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Chronic immune activation from persistent malaria infections can induce immunophenotypic changes associated with T-cell exhaustion. However, associations between T and B cells during chronic exposure remain undefined. We analyzed peripheral blood mononuclear cells from malaria-exposed pregnant women from Papua New Guinea and Spanish malaria-naïve individuals using flow cytometry to profile T-cell exhaustion markers phenotypically. T-cell lineage (CD3, CD4, and CD8), inhibitory (PD1, TIM3, LAG3, CTLA4, and 2B4), and senescence (CD28-) markers were assessed. Dimensionality reduction methods revealed increased PD1, TIM3, and LAG3 expression in malaria-exposed individuals. Manual gating confirmed significantly higher frequencies of PD1+CD4+ and CD4+, CD8+, and double-negative (DN) T cells expressing TIM3 in malaria-exposed individuals. Increased frequencies of T cells co-expressing multiple markers were also found in malaria-exposed individuals. T-cell data were analyzed with B-cell populations from a previous study where we reported an alteration of B-cell subsets, including increased frequencies of atypical memory B cells (aMBC) and reduction in marginal zone (MZ-like) B cells during malaria exposure. Frequencies of aMBC subsets and MZ-like B cells expressing CD95+ had significant positive correlations with CD28+PD1+TIM3+CD4+ and DN T cells and CD28+TIM3+2B4+CD8+ T cells. Frequencies of aMBC, known to associate with malaria anemia, were inversely correlated with hemoglobin levels in malaria-exposed women. Similarly, inverse correlations with hemoglobin levels were found for TIM3+CD8+ and CD28+PD1+TIM3+CD4+ T cells. Our findings provide further insights into the effects of chronic malaria exposure on circulating B- and T-cell populations, which could impact immunity and responses to vaccination. Chronic malaria exposure is associated with increased frequencies of T cells with inhibitory markers and expanded atypical memory B cells, which were found to positively correlate with each other. T cells with inhibitory markers and atypical memory B cells had positive correlations with malaria antibodies and negative correlations with hemoglobin levels in the chronically exposed individuals. T-cell subsets with inhibitory markers and B-cell subsets were able to distinguish malaria exposed versus non-exposed individuals using dimensionality reduction analysis. Graphical Abstract [ABSTRACT FROM AUTHOR]

Background Infectious diseases' outbreak investigation requires, by definition, conducting a thorough epidemiological assessment while simultaneously obtaining biological samples for an adequate screening of potential responsible pathogens. Complete autopsies remain the gold-standard approach for cause-of-death evaluation and characterization of emerging diseases. However, for highly transmissible infections with a significant associated lethality, such as COVID-19, complete autopsies are seldom performed due to biosafety challenges, especially in low-resource settings. Minimally invasive tissue sampling (MITS) is a validated new approach based on obtaining postmortem samples from key organs and body fluids, a procedure that does not require advanced biosafety measures or a special autopsy room. Methods We aimed to review the use of MITS or similar procedures for outbreak investigation up to 27 March 2021 and their performance for evaluating COVID-19 deaths. Results After a literature review, we analyzed in detail the results of 20 studies conducted at international sites, whereby 216 COVID-19–related deaths were investigated. MITS provided a general and more granular understanding of the pathophysiological changes secondary to the infection and high-quality samples where the extent and degree of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–related damage could be evaluated. Conclusions MITS is a useful addition in the investigation and surveillance of infections occurring in outbreaks or epidemics. Its less invasive nature makes the tool more acceptable and feasible and reduces the risk of procedure-associated contagion, using basic biosafety measures. Standardized approaches protocolizing which samples should be collected—and under which exact biosafety measures—are necessary to facilitate and expand its use globally. [ABSTRACT FROM AUTHOR]

