Charles Harding King

: Dengue virus (DENV) is the most common arbovirus globally, with its incidence growing dramatically in recent decades. Although the effects of DENV infection during pregnancy are unclear, reported associations with adverse health outcomes include miscarriage, prematurity, and low birth weight. In this study, we used an IgG ELISA to identify mothers exposed to DENV during pregnancy by testing samples obtained from a previous study that followed a cohort of pregnant women in Kenya to investigate parasitic infections during pregnancy. We compared adverse pregnancy and infant health outcomes between seronegative mothers and those who seroconverted. Of the 289 participants tested for DENV exposure during pregnancy, we estimated that ∼12 women (4%) would have been exposed to DENV during their gestation period. However, we found that 34 mothers (11.8%) had been exposed to DENV during pregnancy. None of these mothers were hospitalized during pregnancy because of severe DENV infection, suggesting that many may have undergone asymptomatic seroconversion. The demographic risk factors of socioeconomic status, education level, bed net use, and maternal age were not associated with mild or asymptomatic DENV in pregnancy. Although mild or asymptomatic DENV during pregnancy was not associated with late prematurity, reduced postnatal childhood developmental measures, or adverse maternal pregnancy outcomes, we observed an increased risk of low birth weight. The larger-than-expected burden of DENV in pregnancy in this coastal Kenyan cohort and the observed potential risk of low birth weight provide evidence that a more comprehensive study is warranted to fully understand DENV infection during pregnancy.

Poor access to diagnostic testing in resource limited settings restricts surveillance for emerging infections, such as dengue virus (DENV), to clinician suspicion, based on history and exam observations alone. We investigated the ability of machine learning to detect DENV based solely on data available at the clinic visit. We extracted symptom and physical exam data from 6,208 pediatric febrile illness visits to Kenyan public health clinics from 2014–2019 and created a dataset with 113 clinical features. Malaria testing was available at the clinic site. DENV testing was performed afterwards. We randomly sampled 70% of the dataset to develop DENV and malaria prediction models using boosted logistic regression, decision trees and random forests, support vector machines, naïve Bayes, and neural networks with 10-fold cross validation, tuned to maximize accuracy. 30% of the dataset was reserved to validate the models. 485 subjects (7.8%) had DENV, and 3,145 subjects (50.7%) had malaria. 220 (3.5%) subjects had co-infection with both DENV and malaria. In the validation dataset, clinician accuracy for diagnosis of malaria was high (82% accuracy, 85% sensitivity, 80% specificity). Accuracy of the models for predicting malaria diagnosis ranged from 53–69% (35–94% sensitivity, 11–80% specificity). In contrast, clinicians detected only 21 of 145 cases of DENV (80% accuracy, 14% sensitivity, 85% specificity). Of the six models, only logistic regression identified any DENV case (8 cases, 91% accuracy, 5.5% sensitivity, 98% specificity). Without diagnostic testing, interpretation of clinical findings by humans or machines cannot detect DENV at 8% prevalence. Access to point-of-care diagnostic tests must be prioritized to address global inequities in emerging infections surveillance.

Complications of urogenital schistosomiasis include acute inflammatory and chronic fibrotic changes within the urogenital tract. Disease burden of this neglected tropical disease is often underestimated, as only active, urine egg-patent Schistosoma infection is formally considered. Previous studies have focussed on short-term effects of praziquantel treatment on urinary tract pathology, demonstrating that acute inflammation is reversible. However, the reversibility of chronic changes is less well studied. Our study compared, at two time points 14 y apart, urine egg-patent infection and urinary tract pathology in a cohort of women living in a highly endemic area having intermittent praziquantel treatment(s). In 2014 we matched 93 women to their findings in a previous study in 2000. Between 2000 and 2014 the rate of egg-patent infection decreased from 34% (95% confidence interval [CI] 25 to 44) to 9% (95% CI 3 to 14). However, urinary tract pathology increased from 15% (95% CI 8 to 22) to 19% (95% CI 11 to 27), with the greatest increase seen in bladder thickening and shape abnormality. Despite praziquantel treatment, fibrosis from chronic schistosomiasis outlasts the presence of active infection, continuing to cause lasting morbidity. We suggest that future efforts to eliminate persistent morbidity attributable to schistosomiasis should include intensified disease management.

