Sickle haemoglobin, haemoglobin C and malaria mortality feedbacks.

BACKGROUND: Sickle haemoglobin (HbS) and haemoglobin C (HbC) are both caused by point mutations in the beta globin gene, and both offer substantial malaria protection. Despite the fact that the blood disorder caused by homozygosity for HbC is much less severe than that caused by homozygosity for HbS (sickle cell anaemia), it is the sickle mutation which has come to dominate many old-world malarious regions, whilst HbC is highly restricted in its geographical distribution. It has been suggested that this discrepancy may be due to sickle cell heterozygotes enjoying a higher level of malaria protection than heterozygotes for HbC. A higher fitness of sickle cell heterozygotes relative to HbC heterozygotes could certainly have allowed the sickle cell allele to spread more rapidly. However, observations that carrying either HbC or HbS enhances an individual's capacity to transmit malaria parasites to mosquitoes could also shed light on this conundrum. METHODS: A population genetic model was used to investigate the evolutionary consequences of the strength of malaria selection being correlated with either HbS frequency or HbC frequency. RESULTS: If the selection pressure from malaria is positively correlated with the frequency of either HbS or HbC, it is easier for HbS to succeed in the competitive interaction between the two alleles. CONCLUSIONS: A feedback process whereby the presence of variant haemoglobins increases the level of malaria selection in a population could have contributed to the global success of HbS relative to HbC, despite the former's higher blood disorder cost

20 million pregnant women with group B streptococcus carriage: consequences, challenges, and opportunities for prevention.

PURPOSE OF REVIEW: Intrapartum antibiotic prophylaxis (IAP) is currently the only recommended preventive approach against clinical consequences of maternal Group B Streptococcus (GBS) colonization. In this review, we discuss new findings of total perinatal GBS burden and relative effectiveness of differing targeting of IAP, notably microbiology-based and risk factor-based screening, including potential limitations. Finally, we provide updates on maternal GBS vaccines and their potential cost-effectiveness in disease reduction. RECENT FINDINGS: Updated estimates of the burden of GBS related to pregnancy outcomes show (1) early-onset GBS disease incidence and deaths are high in some low- and middle-income countries where IAP has not been implemented and (2) late-onset GBS disease, preterm birth, and stillbirth, which are not preventable by IAP, remain a public health problem in both high and low-middle income settings. Observational evidence indicates that microbiology-based screening may be more effective than risk factor-based screening, but even in high-income countries, compliance is imperfect. To address the need for alternative prevention strategies, several maternal vaccine candidates are in clinical development, and modelling suggests these could be cost-effective in most scenarios. SUMMARY: Recent progress in GBS vaccine research holds promise of reducing the large and preventable burden of mortality and disability caused by GBS disease, especially in higher-burden settings where clinical and laboratory services may be limited. Importantly vaccines also hold potential to prevent GBS stillbirths and GBS-associated preterm births

Parasite Burden and Severity of Malaria in Tanzanian Children

BACKGROUND: Severe Plasmodium falciparum malaria is a major cause of death in children. The contribution of the parasite burden to the pathogenesis of severe malaria has been controversial. METHODS: We documented P. falciparum infection and disease in Tanzanian children followed from birth for an average of 2 years and for as long as 4 years. RESULTS: Of the 882 children in our study, 102 had severe malaria, but only 3 had more than two episodes. More than half of first episodes of severe malaria occurred after a second infection. Although parasite levels were higher on average when children had severe rather than mild disease, most children (67 of 102) had high-density infection (>2500 parasites per 200 white cells) with only mild symptoms before severe malaria, after severe malaria, or both. The incidence of severe malaria decreased considerably after infancy, whereas the incidence of high-density infection was similar among all age groups. Infections before and after episodes of severe malaria were associated with similar parasite densities. Nonuse of bed nets, placental malaria at the time of a woman’s second or subsequent delivery, high-transmission season, and absence of the sickle cell trait increased severe-malaria risk and parasite density during infections. CONCLUSIONS: Resistance to severe malaria was not acquired after one or two mild infections. Although the parasite burden was higher on average during episodes of severe malaria, a high parasite burden was often insufficient to cause severe malaria even in children who later were susceptible. The diverging rates of severe disease and high-density infection after infancy, as well as the similar parasite burdens before and after severe malaria, indicate that naturally acquired resistance to severe malaria is not explained by improved control of parasite density. (Funded by the National Institute of Allergy and Infectious Diseases and others.

