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Regulatory T cells (Treg) play a prominent role in utero tolerating non-inherited maternal antigens and in regulating immune responses against pathogens at birth. This study investigates Treg immunity in newborns in West Africa, where sepsis remains a major public health problem. Treg phenotypes on neonates subgroups with early-onset sepsis (EOS), presumed sepsis, and healthy newborn with and without prenatal risk factors were evaluated. Treg phenotypes varied according to prenatal conditions, with increase in Treg frequency and Foxp3 expression in healthy newborns with prenatal risk factors compared to those with none risk. Compared to healthy newborns with prenatal risk factors, EOS neonates had a significantly reduced frequency of Treg and Foxp3 expression. In the Treg pool, higher frequency of activated Treg was observed in EOS neonates, suggesting an in-utero activation upstream of the sepsis onset. Their migration to the infection site may explain the reduced frequency of circulating Integrin α4ß1+ Treg suggestive of homing to the endothelial tissue. EOS neonates show increases expression of CTLA-4, PD-1 and CD39 on Treg, which negatively regulate the activation of effector T cells (Teff) corroborating by the lower frequency of Teff in EOS neonates. The higher frequency of CD39+ Treg and the lower frequency of integrinα4ß1+ Treg in EOS non-survivor suggests that Treg exhaustement and endothelial homing are associated with outcome severity. Neonates developing EOS are born with an altered Treg phenotypic profile. Treg expression of CTLA-4, PD-1, CD39, and integrinα4ß1 cell markers can be considered as early warning or diagnostic markers of EOS.
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Sepse Neonatal , Linfócitos T Reguladores , Humanos , Linfócitos T Reguladores/imunologia , Recém-Nascido , Sepse Neonatal/imunologia , Sepse Neonatal/diagnóstico , Feminino , Masculino , Ativação Linfocitária/imunologia , Fatores de Transcrição Forkhead/metabolismo , Apirase/metabolismo , Antígeno CTLA-4/metabolismo , Antígenos CD , Receptor de Morte Celular Programada 1/metabolismo , BiomarcadoresRESUMO
BACKGROUND: Pregnant women are a vulnerable population to COVID-19 given an increased susceptibility to severe SARS-CoV-2 infection and pregnancy complications. However, few SARS-CoV-2 serological surveys have been performed among this population to assess the extent of the infection in sub-Saharan countries. The objectives of this study were to determine SARS-CoV-2 seroprevalence among Beninese pregnant women, to identify spatial seropositivity clusters and to analyse factors associated with the infection. METHODS: A cross-sectional study including women in their third trimester of pregnancy attending the antenatal care (ANC) clinics at Allada (south Benin) and Natitingou (north Benin) was conducted. Rapid diagnostic tests (RDT) for detection of IgG/IgM against the SARS-CoV-2 spike protein were performed using capillary blood. Seroprevalence of SARS-CoV-2 antibodies and associations between SARS-CoV-2 serostatus and maternal characteristics were analyzed by multivariate logistic regression. Spatial analyses were performed using the spatial scan statistics to identify spatial clusters of SARS-CoV-2 infection. RESULTS: A total of 861 pregnant women were enrolled between May 4 and June 29, 2022. 58/861 (6.7%) participants reported having received COVID-19 vaccine. None of the participants had been diagnosed with COVID-19 during their pregnancy. SARS-CoV-2 antibodies were detected in 607/802 (75.7%; 95% CI 72.56%-78.62%) of unvaccinated participants. Several urban and rural spatial clusters of SARS-CoV-2 cases were identified in Allada and one urban spatial cluster was identified in Natitingou. Unvaccinated participants from Allada with at least one previous morbidity were at a three-times higher risk of presenting SARS-CoV-2 antibodies (OR = 2.89; 95%CI 1.19%-7.00%). CONCLUSION: Three out of four pregnant women had SARS-CoV-2 antibodies, suggesting a high virus circulation among pregnant women in Benin, while COVID-19 vaccination coverage was low. Pregnant women with comorbidities may be at increased risk of SARS-CoV-2 infection. This population should be prioritized for COVID-19 diagnosis and vaccination in order to prevent its deleterious effects. TRIAL REGISTRATION: NCT06170320 (retrospectively registered on December 21, 2023).
