Medical Biology - Research Publications
Permanent URI for this collection
Search Results
1 - 10 of 11
-
ItemA Randomized Open-Label Evaluation of the Antimalarial Prophylactic Efficacy of Azithromycin-Piperaquine versus Sulfadoxine-Pyrimethamine in Pregnant Papua New Guinean Women(American Society for Microbiology, 2019-10-01)Emerging malaria parasite sulfadoxine-pyrimethamine (SP) resistance has prompted assessment of alternatives for intermittent preventive treatment in pregnancy (IPTp). The objective was to evaluate the tolerability and prophylactic efficacy of azithromycin (AZ) plus piperaquine (PQ) in pregnant women in Papua New Guinea. The study was an open-label, randomized, parallel-group trial. A total of 122 women (median gestation, 26 weeks [range, 14 to 32 weeks]) were randomized 1:1 to three daily doses of 1 g AZ plus 960 mg PQ tetraphosphate or single-dose SP (4,500 mg sulfadoxine plus 225 mg pyrimethamine), based on computer-generated block randomization. Tolerability was assessed to day 7, and efficacy was assessed to day 42 (when participants were returned to usual care) and at delivery. Data for 119 participants (AZ-PQ, n = 61; SP, n = 58) were analyzed. Both regimens were well tolerated, but AZ-PQ was associated with more gastrointestinal side effects (31%) and dizziness (21%). Eight women (6.7%) were parasitemic at recruitment but all were aparasitemic by 72 h. There were no differences in blood smear positivity rates between AZ-PQ and SP up to day 42 (0% versus 5.2%; relative risk [RR], 0.14 [95% confidence interval [CI], 0.01 to 2.58] [P = 0.18]; absolute risk reduction [ARR], 5.2% [95% CI, -1.3 to 11.6%]) and at the time of delivery (0% versus 8.7%; RR, 0.11 [95% CI, 0.01 to 2.01] [P = 0.14]; ARR, 8.7% [95% CI, -0.2 to 17.6%]). Of 92 women who were monitored to parturition, 89 (97%) delivered healthy babies; there were 3 stillbirths (SP, n = 1; AZ-PQ, n = 2 [twins]). There was a higher live birth weight (mean ± standard deviation) in the AZ-PQ group (3.13 ± 0.42 versus 2.88 ± 0.55 kg [P = 0.016]; mean difference, 0.25 kg [95% CI, 0.02 to 0.48 kg]). AZ-PQ is a promising candidate for IPTp.
-
ItemMonitoringPlasmodium falciparumandPlasmodium vivaxusing microsatellite markers indicates limited changes in population structure after substantial transmission decline in Papua New Guinea(WILEY, 2020-12)Monitoring the genetic structure of pathogen populations may be an economical and sensitive approach to quantify the impact of control on transmission dynamics, highlighting the need for a better understanding of changes in population genetic parameters as transmission declines. Here we describe the first population genetic analysis of two major human malaria parasites, Plasmodium falciparum (Pf) and Plasmodium vivax (Pv), following nationwide distribution of long-lasting insecticide-treated nets (LLINs) in Papua New Guinea (PNG). Parasite isolates from pre- (2005-2006) and post-LLIN (2010-2014) were genotyped using microsatellite markers. Despite parasite prevalence declining substantially (East Sepik Province: Pf = 54.9%-8.5%, Pv = 35.7%-5.6%, Madang Province: Pf = 38.0%-9.0%, Pv: 31.8%-19.7%), genetically diverse and intermixing parasite populations remained. Pf diversity declined modestly post-LLIN relative to pre-LLIN (East Sepik: Rs = 7.1-6.4, HE = 0.77-0.71; Madang: Rs = 8.2-6.1, HE = 0.79-0.71). Unexpectedly, population structure present in pre-LLIN populations was lost post-LLIN, suggesting that more frequent human movement between provinces may have contributed to higher gene flow. Pv prevalence initially declined but increased again in one province, yet diversity remained high throughout the study period (East Sepik: Rs = 11.4-9.3, HE = 0.83-0.80; Madang: Rs = 12.2-14.5, HE = 0.85-0.88). Although genetic differentiation values increased between provinces over time, no significant population structure was observed at any time point. For both species, a decline in multiple infections and increasing clonal transmission and significant multilocus linkage disequilibrium post-LLIN were positive indicators of impact on the parasite population using microsatellite markers. These parameters may be useful adjuncts to traditional epidemiological tools in the early stages of transmission reduction.