Background: Intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) is a key malaria prevention strategy in areas with moderate to high transmission. As part of the TIPTOP (Transforming IPT for Optimal Pregnancy) project, baseline information about IPTp coverage was collected in eight districts from four sub-Saharan countries: Democratic Republic of Congo (DRC), Madagascar, Mozambique and Nigeria.Methods: Cross-sectional household surveys were conducted using a multistage cluster sampling design to estimate the coverage of IPTp and antenatal care attendance. Eligible participants were women of reproductive age who had ended a pregnancy in the 12 months preceding the interview and who had resided in the selected household during at least the past 4 months of pregnancy. Coverage was calculated using percentages and 95% confidence intervals.Results: A total of 3911 women were interviewed from March to October 2018. Coverage of at least three doses of IPTp (IPTp3+) was 22% and 24% in DRC project districts; 23% and 12% in Madagascar districts; 11% and 16% in Nigeria local government areas; and 63% and 34% in Mozambique districts. In DRC, Madagascar and Nigeria, more than two-thirds of women attending at least four antenatal care visits during pregnancy received less than three doses of IPTp.Conclusions: The IPTp3+ uptake in the survey districts was far from the universal coverage. However, one of the study districts in Mozambique showed a much higher coverage of IPTp3+ than the other areas, which was also higher than the 2018 average national coverage of 41%. The reasons for the high IPTp3+ coverage in this Mozambican district are unclear and require further study. [ABSTRACT FROM AUTHOR]

Background: Innovative approaches are needed to limit antimalarial resistance evolution. Understanding the role of intermittent preventive treatment in pregnancy (IPTp) on the selection for resistance and the impact such selection has on pregnancy outcomes can guide future interventions.Methods: Plasmodium falciparum isolates (n = 914) from 2 randomized clinical trials were screened for pfmdr1 copy number variation and pfcrt, pfmdr1, pfdhfr, and pfdhps resistance markers. The trials were conducted between 2010 and 2013 in Benin, Gabon, Kenya, and Mozambique to establish the efficacy of IPTp-mefloquine (MQ) compared with IPTp-sulphadoxine-pyrimethamine (SP) in human immunodeficiency virus (HIV)-uninfected and to IPTp-placebo in HIV-infected women.Results: In HIV-uninfected women, the prevalence of pfcrt mutants, pfdhfr/pfdhps quintuple mutants, and pfmdr1 copy number was similar between women receiving IPT-SP and IPTp-MQ. However, prevalence of pfmdr1 polymorphism 86Y was lower in the IPTp-MQ group than in the IPTp-SP group, and within the IPTp-MQ group it was lower at delivery compared with recruitment. No effect of IPTp-MQ on resistance markers was observed among HIV-infected women. The carriage of resistance markers was not associated with pregnancy outcomes.Conclusions: Selection of wild-type pfmdr1 polymorphism N86 by IPTp-MQ highlights the strong selective pressure IPTp can exert and the opportunity for using negative cross-resistance in drug choice for clinical treatment and IPTp. [ABSTRACT FROM AUTHOR]

Background Minimally invasive tissue sampling (MITS) is a simplified postmortem examination technique that has shown to be an adequate approach for cause of death investigation in low-resource settings. It requires relatively low level of infrastructures and can be performed by health professionals with no background in pathology. A training program has been developed for the Child Health and Mortality Prevention Surveillance (CHAMPS) network to guarantee standardization of specimen collection techniques, procedures, and laboratory methods. Methods The training program has included assessment of the site capacities and training on a standardized protocol of MITS sampling and histological processing. The project has also introduced a program of training for trainers for the personnel from Mozambique. To guarantee the adequacy of the procedure in each site, a trainer accompanied the local teams when the activities started. Training outcomes were assessed by evaluating the quality of the samples obtained and the quality of the slides produced locally. Results Between June 2016 and October 2018, the laboratories of 7 sites (Bangladesh, Ethiopia, Kenya, Mali, Mozambique, Sierra Leone, and South Africa) have been evaluated and upgraded. Training has been delivered to 63 staff members from all sites. More than 600 MITS procedures have been performed. The quantity of tissue obtained in the MITS by the local teams was sufficient or abundant in 73%, and 87% of the slides were considered as technically acceptable or excellent. Conclusions Satisfactory standardization of MITS and histology procedures has been achieved across all CHAMPS sites through organized capacity-building plans. [ABSTRACT FROM AUTHOR]