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COVID-19 , Complicações Infecciosas na Gravidez , SARS-CoV-2 , Humanos , Feminino , Gravidez , COVID-19/epidemiologia , COVID-19/diagnóstico , Estudos Soroepidemiológicos , Adulto , Estudos Transversais , Complicações Infecciosas na Gravidez/epidemiologia , Benin/epidemiologia , SARS-CoV-2/imunologia , Adulto Jovem , Anticorpos Antivirais/sangue , Terceiro Trimestre da GravidezRESUMO
BACKGROUND: Mutations in the Plasmodium falciparum dhfr gene confer resistance to pyrimethamine, which is widely used for malaria chemoprevention in Africa. We aimed to evaluate the frequency and evolution of dhfr mutations in Plasmodium ovale spp in Africa and their functional consequences, which are incompletely characterised. METHODS: We analysed dhfr mutations and their frequencies in P ovale spp isolates collected between Feb 1, 2004, and Aug 31, 2023, from the French National Malaria Reference Centre collection and from field studies in Benin, Gabon, and Kenya. Genetic patterns of positive selection were investigated. Full-length recombinant wild-type and mutant DHFR enzymes from both P ovale curtisi and P ovale wallikeri were expressed in bacteria to test whether the most common mutations reduced pyrimethamine susceptibility. FINDINGS: We included 518 P ovale spp samples (314 P ovale curtisi and 204 P ovale wallikeri). In P ovale curtisi, Ala15Ser-Ser58Arg was the most common dhfr mutation (39%; 124 of 314 samples). In P ovale wallikeri, dhfr mutations were less frequent, with Phe57Leu-Ser58Arg reaching 17% (34 of 204 samples). These two mutants were the most prevalent in central and east Africa and were fixed in Kenyan isolates. We detected six and four other non-synonymous mutations, representing 8% (24 isolates) and 2% (five isolates) of the P ovale curtisi and P ovale wallikeri isolates, respectively. Whole-genome sequencing and microsatellite analyses revealed reduced genetic diversity around the mutant pocdhfr and powdhfr genes. The mutant DHFR proteins showed structural changes at the pyrimethamine binding site in-silico, confirmed by a 4-times increase in pyrimethamine half-maximal inhibitory concentration in an Escherichia coli growth assay for the Phe57Leu-Ser58Arg mutant and 50-times increase for the Ala15Ser-Ser58Arg mutant, compared with the wild-type counterparts. INTERPRETATION: The widespread use of sulfadoxine-pyrimethamine for malaria chemoprevention might have exerted fortuitous selection pressure for dhfr mutations in P ovale spp. This calls for closer monitoring of dhfr and dhps mutations in P ovale spp. FUNDING: French Ministry of Health, Agence Nationale de la Recherche, and Global Emerging Infections Surveillance branch of the Armed Forces Health Surveillance Division.
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Antimaláricos , Resistência a Medicamentos , Malária , Mutação , Plasmodium ovale , Pirimetamina , Tetra-Hidrofolato Desidrogenase , Tetra-Hidrofolato Desidrogenase/genética , Tetra-Hidrofolato Desidrogenase/metabolismo , Pirimetamina/farmacologia , Pirimetamina/uso terapêutico , Resistência a Medicamentos/genética , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Plasmodium ovale/genética , Plasmodium ovale/efeitos dos fármacos , Humanos , Malária/epidemiologia , Estudos Retrospectivos , África Subsaariana/epidemiologia , Proteínas de Protozoários/genética , Quênia/epidemiologiaRESUMO
Biological sciences, drug discovery and medicine rely heavily on cell phenotype perturbation and microscope observation. However, most cellular phenotypic changes are subtle and thus hidden from us by natural cell variability: two cells in the same condition already look different. In this study, we show that conditional generative models can be used to transform an image of cells from any one condition to another, thus canceling cell variability. We visually and quantitatively validate that the principle of synthetic cell perturbation works on discernible cases. We then illustrate its effectiveness in displaying otherwise invisible cell phenotypes triggered by blood cells under parasite infection, or by the presence of a disease-causing pathological mutation in differentiated neurons derived from iPSCs, or by low concentration drug treatments. The proposed approach, easy to use and robust, opens the door to more accessible discovery of biological and disease biomarkers.
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Células-Tronco Pluripotentes Induzidas , Diferenciação Celular , Descoberta de Drogas/métodos , FenótipoRESUMO
Background: Malaria in pregnancy (MiP) has been associated with fetal growth restriction, the underlying pathogenic mechanisms of which remain poorly understood. Malaria in pregnancy is suspected to induce abnormalities in placental vascularization, leading to impaired placental development. Our study evaluated MIP's effect on uterine artery (UtA) and umbilical artery (UA) blood flow. Methods: The analysis included 253 Beninese women followed throughout pregnancy and screened monthly for submicroscopic and microscopic malaria. Uterine artery Doppler measurement was performed once between 21 and 25 weeks' gestation (wg), and UA Doppler measurement was performed 1-3 times from 28 wg. Linear and logistic regression models were used to assess the effect of malaria infections on UtA Doppler indicators (pulsatility index and presence of a notch), whereas a logistic mixed model was used to assess the association between malaria infections and abnormal UA Doppler (defined as Z-score ≥2 standard deviation or absent/reversed UA end-diastolic flow). Results: Primigravidae represented 7.5% of the study population; 42.3% of women had at least 1 microscopic infection during pregnancy, and 29.6% had at least 1 submicroscopic infection (and no microscopic infection). Both microscopic and submicroscopic infections before Doppler measurement were associated with the presence of a notch (adjusted odds ratio [aOR] 4.5, 95% confidence interval [CI] = 1.2-16.3 and aOR 3.3, 95% CI = .9-11.9, respectively). No associations were found between malaria before the Doppler measurement and abnormal UA Doppler. Conclusions: Malaria infections in the first half of pregnancy impair placental blood flow. This highlights the need to prevent malaria from the very beginning of pregnancy.
