, data are limited on the potential interaction between HIV infection and the association between malnutrition and the risk of malaria. METHODS: A cohort of 100 HIV-unexposed, 203 HIV-exposed (HIV negative children born to HIV-infected mothers) and 48 HIV-infected children aged 6 weeks to 1 year were recruited from an area of high malaria transmission intensity in rural Uganda and followed until the age of 2.5 years. All children were provided with insecticide-treated bed nets at enrolment and daily trimethoprim-sulphamethoxazole prophylaxis (TS) was prescribed for HIV-exposed breastfeeding and HIV-infected children. Monthly routine assessments, including measurement of height and weight, were conducted at the study clinic. Nutritional outcomes including stunting (low height-for-age) and underweight (low weight-for-age), classified as mild (mean z-scores between -1 and -2 during follow-up) and moderate-severe (mean z-scores < -2 during follow-up) were considered. Malaria was diagnosed when a child presented with fever and a positive blood smear. The incidence of malaria was compared using negative binomial regression controlling for potential confounders with measures of association expressed as an incidence rate ratio (IRR). RESULTS: The overall incidence of malaria was 3.64 cases per person year. Mild stunting (IRR = 1.24, 95% CI 1.06-1.46, p = 0.008) and moderate-severe stunting (IRR = 1.24, 95% CI 1.03-1.48, p = 0.02) were associated with a similarly increased incidence of malaria compared to non-stunted children. Being mildly underweight (IRR = 1.09, 95% CI 0.95-1.25, p = 0.24) and moderate-severe underweight (IRR = 1.12, 95% CI 0.86-1.46, p = 0.39) were not associated with a significant difference in the incidence of malaria compared to children who were not underweight. There were no significant interactions between HIV-infected, HIV-exposed children taking TS and the associations between malnutrition and the incidence of malaria. CONCLUSIONS: Stunting, indicative of chronic malnutrition, was associated with an increased incidence of malaria among a cohort of HIV-infected and -uninfected young children living in an area of high malaria transmission intensity. However, caution should be made when making causal inferences given the observational study design and inability to disentangle the temporal relationship between malnutrition and the incidence of malaria. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00527800

Isolation of non-tuberculous mycobacteria from pastoral ecosystems of Uganda: Public Health significance

<p>Abstract</p> <p>Background</p> <p>The importance of non-tuberculous mycobacteria (NTM) infections in humans and animals in sub-Saharan Africa at the human-environment-livestock-wildlife interface has recently received increased attention. NTM are environmental opportunistic pathogens of humans and animals. Recent studies in pastoral ecosystems of Uganda detected NTM in humans with cervical lymphadenitis and cattle with lesions compatible with bovine tuberculosis. However, little is known about the source of these mycobacteria in Uganda. The aim of this study was to isolate and identify NTM in the environment of pastoral communities in Uganda, as well as assess the potential risk factors and the public health significance of NTM in these ecosystems.</p> <p>Method</p> <p>A total of 310 samples (soil, water and faecal from cattle and pigs) were examined for mycobacteria. Isolates were identified by the INNO-Lipa test and by 16S rDNA sequencing. Additionally, a questionnaire survey involving 231 pastoralists was conducted during sample collection. Data were analysed using descriptive statistics followed by a multivariable logistic regression analysis.</p> <p>Results</p> <p>Forty-eight isolates of NTM were detected; 25.3% of soil samples, 11.8% of water and 9.1% from animal faecal samples contained mycobacteria. Soils around water sources were the most contaminated with NTM (29.8%). Of these samples, <it>M. fortuitum-peregrinum </it>complex, <it>M. avium </it>complex, <it>M. gordonae</it>, and <it>M. nonchromogenicum </it>were the most frequently detected mycobacteria. Drinking untreated compared to treated water (OR = 33), use of valley dam versus stream water for drinking and other domestic use (OR = 20), sharing of water sources with wild primates compared to antelopes (OR = 4.6), sharing of water sources with domestic animals (OR = 5.3), and close contact with cattle or other domestic animals (OR = 13.8) were the most plausible risk factors for humans to come in contact with NTM in the environment.</p> <p>Conclusions</p> <p>The study detected a wide range of potentially pathogenic NTM from the environment around the pastoral communities in Uganda. Drinking untreated water and living in close contact with cattle or other domestic animals may be risk factors associated with the possibility of humans and animals acquiring NTM infections from these ecosystems.</p