Background Afebrile Plasmodium falciparum infections usually remain undetected and untreated in the community and could potentially contribute to sustaining local malaria transmission in areas aiming for malaria elimination. Methods Thirty-two men with afebrile P. falciparum infections detected with rapid diagnostic test (RDTs) were followed for 28 days. Kaplan-Meier estimates were computed to estimate probability of parasite positivity and of reducing parasitemia by half of its initial level by day 28. Trends of parasite densities quantified by microscopy and real-time quantitative polymerase chain reaction (qPCR) were assessed using Poisson regression models, and the microscopy-to-qPCR positivity ratio was calculated at each time point. Three survival distributions (Gompertz, Weibull, and gamma) were used to evaluate their strength of fit to the data and to predict the median lifetime of infection. Results The cumulative probability of parasite qPCR positivity by day 28 was 81% (95% confidence interval [CI], 60.2–91.6). Geometric mean parasitemia at recruitment was 516.1 parasites/μL and fell to <100 parasites/μL by day 3, reaching 56.7 parasites/μL on day 28 (P <.001). The ratio of P. falciparum –positive samples by microscopy to qPCR decreased from 0.9 to 0.52 from recruitment to day 28. The best model fit to the data was obtained assuming a Gompertz distribution. Conclusions Afebrile P. falciparum infections detectable by RDT in semi-immune adults fall and stabilize at low-density levels during the first 4 days after detection, suggesting a rapid decline of potential transmissibility in this hidden parasite reservoir. Clincial trials registration NCT02698748 [ABSTRACT FROM AUTHOR]

The present article examines the impact of the current limitations of the microcephaly definition in the context of the Zika virus outbreak. It highlights its dependence on the method used for determining gestational age and other anthropometric parameters, and includes original results of prevalence of microcephaly in four countries from two different continents (Mozambique, Brazil, Guatemala and Colombia). Alternative definitions of microcephaly are proposed to allow the identification of true cases of microcephaly in a more accurate manner. [ABSTRACT FROM AUTHOR]

Background. There are an estimated 2.6 million stillbirths each year, many of which are due to infections, especially in low- and middle-income contexts. This paper, the eighth in a series on the burden of group B streptococcal (GBS) disease, aims to estimate the percentage of stillbirths associated with GBS disease. Methods. We conducted systematic literature reviews (PubMed/Medline, Embase, Literatura Latino-Americana e do Caribe em Ciências da Saúde, World Health Organization Library Information System, and Scopus) and sought unpublished data from investigator groups. Studies were included if they reported original data on stillbirths (predominantly ≥28 weeks' gestation or ≥1000 g, with GBS isolated from a sterile site) as a percentage of total stillbirths. We did meta-analyses to derive pooled estimates of the percentage of GBS-associated stillbirths, regionally and worldwide for recent datasets. Results. We included 14 studies from any period, 5 with recent data (after 2000). There were no data from Asia. We estimated that 1% (95% confidence interval [CI], 0--2%) of all stillbirths in developed countries and 4% (95% CI, 2%--6%) in Africa were associated with GBS. Conclusions. GBS is likely an important cause of stillbirth, especially in Africa. However, data are limited in terms of geographic spread, with no data from Asia, and cases worldwide are probably underestimated due to incomplete case ascertainment. More data, using standardized, systematic methods, are critical, particularly from low- and middle-income contexts where the highest burden of stillbirths occurs. These data are essential to inform interventions, such as maternal GBS vaccination. [ABSTRACT FROM AUTHOR]