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BACKGROUND: Malaria infections during pregnancy can cause adverse birth outcomes, yet many infections are undetected by microscopy. We aimed to describe the epidemiology of submicroscopic malaria infections in pregnant women in Asia, the Americas, and Africa using aggregated and individual participant data (IPD). METHODS: For this systematic review and meta-analysis, studies (published Jan 1, 1997 to Nov 10, 2021) with information on both microscopic and submicroscopic infections during pregnancy from Asia, the Americas, or Africa, identified in the Malaria-in-Pregnancy Library, were eligible. Studies (or subgroups or study groups) that selected participants on the basis of the presence of fever or a positive blood smear were excluded to avoid selection bias. We obtained IPD (when available) and aggregated data. Estimates of malaria transmission intensity and sulfadoxine-pyrimethamine resistance, matched by study location and year, were obtained using publicly available data. One-stage multivariable logit and multinomial models with random intercepts for study site were used in meta-analysis to assess prevalence of and risk factors for submicroscopic infections during pregnancy and at delivery. This study is registered with PROSPERO, number CRD42015027342. FINDINGS: The search identified 87 eligible studies, 68 (78%) of which contributed to the analyses. Of these 68 studies, 45 (66%) studies contributed IPD (48 869 participants) and 23 (34%) studies contributed aggregated data (11 863 participants). During pregnancy, median prevalence estimates were 13·5% (range 0·0-55·9, 66 substudies) for submicroscopic and 8·0% (0·0-50·6, 66 substudies) for microscopic malaria. Among women with positive Plasmodium nucleic acid amplification tests (NAATs), the median proportion of submicroscopic infections was 58·7% (range 0·0-100); this proportion was highest in the Americas (73·3%, 0·0-100), followed by Asia (67·2%, 36·4-100) and Africa (56·5%, 20·5-97·7). In individual patient data analysis, compared with women with no malaria infections, those with submicroscopic infections were more likely to present with fever in Africa (adjusted odds ratio 1·32, 95% CI 1·02-1·72; p=0·038) but not in other regions. Among women with NAAT-positive infections in Asia and the Americas, Plasmodium vivax infections were more likely to be submicroscopic than Plasmodium falciparum infections (3·69, 2·45-5·54; p<0·0001). Risk factors for submicroscopic infections among women with NAAT-positive infections in Africa included older age (age ≥30 years), multigravidity, and no HIV infection. INTERPRETATION: During pregnancy, submicroscopic infections are more common than microscopic infections and are associated with fever in Africa. Malaria control in pregnancy should target both microscopic and submicroscopic infections. FUNDING: Bill & Melinda Gates Foundation through the Worldwide Antimalarial Resistance Network.
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Antimaláricos , Malária Falciparum , Malária , Feminino , Humanos , Gravidez , Adulto , Prevalência , Malária/prevenção & controle , Antimaláricos/uso terapêutico , Malária Falciparum/tratamento farmacológico , Fatores de RiscoRESUMO
BACKGROUND: Many SARS-CoV-2 seroprevalence surveys since the end of 2020 have disqualified the first misconception that Africa had been spared by the pandemic. Through the analysis of three SARS-CoV-2 seroprevalence surveys carried out in Benin as part of the ARIACOV project, we argue that the integration of epidemiological serosurveillance of the SARS-CoV-2 infection in the national surveillance packages would be of great use to refine the understanding of the COVID-19 pandemic in Africa. METHODS: We carried out three repeated cross-sectional surveys in Benin: two in Cotonou, the economic capital in March and May 2021, and one in Natitingou, a semi-rural city in the north of the country in August 2021. Total and weighted-by-age-group seroprevalences were estimated and the risk factors for SARS-CoV-2 infection were assessed by multivariate logistic regression. RESULTS: In Cotonou, a slight increase in overall age-standardised SARS-CoV-2 seroprevalence from 29.77% (95% CI: 23.12%-37.41%) at the first survey to 34.86% (95% CI: 31.57%-38.30%) at the second survey was observed. In Natitingou, the globally adjusted seroprevalence was 33.34% (95% CI: 27.75%-39.44%). A trend of high risk for SARS-CoV 2 seropositivity was observed in adults over 40 versus the young (less than 18 years old) during the first survey in Cotonou but no longer in the second survey. CONCLUSIONS: Our results show that, however, rapid organisation of preventive measures aimed at breaking the chains of transmission, they were ultimately unable to prevent a wide spread of the virus in the population. Routine serological surveillance on strategic sentinel sites and/or populations could constitute a cost-effective compromise to better anticipate the onset of new waves and define public health strategies.