Preparing for future efficacy trials of severe malaria vaccines

Severe malaria is a major cause of mortality in children, but comprises only a small proportion of Plasmodium falciparum infections in naturally exposed populations. The evaluation of vaccines that prevent severe falciparum disease will require clinical trials whose primary efficacy endpoint will be severe malaria risk during follow-up. Here, we show that such trials are feasible with fewer than 1,000 participants in areas with intense malaria transmission during the age interval when severe malaria incidence peaks

Group B streptococcus infection during pregnancy and infancy: estimates of regional and global burden

Background: Group B streptococcus (GBS) colonisation during pregnancy can lead to invasive GBS disease (iGBS) in infants, including meningitis or sepsis, with a high mortality risk. Other outcomes include stillbirths, maternal infections, and prematurity. There are data gaps, notably regarding neurodevelopmental impairment (NDI), especially after iGBS sepsis, which have limited previous global estimates. In this study, we aimed to address this gap using newly available multicountry datasets. Methods: We collated and meta-analysed summary data, primarily identified in a series of systematic reviews published in 2017 but also from recent studies on NDI and stillbirths, using Bayesian hierarchical models, and estimated the burden for 183 countries in 2020 regarding: maternal GBS colonisation, iGBS cases and deaths in infants younger than 3 months, children surviving iGBS affected by NDI, and maternal iGBS cases. We analysed the proportion of stillbirths with GBS and applied this to the UN-estimated stillbirth risk per country. Excess preterm births associated with maternal GBS colonisation were calculated using meta-analysis and national preterm birth rates. Findings: Data from the seven systematic reviews, published in 2017, that informed the previous burden estimation (a total of 515 data points) were combined with new data (17 data points) from large multicountry studies on neurodevelopmental impairment (two studies) and stillbirths (one study). A posterior median of 19·7 million (95% posterior interval 17·9–21·9) pregnant women were estimated to have rectovaginal colonisation with GBS in 2020. 231800 (114 100–455000) early-onset and 162 200 (70200–394 400) late-onset infant iGBS cases were estimated to have occurred. In an analysis assuming a higher case fatality rate in the absence of a skilled birth attendant, 91 900 (44800–187 800) iGBS infant deaths were estimated; in an analysis without this assumption, 58300 (26 500–125800) infant deaths from iGBS were estimated. 37100 children who recovered from iGBS (14600–96200) were predicted to develop moderate or severe NDI. 40500 (21500–66 200) maternal iGBS cases and 46200 (20 300–111300) GBS stillbirths were predicted in 2020. GBS colonisation was also estimated to be potentially associated with considerable numbers of preterm births. Interpretation: Our analysis provides a comprehensive assessment of the pregnancy-related GBS burden. The Bayesian approach enabled coherent propagation of uncertainty, which is considerable, notably regarding GBS-associated preterm births. Our findings on both the acute and long-term consequences of iGBS have public health implications for understanding the value of investment in maternal GBS immunisation and other preventive strategies

Haemolysis and haem oxygenase-1 induction during persistent "asymptomatic" malaria infection in Burkinabé children