Background. Invasive nontyphoidal Salmonella (iNTS) has emerged as a cause of bacteremia in African children and HIV-infected adults, which is associated with high mortality. Epidemiological data and burden of iNTS infections in resource-constrained settings are needed to better define preventive and curative strategies. Methods. Blood and, if appropriate, cerebrospinal fluid, were collected from children <15 years of age with fever or severe disease admitted to the Manhiça District Hospital and cultured for NTS; isolates were then characterized. Results. From January 2001 to December 2014, 41 668 of the 51 878 admitted children had a blood culture performed. Invasive NTS was isolated from 670 (1.6%) specimens collected from 41 668 patients; 69 (10.3% died). Salmonella enterica subspecies enterica serovar Typhi or Salmonella enterica subspecies enterica serovar Paratyphi A or C were only isolated in 14 (0.03%) patients. A total of 460 of 620 (74.2%) NTS isolates serotyped were Salmonella enterica subspecies enterica serovar Typhimurium (45% [116/258] of which were multilocus sequence type 313). The incidence of iNTS was 61.8 (95% confidence interval, 55.4–68.9) cases per 100 000 child-years, being highest among infants (217.7 cases/100 000 child-years). The incidence of iNTS declined significantly (P < .0001) over time, but the case fatality ratio remained constant at approximately 10%. Antimicrobial resistance of iNTS against most available antimicrobials has steadily increased, with a predominance of multidrug-resistant strains. Conclusions. The decreasing but still high incidence of iNTS, its high associated case fatality ratio, and the common detection of multidrug-resistant strains call for a need to improve treatment and prevention strategies for iNTS. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study was to inform public health actions to limit first-line ART failure and HIV drug resistance in Mozambique. Methods: This was a cross-sectional study. HIV-1-infected adults on first-line ART for at least 1 year attending routine visits in the Manhiça District Hospital, in a semi-rural area in southern Mozambique with no HIV-1 RNA monitoring available, were evaluated for clinical, socio-demographic, therapeutic, immunological and virological characteristics. Factors associated with HIV-1 RNA ≥1000 copies/mL and HIV drug resistance were determined using multivariate logistic regression. Results: The study included 334 adults on first-line ART for a median of 3 years, of which 65% (214/332) had suppressed viraemia, 11% (37/332) had low-level viraemia (HIV-1 RNA 150-999 copies/mL) and 24% (81/332) had overt virological failure (HIV-1 RNA ≥1000 copies/mL). HIV drug resistance was detected in 89% of subjects with virological failure, but in none with low-level viraemia. Younger age [OR = 0.97 per additional year (95% 0 = 0.94-1.00), P=0.039], ART initiation at WHO stage III/IV [OR=2.10 (95% 0 = 1.23-3.57), P=0.003] and low ART adherence [OR = 2.69 (95% 0 = 1.39-5.19), P=0.003] were associated with virological failure. Longer time on ART [OR = 1.55 per additional year (95% 0 = 1.00-2.43), P=0.052] and illiteracy [OR = 0.24 (95% 0 = 0.07-0.89), P=0.033] were associated with HIV drug resistance. Compared with HIV-1 RNA, clinician's judgement of ART failure, based on clinical and immunological outcomes, only achieved 29% sensitivity and misdiagnosed 1 out of every 4.5 subjects. Conclusions: Public health programmes in Mozambique should focus on early HIV diagnosis, early ART initiation and adherence support. Virological monitoring drastically improves the diagnosis of ART failure, enabling a better use of resources. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the clinical, nutritional and neurodevelopment status of HIV-infected children in a high HIV prevalence area. Methods: All HIV-infected children under 15 years of age attending an outpatient clinic of Mozambique between April and May 2010 were recruited. Clinical data were collected and physical examination was performed. Results: In all, 140 children were recruited. The median age at HIV diagnosis was 2.1 years. Fifty-one percent of the children were classified in WHO clinical Stages 3 or 4. Median age of antiretroviral treatment commencement was 3.9 years. Overall, 68% were undernourished, mainly stunted. Forty-four percent failed to pass the national psychomotor developmental test. Conclusions: The pathways for early HIV diagnosis and start of antiretrovirals in children should be improved in Mozambique. Malnutrition, especially stunting, and developmental delay were highly prevalent. Further research focused on early diagnosis of neurocognitive disorders and on the indications of antiretroviral treatment commencement based on chronic malnutrition is required. [ABSTRACT FROM AUTHOR]

Background. Malaria and human immunodeficiency virus (HIV) infection during pregnancy affect the transplacental transfer of antibodies against several pathogens from mother to fetus, although the effect of malaria and HIV infection on the transfer of antimalarial antibodies remains unclear.Methods. Levels of total immunoglobulin G (IgG), immunoglobulin M (IgM), and IgG subtypes against the following Plasmodium falciparum antigens were measured in 187 pairs of mother-cord plasma specimens from Mozambique: 19-kDa fragment of merozoite surface protein 1 (MSP119), erythrocyte binding antigen 175 (EBA175), apical membrane antigen 1 (AMA1), and parasite lysate. Placental antibody transfer was defined as the cord-to-mother ratio (CMR) of antibody levels.Results. Maternal malaria was associated with reduced CMR of EBA175 IgG (P = .014) and IgG1 (P = .029), AMA1 IgG (P = .002), lysate IgG1 (P = .001), and MSP1 IgG3 (P = .01). Maternal HIV was associated with reduced CMR of MSP1 IgG1 (P = .022) and IgG3 (P = .023), lysate IgG1 (P = .027) and IgG3 (P = .025), AMA1 IgG1 (P = .001), and EBA175 IgG3 (P = .001). Decreased CMR was not associated with increased adverse pregnancy outcomes or augmented risk of malaria in the infant during the first year of life.Conclusions. Placental transfer of antimalarial antibodies is reduced in pregnant women with malaria and HIV infection. However, this decrease does not contribute to an increased risk of malaria-associated morbidity during infancy. [ABSTRACT FROM AUTHOR]