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COVID-19 , SARS-CoV-2 , Humanos , Adolescente , Benin/epidemiologia , COVID-19/epidemiologia , Pandemias , Estudos Transversais , Estudos Soroepidemiológicos , Anticorpos AntiviraisRESUMO
BACKGROUND: The objective of this study was to estimate malaria transmission and insecticide resistance status in malaria vectors in Adjrako village from Zè District in Southern Benin. The present study was carried out prior to investigations on infectivity of blood from asymptomatic carriers of Plasmodium falciparum to malaria vector mosquitoes. METHODS: Human landing collections (HLCs) were performed in Adjrako village during the rainy season (September-November 2021). In this village, host-seeking mosquitoes were collected during three nights per survey from 22:00 to 06:00 in six randomly selected houses. Malaria vectors were dissected in orders to determinate their parity. Plasmodium falciparum infection in malaria vectors was determined by qPCR and the entomological inoculation rate (EIR) was calculated. The World Health Organization (WHO) insecticide susceptibility test-kits were used to evaluate the susceptibility of Anopheles gambiae sensu lato (s.l.) to deltamethrin at 0.05% and bendiocarb at 0.1%. RESULTS: A total of 3260 females of mosquitoes belonging to 4 genera (Anopheles, Culex, Aedes and Mansonia) were collected. Most of the mosquitoes collected were An. gambiae sensu lato (s.l.). The entomological inoculation rate (EIR) for the three collection months was 8.7 infective bites per person and the parity rate was 84%. Mortality rates of An. gambiae s.l. exposed to 0.05% deltamethrin and 0.1% bendiocarb were 18% and 96%, respectively, indicating that this vector population was resistant to deltamethrin and possibly resistant to bendiocarb in the study area. CONCLUSION: This study showed that malaria transmission is effective in the study area and that An. gambiae s.l. is the main malaria vector. The entomological parameters indicate this study area is potentially favourable for investigations on P. falciparum asymptomatic carriers.
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Anopheles , Malária Falciparum , Malária , Animais , Feminino , Humanos , Plasmodium falciparum/genética , Benin/epidemiologia , Mosquitos Vetores , Malária Falciparum/epidemiologia , Resistência a InseticidasRESUMO
Background: Placental malaria (PM) is associated with a higher susceptibility of infants to Plasmodium falciparum (Pf) malaria. A hypothesis of immune tolerance has been suggested but no clear explanation has been provided so far. Our goal was to investigate the involvement of inhibitory receptors LILRB1 and LILRB2, known to drive immune evasion upon ligation with pathogen and/or host ligands, in PM-induced immune tolerance. Method: Infants of women with or without PM were enrolled in Allada, southern Benin, and followed-up for 24 months. Antibodies with specificity for five blood stage parasite antigens were quantified by ELISA, and the frequency of immune cell subsets was quantified by flow cytometry. LILRB1 or LILRB2 expression was assessed on cells collected at 18 and 24 months of age. Findings: Infants born to women with PM had a higher risk of developing symptomatic malaria than those born to women without PM (IRR=1.53, p=0.040), and such infants displayed a lower frequency of non-classical monocytes (OR=0.74, p=0.01) that overexpressed LILRB2 (OR=1.36, p=0.002). Moreover, infants born to women with PM had lower levels of cytophilic IgG and higher levels of IL-10 during active infection. Interpretation: Modulation of IgG and IL-10 levels could impair monocyte functions (opsonisation/phagocytosis) in infants born to women with PM, possibly contributing to their higher susceptibility to malaria. The long-lasting effect of PM on infants' monocytes was notable, raising questions about the capacity of ligands such as Rifins or HLA-I molecules to bind to LILRB1 and LILRB2 and to modulate immune responses, and about the reprogramming of neonatal monocytes/macrophages.