BACKGROUND: The haemolysis associated with clinical episodes of malaria results in the liberation of haem, which activates the enzyme haem oxygenase-1 (HO-1). HO-1 has been shown to reduce neutrophil function and increase susceptibility to invasive bacterial disease. However, the majority of community-associated malaria infections are subclinical, often termed "asymptomatic" and the consequences of low-grade haemolysis during subclinical malaria infection are unknown. STUDY DESIGN AND RESULTS: As part of an ongoing study of subclinical malaria in Burkina Faso, 23 children with subclinical Plasmodium falciparum infections (determined by qPCR) were compared with 21 village-matched uninfected control children. Infected children showed evidence of persistent haemolysis over 35 days, with raised plasma haem and HO-1 concentrations. Concentrations of IL-10, which can also directly activate HO-1, were also higher in infected children compared to uninfected children. Regression analysis revealed that HO-1 was associated with haemolysis, but not with parasite density, anaemia or IL-10 concentration. CONCLUSIONS: This study reveals that subclinical P. falciparum malaria infection is associated with sustained haemolysis and the induction of HO-1. Given the association between HO-1, neutrophil dysfunction and increased risk of Salmonella bacteraemia, prolonged HO-1 induction may explain epidemiological associations and geographic overlap between malaria and invasive bacterial disease. Further studies are needed to understand the consequences of persistent subclinical malaria infection, low-grade haemolysis and raised HO-1 on immune cell function and risk of comorbidities

Quantifying long-term health and economic outcomes for survivors of group B Streptococcus invasive disease in infancy: protocol of a multi-country study in Argentina, India, Kenya, Mozambique and South Africa

Sepsis and meningitis due to invasive group B Streptococcus (iGBS) disease during early infancy is a leading cause of child mortality. Recent systematic estimates of the worldwide burden of GBS suggested that there are 319,000 cases of infant iGBS disease each year, and an estimated 147,000 stillbirths and young-infant deaths, with the highest burden occurring in Sub-Saharan Africa. The following priority data gaps were highlighted: (1) long-term outcome data after infant iGBS, including mild disability, to calculate quality-adjusted life years (QALYs) or disability-adjusted life years (DALYs) and (2) economic burden for iGBS survivors and their families. Geographic data gaps were also noted with few studies from low- and middle- income countries (LMIC), where the GBS burden is estimated to be the highest. In this paper we present the protocol for a multi-country matched cohort study designed to estimate the risk of long-term neurodevelopmental impairment (NDI), socioemotional behaviors, and economic outcomes for children who survive invasive GBS disease in Argentina, India, Kenya, Mozambique, and South Africa. Children will be identified from health demographic surveillance systems, hospital records, and among participants of previous epidemiological studies. The children will be aged between 18 months to 17 years. A tablet-based custom-designed application will be used to capture data from direct assessment of the child and interviews with the main caregiver. In addition, a parallel sub-study will prospectively measure the acute costs of hospitalization due to neonatal sepsis or meningitis, irrespective of underlying etiology. In summary, these data are necessary to characterize the consequences of iGBS disease and enable the advancement of effective strategies for survivors to reach their developmental and economic potential. In particular, our study will inform the development of a full public health value proposition on maternal GBS immunization that is being coordinated by the World Health Organization

Molecular Markers for Sensitive Detection of Plasmodium falciparum Asexual Stage Parasites and their Application in a Malaria Clinical Trial.

Plasmodium falciparum parasite life stages respond differently to antimalarial drugs. Sensitive stage-specific molecular assays may help to examine parasite dynamics at microscopically detectable and submicroscopic parasite densities in epidemiological and clinical studies. In this study, we compared the performance of skeleton-binding protein 1 (SBP1), ring-infected erythrocyte surface antigen, Hyp8, ring-exported protein 1 (REX1), and PHISTb mRNA for detecting ring-stage trophozoite-specific transcripts using quantitative reverse transcriptase polymerase chain reaction. Markers were tested on tightly synchronized in vitro parasites and clinical trial samples alongside established markers of parasite density (18S DNA and rRNA) and gametocyte density (Pfs25 mRNA). SBP1 was the most sensitive marker but showed low-level expression in mature gametocytes. Novel markers REX1 and PHISTb showed lower sensitivity but higher specificity for ring-stage trophozoites. Using in vivo clinical trial samples from gametocyte-negative patients, we observed evidence of persisting trophozoite transcripts for at least 14 days postinitiation of treatment. It is currently not clear if these transcripts represent viable parasites that may have implications for clinical treatment outcome or transmission potential