Background. Antibodies against VAR2CSA, the Plasmodium falciparum variant surface antigen that binds placental chondroitin sulfate A, have been suggested to mediate protection against malaria in pregnancy but also to be markers of infection. Here, we aimed to identify clinically relevant antibody responses, taking into consideration variations in parasite exposure and human immunodeficiency virus type 1 (HIV) infection status.Methods. Levels of immunoglobulin G (IgG) against placental and pediatric isolates, VAR2CSA (DBL2X, DBL3X, DBL5ε, and DBL6ε domains), and other blood-stage antigens (DBLγ, DBLα, MSP119, AMA1, and EBA175) were measured in plasma specimens from 293 pregnant Mozambican women at delivery. Associations between antibody responses, factors influencing malaria exposure, HIV infection status, and pregnancy outcomes were assessed.Results. Maternal antibodies were affected by placental infection, parity, season, and neighborhood of residence. HIV infection modified these associations and attenuated the parity-dependent increase in IgG level. High levels of antibody against AMA1, DBL3X, DBL6ε, placental isolates, and pediatric isolates were associated with increased weight and gestational age of newborns (P ≤ .036) among women with malaria episodes during pregnancy.Conclusions. Antiparasite IgGs in women at delivery are affected by HIV infection, as well as by variations in the exposure to P. falciparum. Heterogeneity of malaria transmission needs to be considered to identify IgGs against VAR2CSA and other parasite antigens associated with improved pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Background. Evidence of the presence of Plasmodium vivax in the placenta is scarce and inconclusive. This information is relevant to understanding whether P. vivax affects placental function and how it may contribute to poor pregnancy outcomes.Methods. Histopathologic examination of placental biopsies from 80 Papua New Guinean pregnant women was combined with quantitative polymerase chain reaction (qPCR) to confirm P. vivax infection and rule out coinfection with other Plasmodium species in placental and peripheral blood. Leukocytes and monocytes/macrophages were detected in placental sections by immunohistochemistry.Results. Monoinfection by P. vivax and Plasmodium falciparum was detected by qPCR in 8 and 10 placentas, respectively. Seven of the 8 women with P. vivax placental monoinfection were negative in peripheral blood. By histology, 3 placentas with P. vivax monoinfection showed parasitized erythrocytes in the intervillous space but no hemozoin in macrophages nor increased intervillous inflammatory cells. In contrast, 7 placentas positive for P. falciparum presented parasites and hemozoin in macrophages or fibrin as well as intervillous inflammatory infiltrates.Conclusions. Plasmodium vivax can be associated with placental infection. However, placental inflammation is not observed in P. vivax monoinfections, suggesting other causes of poor delivery outcomes associated with P. vivax infection. [ABSTRACT FROM AUTHOR]

Microscopy, placental histology, and histidine-rich protein 2–based plasma diagnosis fail to identify 60% of Plasmodium falciparum infections detected by quantitative polymerase chain reaction in Mozambican pregnant women. Undetected infections are associated with maternal anemia, highlighting their clinical relevance and the need for more accurate diagnostic methods.Background. Accurate diagnosis of malaria infection during pregnancy remains challenging because of low parasite densities and placental sequestration of Plasmodium falciparum. The performance of different methods to detect P. falciparum in pregnancy and the clinical relevance of undetected infections were evaluated.Methods. P. falciparum infections were assessed in 272 Mozambican women at delivery by microscopy, placental histology, quantitative polymerase chain reaction (qPCR) and detection of histidine-rich protein 2 (HRP2) in plasma by enzyme-linked immunosorbent assay (ELISA) and a rapid diagnostic test (RDT). Association between infection and delivery outcomes was determined.Results. Among the 122 women qPCR-positive for P. falciparum in peripheral and/or placental blood samples, 87 (71.3%) did not receive a positive diagnosis by peripheral microscopy, 75 (61.5%) by HRP2 ELISA, and 74 (60.7%) by HRP2 RDT in plasma. Fifty-seven of the 98 qPCR-positive placental infections (58.2%) were not detected by histology. Women who were qPCR-positive but negative in their peripheral blood by microscopy or HRP2 RDT in plasma (n = 62) were at increased risk of anemia, compared with negative women (n = 141; odds ratio, 2.03; 95% confidence interval, 1.07–3.83; P = .029).Conclusions. Microscopy, placental histology and HRP2-based plasma diagnostic methods fail to identify the majority of the P. falciparum infections detected by qPCR in peripheral and placental blood. Undetected infections were associated with maternal anemia, highlighting the urgent need for more accurate malaria diagnostic tools for pregnant women to avoid the negative clinical impact that hidden infections can have during pregnancy.Clinical Trials Registration. NCT00209781. [ABSTRACT FROM AUTHOR]