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Antimaláricos , Malária Falciparum , Glicoproteínas de Membrana , Placenta , Receptores Imunológicos , Anticorpos Antiprotozoários , Feminino , Humanos , Imunoglobulina G/sangue , Lactente , Recém-Nascido , Interleucina-10 , Receptor B1 de Leucócitos Semelhante a Imunoglobulina/genética , Receptor B1 de Leucócitos Semelhante a Imunoglobulina/imunologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Monócitos/metabolismo , Placenta/parasitologia , Plasmodium falciparum , Gravidez , Receptores Imunológicos/genética , Receptores Imunológicos/imunologiaRESUMO
BACKGROUND: Malaria in early pregnancy occurs at a time when the placenta is developing, with possible consequences for placental function and fetal growth. We assessed the association between first trimester malaria and fetal growth documented through repeated ultrasound scans. METHODS: The RECIPAL preconceptional cohort included 411 Beninese pregnant women followed from 7 weeks' gestation (wg) until delivery. Among them, 218 had 4 scans for fetal monitoring at 16, 22, 28, and 34 wg. Multivariate seemingly unrelated regression models were used to assess association of microscopic malaria in the first trimester (<15 wg) with abdominal circumference, head circumference, biparietal diameter, and femur length throughout pregnancy. RESULTS: Of 39% (86/218) of women with at least 1 microscopic malarial infection during pregnancy, 52.3% (45/86) were infected in the first trimester. Most women (88.5%) were multiparous. There was no association between adjusted z-scores for fetal growth parameters and first trimester malaria. Parity, newborn sex, socioeconomic level, and maternal body mass index significantly influenced fetal growth. CONCLUSIONS: In a context where malaria infections in pregnancy are well detected and treated, their adverse effect on fetal growth may be limited. Our results argue in favor of preventing and treating infections as early as the first trimester.
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Malária , Ultrassonografia Pré-Natal , Feminino , Desenvolvimento Fetal , Idade Gestacional , Humanos , Recém-Nascido , Placenta , Gravidez , Primeiro Trimestre da GravidezRESUMO
BACKGROUND: Despite several years of school-based MDA implementation, STH infections remain an important public health problem in Benin, with a country-wide prevalence of 20% in 2015. The DeWorm3 study is designed to assess the feasibility of using community-based MDA with albendazole to interrupt the transmission of STH, through a series of cluster-randomized trials in Benin, India and Malawi. We used the pre-treatment baseline survey data to describe and analyze the factors associated with STH infection in Comé, the study site of the DeWorm3 project in Benin. These data will improve understanding of the challenges that need to be addressed in order to eliminate STH as a public health problem in Benin. METHODS: Between March and April 2018, the prevalence of STH (hookworm spp., Ascaris and Trichuris trichiura) was assessed by Kato-Katz in stool samples collected from 6,153 residents in the community of Comé, Benin using a stratified random sampling procedure. A standardized survey questionnaire was used to collect information from individual households concerning factors potentially associated with the presence and intensity of STH infections in pre-school (PSAC, aged 1-4), school-aged children (SAC, aged 5-14) and adults (aged 15 and above). Multilevel mixed-effects models were used to assess associations between these factors and STH infection. RESULTS: The overall prevalence of STH infection was 5.3%; 3.2% hookworm spp., 2.1% Ascaris lumbricoides and 0.1% Trichuris. Hookworm spp. were more prevalent in adults than in SAC (4.4% versus 2.0%, respectively; p = 0.0001) and PSAC (4.4% versus 1.0%, respectively; p<0.0001), whilst Ascaris lumbricoides was more prevalent in SAC than in adults (3.0% versus 1.7%, respectively; p = 0.004). Being PSAC (adjusted Odds Ratio (aOR) = 0.2, p< 0.001; adjusted Infection Intensity Ratio (aIIR) = 0.1, p<0.001) or SAC (aOR = 0.5, p = 0.008; aIIR = 0.3, p = 0.01), being a female (aOR = 0.6, p = 0.004; aIIR = 0.3, p = 0.001), and having received deworming treatment the previous year (aOR = 0.4, p< 0.002; aIIR = 0.2, p<0.001) were associated with a lower prevalence and intensity of hookworm infection. Lower income (lowest quintile: aOR = 5.0, p<0.001, 2nd quintile aOR = 3.6, p = 0.001 and 3rd quintile aOR = 2.5, p = 0.02), being a farmer (aOR = 1.8, p = 0.02), medium population density (aOR = 2.6, p = 0.01), and open defecation (aOR = 0.5, p = 0.04) were associated with a higher prevalence of hookworm infection. Lower education-no education, primary or secondary school- (aIIR = 40.1, p = 0.01; aIIR = 30.9, p = 0.02; aIIR = 19.3, p = 0.04, respectively), farming (aIIR = 3.9, p = 0.002), natural flooring (aIIR = 0.2, p = 0.06), peri-urban settings (aIIR = 6.2, 95%CI 1.82-20.90, p = 0.003), and unimproved water source more than 30 minutes from the household (aIIR = 13.5, p = 0.02) were associated with a higher intensity of hookworm infection. Improved and unshared toilet was associated with lower intensity of hookworm infections (aIIR = 0.2, p = 0.01). SAC had a higher odds of Ascaris lumbricoides infection than adults (aOR = 2.0, p = 0.01) and females had a lower odds of infection (aOR = 0.5, p = 0.02). CONCLUSION: Hookworm spp. are the most prevalent STH in Comé, with a persistent reservoir in adults that is not addressed by current control measures based on school MDA. Expanding MDA to target adults and PSAC is necessary to substantially impact population prevalence, particularly for hookworm. TRIAL REGISTRATION: ClinicalTrials.gov NCT03014167.