-
ItemSustained Malaria Control Over an 8-Year Period in Papua New Guinea: The Challenge of Low-Density Asymptomatic Plasmodium Infections(OXFORD UNIV PRESS INC, 2017-12-01)BACKGROUND: The scale-up of effective malaria control in the last decade has resulted in a substantial decline in the incidence of clinical malaria in many countries. The effects on the proportions of asymptomatic and submicroscopic infections and on transmission potential are yet poorly understood. METHODS: In Papua New Guinea, vector control has been intensified since 2008, and improved diagnosis and treatment was introduced in 2012. Cross-sectional surveys were conducted in Madang Province in 2006 (with 1280 survey participants), 2010 (with 2117 participants), and 2014 (with 2516 participants). Infections were quantified by highly sensitive quantitative polymerase chain reaction (PCR) analysis, and gametocytes were quantified by reverse-transcription qPCR analysis. RESULTS: Plasmodium falciparum prevalence determined by qPCR decreased from 42% in 2006 to 9% in 2014. The P. vivax prevalence decreased from 42% in 2006 to 13% in 2010 but then increased to 20% in 2014. Parasite densities decreased 5-fold from 2006 to 2010; 72% of P. falciparum and 87% of P. vivax infections were submicroscopic in 2014. Gametocyte density and positivity correlated closely with parasitemia, and population gametocyte prevalence decreased 3-fold for P. falciparum and 29% for P. vivax from 2010 to 2014. CONCLUSIONS: Sustained control has resulted in reduced malaria transmission potential, but an increasing proportion of gametocyte carriers are asymptomatic and submicroscopic and represent a challenge to malaria control.
-
ItemMultiplicity of Infection Is a Poor Predictor of Village-Level Plasmodium vivax and P. falciparum Population Prevalence in the Southwest Pacific(OXFORD UNIV PRESS INC, 2018-11)Across 8101 individuals in 46 villages, the proportion of Plasmodium spp. multiple clone infections (0%-53.8%) did not reflect prevalence by quantitative polymerase chain reaction (qPCR; 1.9%-38.4%), except for P. vivax in Solomon Islands (P < .001). Thus this parameter was not informative to identify transmission foci. In contrast, prevalence by microscopy and qPCR correlated well.
-
ItemCytokine signatures of Plasmodium vivax infection during pregnancy and delivery outcomes(PUBLIC LIBRARY SCIENCE, 2020-05)Plasmodium vivax malaria is a neglected disease, particularly during pregnancy. Severe vivax malaria is associated with inflammatory responses but in pregnancy immune alterations make it uncertain as to what cytokine signatures predominate, and how the type and quantity of blood immune mediators influence delivery outcomes. We measured the plasma concentrations of a set of thirty-one biomarkers, comprising cytokines, chemokines and growth factors, in 987 plasma samples from a cohort of 572 pregnant women from five malaria-endemic tropical countries and related these concentrations to delivery outcomes (birth weight and hemoglobin levels) and malaria infection. Samples were collected at recruitment (first antenatal visit) and at delivery (periphery, cord and placenta). At recruitment, we found that P. vivax-infected pregnant women had higher plasma concentrations of proinflammatory (IL-6, IL-1β, CCL4, CCL2, CXCL10) and TH1-related cytokines (mainly IL-12) than uninfected women. This biomarker signature was essentially lost at delivery and was not associated with birth weight nor hemoglobin levels. Antiinflammatory cytokines (IL-10) were positively associated with infection and poor delivery outcomes. CCL11 was the only biomarker to show a negative association with P. vivax infection and its concentration at recruitment was positively associated with hemoglobin levels at delivery. Birth weight was negatively associated with peripheral IL-4 levels at delivery. Our multi-biomarker multicenter study is the first comprehensive one to characterize the immunological signature of P. vivax infection in pregnancy thus far. In conclusion, data show that while TH1 and pro-inflammatory responses are dominant during P. vivax infection in pregnancy, antiinflammatory cytokines may compensate excessive inflammation avoiding poor delivery outcomes, and skewness toward a TH2 response may trigger worse delivery outcomes. CCL11, a chemokine largely neglected in the field of malaria, emerges as an important marker of exposure or mediator in this condition.