Background. Plasmodium falciparum infection in pregnancy can lead to congenital malaria, which has detrimental health consequences for infants. Human immunodeficiency virus (HIV) might increase cord blood P. falciparum infection by decreasing maternal antimalarial-specific antibodies. Methods. HIV-negative (n5133) and HIV-positive (n555) Mozambican pregnant women were assessed at delivery for maternal and cord P. falciparum infection by quantitative polymerase chain reaction (qPCR) and P. falciparum-specific antibodies by enzyme-linked immunosorbent assay and flow cytometry. Results. Prevalence of qPCR-detected cord blood infection was 8.0%. Risk of cord infection was increased in presence of HIV (adjusted odds ratio [AOR], 3.80; P = .04) and placentalmalaria (AOR, 22.08; P = .002) after adjusting for clinical variables. The odds of having a high immunoglobulin G response to chondrotin sulphate A-binding infected erythrocytes, parasite lysate, and erythrocyte-binding antigen-175 were reduced among HIV-positive women (P < .001, .048, and .056, respectively) and among women with cord P. falciparum infection (P = .009, .04, and .046, respectively). In multivariate analysis including maternal HIV status, placental malaria, and antibody responses, HIV was no longer associated with cord blood infection (P 5 .11). Conclusions. HIV-associated impairment of antibody responses in pregnant women may contribute to a higher transmission of P. falciparum to their infants. [ABSTRACT FROM AUTHOR]

Background. Increased susceptibility to Plasmodium falciparum infection during pregnancy has been attributed to the accumulation of infected erythrocytes in the placenta. This phenomenon is mediated by a var gene coding for VAR2CSA, which adheres to chondroitin sulphate A. However, the contribution of parasites transcribing other var genes to maternal infections has not been well characterized.Methods. Transcription of var2csa and var groups A, B, and C was measured by real-time polymerase chain reaction in 30 placental and 21 peripheral P. falciparum isolates from pregnant women and in 42 isolates from nonpregnant adults and children. Associations of infections with non-var2csa isolates with maternal parasitemia and immune responses were assessed.Results. Placental parasites showed the highest levels of var2csa. ABC var genes were transcribed by 20 (67%) of 30 placental isolates and were associated with higher parasitemia compared with infections by parasites only transcribing var2csa (P = .004). Peripheral isolates from pregnant women transcribed ABC var genes at levels similar to those of parasites infecting nonpregnant adults with clinical malaria (P[varA] = .420, P[varB] = .808, and P[varC] = .619).Conclusions. Transcripts of var2csa are abundant in pregnancy-associated P. falciparum infections; however, ABC var types are also common, especially in peripheral blood, with transcription levels similar to those of infections out of pregnancy. These findings are of interest for the design of malaria vaccines for pregnant women. [ABSTRACT FROM PUBLISHER]

Background: There is some consensus that malaria in pregnancy may negatively affect infant's mortality and malaria morbidity, but there is less evidence concerning the factors involved.Methods: A total of 1030 Mozambican pregnant women were enrolled in a randomized, placebo-controlled trial of intermittent preventive treatment with sulfadoxine-pyrimethamine, and their infants were followed up throughout infancy. Overall mortality and malaria morbidity rates were recorded. The association of maternal and fetal risk factors with infant mortality and malaria morbidity was assessed.Results: There were 58 infant deaths among 997 live-born infants. The risk of dying during infancy was increased among infants born to women with acute placental infection (odds ratio [OR], 5.08 [95% confidence interval (CI), 1.77-14.53)], parasitemia in cord blood (OR, 19.31 [95% CI, 4.44-84.02]), low birth weight (OR, 2.82 [95% CI, 1.27-6.28]) or prematurity (OR, 3.19 [95% CI, 1.14-8.95]). Infants born to women who had clinical malaria during pregnancy (OR, 1.96 [95% CI, 1.13-3.41]) or acute placental infection (OR, 4.63 [95% CI, 2.10-10.24]) had an increased risk of clinical malaria during infancy.Conclusions: Malaria infection at the end of pregnancy and maternal clinical malaria negatively impact survival and malaria morbidity in infancy. Effective clinical management and prevention of malaria in pregnancy may improve infant's health and survival. [ABSTRACT FROM AUTHOR]