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Ascaríase/epidemiologia , Infecções por Uncinaria/epidemiologia , Saneamento , Solo/parasitologia , Tricuríase/epidemiologia , Adolescente , Ancylostomatoidea/isolamento & purificação , Animais , Ascaríase/parasitologia , Ascaríase/transmissão , Ascaris lumbricoides/isolamento & purificação , Benin/epidemiologia , Criança , Pré-Escolar , Características da Família , Fezes/parasitologia , Feminino , Infecções por Uncinaria/parasitologia , Infecções por Uncinaria/transmissão , Humanos , Modelos Logísticos , Masculino , Prevalência , Fatores de Risco , Instituições Acadêmicas , Tricuríase/parasitologia , Tricuríase/transmissão , Trichuris/isolamento & purificaçãoRESUMO
OBJECTIVE: In the framework of EVALMOUS study aiming to assess the use and effectiveness of mosquito nets by pregnant women and other members of their household in a lagoon area in southern Benin, the behaviour of pregnant women relative to the time they go to bed using the net were recorded. Malaria vectors biting rhythm, Plasmodium falciparum infection and insecticide resistance genes in malaria vectors were also determined. RESULTS: Overall, 3848 females of Anopheles gambiae s. l were collected and 280 pregnant women responded to the survey. Almost all Anopheles gambiae s. l. tested were Anopheles coluzzi Coetzee and Wilkerson 2013 (Diptera: Culicidae). The CSP index in malaria vector was 1.85% and the allelic frequency of kdr gene was 74.4%. Around 90% of bites and Plasmodium falciparum Welch, 1897 (Haemosporida: Plasmodiidae) transmission occurred between 10 p.m. and 6 a.m., which coincides with the period when more than 80% of pregnant women were under bednet. Despite a slight early evening and early morning biting activity of malaria vectors in the study area, the good use of nets might remain a useful protection tool against mosquito biting and malaria transmission.
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Anopheles , Inseticidas , Malária , Animais , Anopheles/genética , Benin , Comportamento Alimentar , Feminino , Humanos , Malária/prevenção & controle , Mosquitos Vetores , Gravidez , GestantesRESUMO
Ultrasensitive molecular diagnostics are lowering the limit of detection for malaria parasites in the blood and providing insights not captured by conventional tools such as microscopy and rapid antigen tests. Low-level malaria infections identified by molecular tools may influence clinical outcomes, transmission events, and elimination efforts. While many ultrasensitive molecular methods require well-equipped laboratories, technologies such as loop-mediated isothermal amplification and recombinase polymerase amplification provide more portable and analytically sensitive solutions. These tools may benefit asymptomatic patient screening, antenatal care, and elimination campaigns. We review the recent evidence, offer our perspective on the impact of these new tests, and identify future research priorities.
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Malária , Técnicas de Amplificação de Ácido Nucleico , Feminino , Humanos , Malária/diagnóstico , Microscopia , Técnicas de Diagnóstico Molecular , GravidezRESUMO
BACKGROUND: The DeWorm3 project is an ongoing cluster-randomised trial assessing the feasibility of interrupting the transmission of soil-transmitted helminths (STH) through mass drug administration (MDA) using study sites in India, Malawi and Benin. In this article, we describe an approach which uses a combination of statistical and mathematical methods to forecast the outcome of the trial with respect to its stated goal of reducing the prevalence of infection to below 2%. METHODS: Our approach is first to define the local patterns of transmission within each study site, which is achieved by statistical inference of key epidemiological parameters using the baseline epidemiological measures of age-related prevalence and intensity of STH infection which have been collected by the DeWorm3 trials team. We use these inferred parameters to calibrate an individual-based stochastic simulation of the trial at the cluster and study site level, which is subsequently run to forecast the future prevalence of STH infections. The simulator takes into account both the uncertainties in parameter estimation and the variability inherent in epidemiological and demographic processes in the simulator. We interpret the forecast results from our simulation with reference to the stated goal of the DeWorm3 trial, to achieve a target of [Formula: see text] prevalence at a point 24 months post-cessation of MDA. RESULTS: Simulated output predicts that the two arms will be distinguishable from each other in all three country sites at the study end point. In India and Malawi, measured prevalence in the intervention arm is below the threshold with a high probability (90% and 95%, respectively), but in Benin the heterogeneity between clusters prevents the arm prevalence from being reduced below the threshold value. At the level of individual study arms within each site, heterogeneity among clusters leads to a very low probability of achieving complete elimination in an intervention arm, yielding a post-study scenario with widespread elimination but a few 'hot spot' areas of persisting STH transmission. CONCLUSIONS: Our results suggest that geographical heterogeneities in transmission intensity and worm aggregation have a large impact on the effect of MDA. It is important to accurately assess cluster-level, or even smaller scale, heterogeneities in factors which influence transmission and aggregation for a clearer perspective on projecting the outcomes of MDA control of STH and other neglected tropical diseases.