-
ItemDifferential impact of malaria control interventions on P. falciparum and P. vivax infections in young Papua New Guinean children(BMC, 2019-12-09)INTRODUCTION: As malaria transmission declines, understanding the differential impact of intensified control on Plasmodium falciparum relative to Plasmodium vivax and identifying key drivers of ongoing transmission is essential to guide future interventions. METHODS: Three longitudinal child cohorts were conducted in Papua New Guinea before (2006/2007), during (2008) and after scale-up of control interventions (2013). In each cohort, children aged 1-5 years were actively monitored for infection and illness. Incidence of malaria episodes, molecular force of blood-stage infections (molFOB) and population-averaged prevalence of infections were compared across the cohorts to investigate the impact of intensified control in young children and the key risk factors for malaria infection and illness in 2013. RESULTS: Between 2006 and 2008, P. falciparum infection prevalence, molFOB, and clinical malaria episodes reduced by 47%, 59% and 69%, respectively, and a further 49%, 29% and 75% from 2008 to 2013 (prevalence 41.6% to 22.1% to 11.2%; molFOB: 3.4 to 1.4 to 1.0 clones/child/year; clinical episodes incidence rate (IR) 2.6 to 0.8 to IR 0.2 episodes/child/year). P. vivax clinical episodes declined at rates comparable to P. falciparum between 2006, 2008 and 2013 (IR 2.5 to 1.1 to 0.2), while P. vivax molFOB (2006, 9.8; 2008, 12.1) and prevalence (2006, 59.6%; 2008, 65.0%) remained high in 2008. However, in 2013, P. vivax molFOB (1.2) and prevalence (19.7%) had also substantially declined. In 2013, 89% of P. falciparum and 93% of P. vivax infections were asymptomatic, 62% and 47%, respectively, were sub-microscopic. Area of residence was the major determinant of malaria infection and illness. CONCLUSION: Intensified vector control and routine case management had a differential impact on rates of P. falciparum and P. vivax infections but not clinical malaria episodes in young children. This suggests comparable reductions in new mosquito-derived infections but a delayed impact on P. vivax relapsing infections due to a previously acquired reservoir of hypnozoites. This demonstrates the need to strengthen implementation of P. vivax radical cure to maximise impact of control in co-endemic areas. The high heterogeneity of malaria in 2013 highlights the importance of surveillance and targeted interventions to accelerate towards elimination.
-
ItemSulphadoxine-pyrimethamine plus azithromycin may improve birth outcomes through impacts on inflammation and placental angiogenesis independent of malarial infection(NATURE PORTFOLIO, 2019-02-19)Intermittent preventive treatment with sulphadoxine-pyrimethamine (SP) and SP plus azithromycin (SPAZ) reduces low birthweight (<2,500 g) in women without malarial and reproductive tract infections. This study investigates the impact of SPAZ on associations between plasma biomarkers of inflammation and angiogenesis and adverse pregnancy outcomes in 2,012 Papua New Guinean women. Concentrations of C-reactive protein (CRP), α-1-acid glycoprotein (AGP), soluble endoglin (sEng), soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) were measured at enrolment and delivery in a trial comparing SPAZ to SP plus chloroquine (SPCQ). At antenatal enrolment higher CRP (adjusted odds ratio 1.52; 95% confidence interval [CI] 1.03-2.25), sEng (4.35; 1.77, 10.7) and sFlt1 (2.21; 1.09, 4.48) were associated with preterm birth, and higher sEng with low birthweight (1.39; 1.11,3.37), in SPCQ recipients only. Increased enrolment sFlt1:PlGF ratios associated with LBW in all women (1.46; 1.11, 1.90). At delivery, higher AGP levels were strongly associated with low birthweight, preterm birth and small-for-gestational age babies in the SPCQ arm only. Restricting analyses to women without malaria infection did not materially alter these relationships. Women receiving SPAZ had lower delivery AGP and CRP levels (p < 0.001). SPAZ may protect against adverse pregnancy outcomes by reducing inflammation and preventing its deleterious consequences, including dysregulation of placental angiogenesis, in women with and without malarial infection.
-
ItemCorrigendum: Chronic Exposure to Malaria Is Associated with Inhibitory and Activation Markers on Atypical Memory B Cells and Marginal Zone-Like B Cells (vol 8, 966, 2017)(Frontiers Media, 2019-10-17)[This corrects the article DOI: 10.3389/fimmu.2017.00966.].