Background. Factors involved in the development of resistance to sulphadoxine-pyrimethamine (SP) by Plasmodium falciparum, particularly in the context of intermittent preventive treatment during pregnancy (IPTp), are not well known. We aimed to determine the impact of IPTp and human immunodeficiency virus (HIV) infection on molecular markers of SP resistance and the clinical relevance of resistant infections.Methods. SP resistance alleles were determined in peripheral (n = 125) and placental (n = 145) P. falciparum isolates obtained from pregnant women enrolled in a randomized, placebo-controlled trial of IPTp in Manhiça, Mozambique.Results. Prevalence of quintuple mutant infections was 12% (23 of 185 isolates) in pregnant women who received placebo and 24% (20 of 85 isolates) in those who received SP (P = .031). When the last IPTp dose was administered at late pregnancy, mutant infections at delivery were more prevalent in placental samples (7 [23%] of 30, samples) than in peripheral blood samples (2 [7%] of 30 samples; P = .025), more prevalent in women who received IPTp-SP than in those who received placebo (odds ratio [OR], 8.13; 95% confidence interval [CI], 1.69–39.08), and more prevalent in HIV-positive women than in HIV-negative women (OR, 5.17; 95% CI, 1.23–21.66). No association was found between mutant infections and increased parasite density or malaria-related morbidity in mothers and children.Conclusions. IPTp with SP increases the prevalence of resistance markers in the placenta and in HIV-infected women at delivery, which suggests that host immunity is key for the clearance of drug-resistant infections. However, this effect of IPTp is limited to the period when blood levels of SP are likely to be significant and does not translate into more-severe infections or adverse clinical outcomes. [ABSTRACT FROM AUTHOR]

Background. Intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended for malaria prevention in sub-Saharan Africa. However, studies reporting the effect of IPTp on malaria-specific immunity are scarce and are based on findings in human immunodeficiency virus (HIV)-negative primigravidae. Methods. Plasma samples obtained from 302 pregnant women (177 who were HIV negative, 88 who were HIV positive, and 37 who were of unknown HIV status) participating in a placebo-controlled trial of IPTp with SP (IPTp-SP) were analyzed for the presence of antibodies against merozoite antigens, whole asexual parasites, and variant surface antigens from chondroitin sulfate A-binding and nonbinding lines. Antibody levels were compared between intervention groups, and their association with morbidity outcomes was assessed. Results. HIV-positive mothers receiving SP had lower levels of peripheral antibodies against apical membrane antigen-1 and variant surface antigens, as well as lower levels of cord antibodies against erythrocyte-binding antigen-175 and parasite lysate, than did HIV-positive placebo recipients. No difference between intervention groups was observed among HIV-negative mothers. High antibody levels were associated with maternal infection and an increased risk of a first malaria episode in infants. Antibody responses were not consistently associated with reduced maternal anemia, prematurity, or low birth weight. Conclusions. The IPTp-associated reduction in antibodies in HIV-infected women, but not in HIV-uninfected women, may reflect a higher efficacy of the intervention in preventing malaria among HIV-positive mothers. This reduction did not translate into an enhanced risk of malaria-associated morbidity in mothers and infants. Trial registration. Clinicaltrials.gov identifier NCT00209781. [ABSTRACT FROM AUTHOR]