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Anti-Helmínticos/uso terapêutico , Helmintíase/prevenção & controle , Helmintos/efeitos dos fármacos , Administração Massiva de Medicamentos/normas , Ensaios Clínicos Controlados Aleatórios como Assunto , Solo/parasitologia , Animais , Benin/epidemiologia , Simulação por Computador , Feminino , Previsões , Helmintíase/epidemiologia , Helmintíase/transmissão , Helmintos/classificação , Helmintos/isolamento & purificação , Humanos , Índia/epidemiologia , Malaui/epidemiologia , Administração Massiva de Medicamentos/métodos , Administração Massiva de Medicamentos/estatística & dados numéricos , Modelos Estatísticos , Modelos Teóricos , PrevalênciaRESUMO
BACKGROUND: Harmful maternal and neonatal health outcomes result from malaria in pregnancy, the prevention of which primarily relies on intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP). The World Health Organization recommends IPTp-SP in sub-Saharan Africa, but implementation is highly heterogeneous and often suboptimal in terms of the number of doses and their timing. In this study, we assessed the impact of this heterogeneity on malaria in pregnancy, mainly with respect to submicroscopic Plasmodium falciparum infections. METHODS: We used data from 273 Beninese women followed throughout pregnancy. Screening for P. falciparum infections, using both microscopy-based and polymerase chain reaction (PCR)-based methods, was performed monthly, and information on IPTp-SP doses was collected. Gestational age was estimated by repeated ultrasound scans. Using a negative binomial model, we investigated the effect of IPTp-SP doses and timing after 17 weeks of gestation on the number of P. falciparum infections, focusing on submicroscopic infections detectable only by PCR. RESULTS: At least 2 IPTp-SP doses were taken by 77.3% of the women. The median gestational age at the first IPTp-SP dose was 22 weeks. A late first IPTp-SP dose (>21.2 weeks) was marginally associated with an increased number of P. falciparum infections (adjusted incidence rate ratio [aIRR]â =â 1.3; Pâ =â .098). The number of IPTp-SP doses was not associated with the number of submicroscopic infections (aIRRâ =â 1.2, Pâ =â .543). CONCLUSIONS: A late first IPTp-SP dose failed to provide optimal protection against P. falciparum, especially submicroscopic infections. This highlights the need for a new antimalarial drug for IPTp that could be taken early in pregnancy.
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Antimaláricos , Malária Falciparum , Complicações Parasitárias na Gravidez , Antimaláricos/administração & dosagem , Antimaláricos/uso terapêutico , Benin/epidemiologia , Combinação de Medicamentos , Feminino , Humanos , Recém-Nascido , Malária Falciparum/tratamento farmacológico , Malária Falciparum/prevenção & controle , Plasmodium falciparum , Gravidez , Complicações Parasitárias na Gravidez/tratamento farmacológico , Complicações Parasitárias na Gravidez/prevenção & controle , Estudos Prospectivos , Pirimetamina/administração & dosagem , Pirimetamina/uso terapêutico , Sulfadoxina/administração & dosagem , Sulfadoxina/uso terapêuticoRESUMO
An amendment to this paper has been published and can be accessed via the original article.
RESUMO
INTRODUCTION: Neonatal sepsis outreaches all causes of neonatal mortality worldwide and remains a major societal burden in low and middle income countries. In addition to limited resources, endemic morbidities, such as malaria and prematurity, predispose neonates and infants to invasive infection by altering neonatal immune response to pathogens. Nevertheless, thoughtful epidemiological, diagnostic and immunological evaluation of neonatal sepsis and the impact of gestational malaria have never been performed. METHODS AND ANALYSIS: A prospective longitudinal multicentre follow-up of 580 infants from birth to 3 months of age in urban and suburban Benin will be performed. At delivery, and every other week, all children will be examined and clinically evaluated for occurrence of sepsis. At delivery, cord blood systematic analysis of selected plasma and transcriptomic biomarkers (procalcitonin, interleukin (IL)-6, IL-10, IP10, CD74 and CX3CR1) associated with sepsis pathophysiology will be evaluated in all live births as well as during the follow-up, and when sepsis will be suspected. In addition, whole blood response to selected innate stimuli and extensive peripheral blood mononuclear cells phenotypic characterisation will be performed. Reference intervals specific to sub-Saharan neonates will be determined from this cohort and biomarkers performances for neonatal sepsis diagnosis and prognosis tested. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Comité d'Ethique de la Recherche - Institut des Sciences Biomédicales Appliquées (CER-ISBA 85 - 5 April 2016, extended on 3 February 2017). Results will be disseminated through international presentations at scientific meetings and publications in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov registration number: NCT03780712.