-
ItemMicroscopic and submicroscopic Plasmodium falciparum infection, maternal anaemia and adverse pregnancy outcomes in Papua New Guinea: a cohort study(BMC, 2019-09-02)BACKGROUND: Infection during pregnancy with Plasmodium falciparum is associated with maternal anaemia and adverse birth outcomes including low birth weight (LBW). Studies using polymerase chain reaction (PCR) techniques indicate that at least half of all infections in maternal venous blood are missed by light microscopy or rapid diagnostic tests. The impact of these subpatent infections on maternal and birth outcomes remains unclear. METHODS: In a cohort of women co-enrolled in a clinical trial of intermittent treatment with sulfadoxine-pyrimethamine (SP) plus azithromycin for the prevention of LBW (< 2500 g) in Papua New Guinea (PNG), P. falciparum infection status at antenatal enrolment and delivery was assessed by routine light microscopy and real-time quantitative PCR. The impact of infection status at enrolment and delivery on adverse birth outcomes and maternal haemoglobin at delivery was assessed using logistic and linear regression models adjusting for potential confounders. Together with insecticide-treated bed nets, women had received up to 3 monthly intermittent preventive treatments with SP plus azithromycin or a single clearance treatment with SP plus chloroquine. RESULTS: A total of 9.8% (214/2190) of women had P. falciparum (mono-infection or mixed infection with Plasmodium vivax) detected in venous blood at antenatal enrolment at 14-26 weeks' gestation. 4.7% of women had microscopic, and 5.1% submicroscopic P. falciparum infection. At delivery (n = 1936), 1.5% and 2.0% of women had submicroscopic and microscopic P. falciparum detected in peripheral blood, respectively. Submicroscopic P. falciparum infections at enrolment or at delivery in peripheral or placental blood were not associated with maternal anaemia or adverse birth outcomes such as LBW. Microscopic P. falciparum infection at antenatal enrolment was associated with anaemia at delivery (adjusted odds ratio [aOR] 2.00, 95% confidence interval [CI] 1.09, 3.67; P = 0.025). Peripheral microscopic P. falciparum infection at delivery was associated with LBW (aOR 2.75, 95% CI 1.27; 5.94, P = 0.010) and preterm birth (aOR 6.58, 95% CI 2.46, 17.62; P < 0.001). CONCLUSIONS: A substantial proportion of P. falciparum infections in pregnant women in PNG were submicroscopic. Microscopic, but not submicroscopic, infections were associated with adverse outcomes in women receiving malaria preventive treatment and insecticide-treated bed nets. Current malaria prevention policies that combine insecticide-treated bed nets, intermittent preventive treatment and prompt treatment of symptomatic infections appear to be appropriate for the management of malaria in pregnancy in settings like PNG.
-
ItemEffects of Plasmodium falciparum infection on umbilical artery resistance and intrafetal blood flow distribution: a Doppler ultrasound study from Papua New Guinea(BMC, 2017-01-19)BACKGROUND: Doppler velocimetry studies of umbilical artery (UA) and middle cerebral artery (MCA) flow help to determine the presence and severity of fetal growth restriction. Increased UA resistance and reduced MCA pulsatility may indicate increased placental resistance and intrafetal blood flow redistribution. Malaria causes low birth weight and fetal growth restriction, but few studies have assessed its effects on uteroplacental and fetoplacental blood flow. METHODS: Colour-pulsed Doppler ultrasound was used to assess UA and MCA flow in 396 Papua New Guinean singleton fetuses. Abnormal flow was defined as an UA resistance index above the 90th centile, and/or a MCA pulsatility index and cerebroplacental ratio (ratio of MCA and UA pulsatility index) below the 10th centile of population-specific models fitted to the data. Associations between malaria (peripheral infection prior to and at ultrasound examination, and any gestational infection, i.e., 'exposure') and abnormal flow, and between abnormal flow and birth outcomes, were estimated. RESULTS: Of 78 malaria infection episodes detected before or at the ultrasound visit, 62 (79.5%) were Plasmodium falciparum (34 sub-microscopic infections), and 16 were Plasmodium vivax. Plasmodium falciparum infection before or at Doppler measurement was associated with increased UA resistance (adjusted odds ratio (aOR) 2.3 95% CI 1.0-5.2, P = 0.047). When assessed by 'exposure', P. falciparum infection was significantly associated with increased UA resistance (all infections: 2.4, 1.1-4.9, P = 0.024; sub-microscopic infections 2.6, 1.0-6.6, P = 0.051) and a reduced MCA pulsatility index (all infections: 2.6, 1.2-5.3, P = 0.012; sub-microscopic infections: 2.8, 1.1-7.5, P = 0.035). Sub-microscopic P. falciparum infections were additionally associated with a reduced cerebroplacental ratio (3.64, 1.22-10.88, P = 0.021). There were too few P. vivax infections to draw robust conclusions. An increased UA resistance index was associated with histological evidence of placental malaria (5.1, 2.3-10.9, P < 0.001; sensitivity 0.26, specificity 0.93). A low cerebroplacental Doppler ratio was associated with concurrently measuring small-for-gestational-age, and with low birth weight. DISCUSSION/CONCLUSION: Both microscopic and sub-microscopic P. falciparum infections impair fetoplacental and intrafetal flow, at least temporarily. Increased UA resistance has high specificity but low sensitivity for the detection of placental infection. These findings suggest that interventions to protect the fetus should clear and prevent both microscopic and sub-microscopic malarial infections. Trial Registration ClinicalTrials.gov NCT01136850. Registered 06 April 2010.