Background: Pneumonia is a leading cause of hospitalization and death among children in Africa. We describe the clinical presentation of severe pneumonia among hospitalized children in a malaria endemic area with a high prevalence of HIV infection. Methods: As part of a 2-year prospective study of radiologically confirmed pneumonia, chest radiographs, malaria parasite counts and bacterial blood cultures were systematically performed for children 0-23 months admitted with severe pneumonia. Radiographs were interpreted according to WHO guidelines. HIV tests were performed during a 12-month period. Results: Severe pneumonia accounted for 16% of 4838 hospital admissions among children 0-23 months; 43% of episodes had endpoint consolidation, 15% were associated with bacteremia and 11% were fatal. Fever, cough >3 days, crepitations, hypoxemia and absence of malaria parasitemia were associated with radiologically confirmed pneumonia. Nineteen per cent of children with severe pneumonia and 27% with radiologically confirmed pneumonia had clinical malaria. HIV-prevalence was 26% among children hospitalized with severe pneumonia and HIV-testing results. HIV infection, anaemia, malnutrition, hypoxemia and bacteremia were associated with fatal episodes of severe pneumonia. Conclusion: Treatment of admitted children with severe pneumonia is complicated in settings with prevalent HIV and malaria. Children with severe pneumonia and clinical malaria require antibiotic and antimalarial treatment. In addition to vertical programs, integrated approaches may greatly contribute to reduction of pneumonia-related mortality. [ABSTRACT FROM AUTHOR]

Background. We previously reported that the RTS,S/AS02A vaccine had an acceptable safety profile, was immunogenic, and demonstrated efficacy against Plasmodium falciparum malaria disease for 21 months. Methods. We conducted a randomized, controlled, phase 2b trial of RTS,S/AS02A in 2022 Mozambican children aged 1-4 years. We now report safety results for all randomized subjects and vaccine efficacy (VE) findings for children in the Manhiça area over the 45-month surveillance period. Results. During the surveillance period, the VE(2.5-45) (VE over months 2.5-45 of surveillance) against a first or only episode of clinical malaria disease was 30.5% (95% confidence interval [CI], 18.9%-40.4%; P < .001), and the VE(2.5-45) against all episodes was 25.6% (95% CI, 11.9%-37.1%;P < .001). When the same period was considered, the VE(2.5-45) for subjects protected against severe malaria was 38.3% (95% CI, 3.4%-61.3%; P=.045). At study month 45, the prevalence of P. falciparum was 34% lower in the RTS,S/AS02A group than in the control group (66 [12.2%] of 541 patients vs 101 [18.5%] of 547 patients) (P=.004). Conclusion. These results show evidence that RTS,S/AS02A maintained protection during the 45-month surveillance period, and they highlight the feasibility of developing an effective vaccine against malaria. In combination with other malaria-control measures, such a vaccine could greatly contribute to reducing the intolerable global burden of this disease. [ABSTRACT FROM AUTHOR]

Background. Intermittent preventive treatment in infants (IPTi) with sulfadoxine-pyrimethamine (SP) is a potential malaria control strategy. There is concern about the impact that increasing in vivo resistance to SP has on the efficacy of IPTi, as well as about the potential contribution of IPTi to increases in resistance. Methods. We compared the frequency of clinical episodes of malaria caused by P. falciparum parasites with mutations in dhfr and dhps among sick children who received SP or placebo in the context of a randomized, doubleblind, placebo-controlled IPTi trial in Mozambique. Results. Half of the children who received placebo harbored quintuple-pure mutant parasites. Nevertheless, the protective efficacy of IPTi within the 35 days after the third dose was 70.8% (95% confidence interval [CI], 40.7%-85.6%). Between month 2 after the third IPTi dose and the end of the follow-up period, children receiving SP harbored more dhps codon 437 mixed infections (odds ratio [OR], 10.56 [95% CI, 1.30-86.14]) and fewer dhps double-pure mutant parasites (OR, 0.43 [95% CI, 0.22- 0.84]) than did placebo recipients. Conclusions. IPTi appears to be associated with some changes in the prevalence of genotypes involved in SP resistance. In the face of a high prevalence of quintuple-mutant parasites, SP exhibited a high level of efficacy in the prevention of new episodes of malaria in infants. [ABSTRACT FROM AUTHOR]

Abstract: Monitoring interventions to prevent malaria in pregnancy requires sensitive detection of placental infection. Rapid diagnostic tests (RDTs) are good candidates, but little information is available on their sensitivity on placental blood. We have evaluated the agreement (kappa coefficient) between microscopy and a Plasmodium falciparum histidine-rich protein 2 (HRP2)-based immuno-chromatographic test (ICT) on placental blood from 1151 women at delivery. Prevalences of placental infection by microscopy and RDT were 5.1% and 5.0%, respectively, showing 82.9% agreement (p<0.0001). Discordances were found at low parasitemias (<500 parasites/μL) or negative microscopy. The results suggest that the HRP2-RDTs from ICT diagnostics is a good alternative to microscopy for diagnosing placental malaria at delivery. [Copyright &y& Elsevier]