Assuntos
Malária , Sepse Neonatal , Sepse , África do Norte , Benin , Biomarcadores , Criança , Humanos , Imunidade , Lactente , Recém-Nascido , Leucócitos Mononucleares , Malária/diagnóstico , Malária/epidemiologia , Sepse Neonatal/diagnóstico , Sepse Neonatal/epidemiologia , Estudos Prospectivos , Sepse/diagnóstico , Sepse/epidemiologiaRESUMO
BACKGROUND: While sub-microscopic malarial infections are frequent and potentially deleterious during pregnancy, routine molecular detection is still not feasible. This study aimed to assess the performance of a Histidine Rich Protein 2 (HRP2)-based ultrasensitive rapid diagnostic test (uRDT, Alere Malaria Ag Pf) for the detection of infections of low parasite density in pregnant women. METHODS: This was a retrospective study based on samples collected in Benin from 2014 to 2017. A total of 942 whole blood samples collected in 327 women in the 1st and 3rd trimesters and at delivery were tested by uRDT, conventional RDT (cRDT, SD BIOLINE Malaria Ag Pf), microscopy, quantitative polymerase chain-reaction (qPCR) and Luminex-based suspension array technology targeting P. falciparum HRP2. The performance of each RDT was evaluated using qPCR as reference standard. The association between infections detected by uRDT, but not by cRDT, with poor maternal and birth outcomes was assessed using multivariate regression models. RESULTS: The overall positivity rate detected by cRDT, uRDT, and qPCR was 11.6% (109/942), 16.2% (153/942) and 18.3% (172/942), respectively. Out of 172 qPCR-positive samples, 68 were uRDT-negative. uRDT had a significantly better sensitivity (60.5% [52.7-67.8]) than cRDT (44.2% [36.6-51.9]) and a marginally decreased specificity (93.6% [91.7-95.3] versus 95.7% [94.0-97.0]). The gain in sensitivity was particularly high (33%) and statistically significant in the 1st trimester. Only 28 (41%) out of the 68 samples which were qPCR-positive, but uRDT-negative had detectable but very low levels of HRP2 (191 ng/mL). Infections that were detected by uRDT but not by cRDT were associated with a 3.4-times (95%CI 1.29-9.19) increased risk of anaemia during pregnancy. CONCLUSIONS: This study demonstrates the higher performance of uRDT, as compared to cRDTs, to detect low parasite density P. falciparum infections during pregnancy, particularly in the 1st trimester. uRDT allowed the detection of infections associated with maternal anaemia.
Assuntos
Antígenos de Protozoários/análise , Testes Diagnósticos de Rotina/estatística & dados numéricos , Malária Falciparum/epidemiologia , Plasmodium falciparum/isolamento & purificação , Proteínas de Protozoários/análise , Adulto , Feminino , Humanos , Malária Falciparum/parasitologia , Gravidez , Prevalência , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto JovemRESUMO
BACKGROUND: In the context of global malaria elimination efforts, special attention is being paid to submicroscopic Plasmodium falciparum infections. In pregnant, sub-Saharan African women, such infections are more prevalent than microscopic infections, and are thought to have adverse effects on both mothers' and newborns' health. However, no study has studied the dynamics and determinants of these infections throughout pregnancy. Retard de Croissance Intra-uterin et Paludisme (RECIPAL), a preconception cohort study carried out in Benin between 2014 and 2017, represented a unique opportunity to assess this issue. METHODS: We used data from 273 pregnant Beninese women who were followed-up from preconception to delivery. We studied the dynamics of and factors influencing submicroscopic (and microscopic) P. falciparum infections during the 3 trimesters of pregnancy, using an ordinal logistic mixed model. RESULTS: The incidence rate of submicroscopic P. falciparum infections during pregnancy was 12.7 per 100 person-months (95% confidence interval [CI] 10.8-14.9), compared to 6.7 per 100 person-months (95% CI 5.5-8.1) for microscopic infections. The prevalences were highest in the first trimester for both submicroscopic and microscopic infections. After adjustment for potential confounding factors, we found that those of young age and those with a submicroscopic P. falciparum infection prior to pregnancy were at significantly higher risks of submicroscopic and microscopic infections throughout pregnancy, with a more pronounced effect in the first trimester of pregnancy. CONCLUSIONS: The first trimester of pregnancy is a particularly high-risk period for P. falciparum infection during pregnancy, especially for the youngest women. Malaria prevention tools covering the preconception period and early pregnancy are urgently needed to better protect pregnant women and their newborns.