Background: Rift Valley fever virus (RVFV) is a lethal threat to humans and livestock in many parts of Africa, the Arabian Peninsula, and the Indian Ocean. This systematic review’s objective was to consolidate understanding of RVFV epidemiology during 1999–2021 and highlight knowledge gaps relevant to plans for human vaccine trials. Methodology/Principal findings: The review is registered with PROSPERO (CRD42020221622). Reports of RVFV infection or exposure among humans, animals, and/or vectors in Africa, the Arabian Peninsula, and the Indian Ocean during the period January 1999 to June 2021 were eligible for inclusion. Online databases were searched for publications, and supplemental materials were recovered from official reports and research colleagues. Exposures were classified into five groups: 1) acute human RVF cases, 2) acute animal cases, 3) human RVFV sero-surveys, 4) animal sero-surveys, and 5) arthropod infections. Human risk factors, circulating RVFV lineages, and surveillance methods were also tabulated. In meta-analysis of risks, summary odds ratios were computed using random-effects modeling. 1104 unique human or animal RVFV transmission events were reported in 39 countries during 1999–2021. Outbreaks among humans or animals occurred at rates of 5.8/year and 12.4/year, respectively, with Mauritania, Madagascar, Kenya, South Africa, and Sudan having the most human outbreak years. Men had greater odds of RVFV infection than women, and animal contact, butchering, milking, and handling aborted material were significantly associated with greater odds of exposure. Animal infection risk was linked to location, proximity to water, and exposure to other herds or wildlife. RVFV was detected in a variety of mosquito vectors during interepidemic periods, confirming ongoing transmission. Conclusions/Significance: With broad variability in surveillance, case finding, survey design, and RVFV case confirmation, combined with uncertainty about populations-at-risk, there were inconsistent results from location to location. However, it was evident that RVFV transmission is expanding its range and frequency. Gaps assessment indicated the need to harmonize human and animal surveillance and improve diagnostics and genotyping. Given the frequency of RVFV outbreaks, human vaccination has strong potential to mitigate the impact of this now widely endemic disease.

Background: Rift Valley fever virus (RVFV) is a lethal threat to humans and livestock in many parts of Africa, the Arabian Peninsula, and the Indian Ocean. This systematic review’s objective was to consolidate understanding of RVFV epidemiology during 1999-2021 and highlight knowledge gaps relevant to plans for human vaccine trials. Methodology/Principal Findings: The review is registered with PROSPERO (CRD42020221622). Reports of RVFV infection or exposure among humans, animals, and/or vectors in Africa, the Arabian Peninsula, and the Indian Ocean during the period January 1999 to June 2021 were eligible for inclusion. Online databases were searched for publications, and supplemental materials were recovered from official reports and research colleagues. Exposures were classified into five groups: 1) acute human RVF cases, 2) acute animal cases, 3) human RVFV sero-surveys, 4) animal sero-surveys, and 5) arthropod infections. Human risk factors, circulating RVFV lineages, and surveillance methods were also tabulated. In meta-analysis of risks, summary odds ratios were computed using random-effects modeling. 1104 unique human or animal RVFV transmission events were reported in 39 countries during 1999-2021. Outbreaks among humans or animals occurred at rates of 5.8/year and 12.4/year, respectively, with Mauritania, Madagascar, Kenya, South Africa, and Sudan having the most human outbreak years. Men had greater odds of RVFV infection than women, and animal contact, butchering, milking, and handling aborted material were significantly associated with greater odds of exposure. Animal infection risk was linked to location, proximity to water, and exposure to other herds or wildlife. RVFV was detected in a variety of mosquito vectors during interepidemic periods, confirming ongoing transmission. Conclusions/Significance: With broad variability in surveillance, case finding, survey design, and RVFV case confirmation, combined with uncertainty about populations-at-risk, there were inconsistent results from location to location. However, it was evident that RVFV transmission is expanding its range and frequency. Gaps assessment indicated the need to harmonize human and animal surveillance and improve diagnostics and genotyping. Given the frequency of RVFV outbreaks, human vaccination has strong potential to mitigate the impact of this now widely endemic disease. Author Summary: Rift Valley fever virus (RVFV) is a globally important mosquito-transmitted zoonosis that is also directly transmissible via aerosolization of body fluids from infected animals. RVFV outbreaks cause mass mortality of young livestock and pregnancy losses in both humans and animals. Severe human cases also result in hemorrhagic fever, encephalitis, and death. Loss of livestock additionally threatens the livelihood of people who depend on animals for income and food. In endemic areas, initiation of RVFV outbreaks is connected to weather events that cause excess rainfall, leading to flooding and subsequent mosquito blooms. However, the natural cycle of RVFV transmission is complex, requiring congregation of susceptible mammalian hosts and mosquito vectors in suitable environments. Several human vaccine candidates are in different stages of development, but none are yet licensed for use in human populations. In this systematic review, we assessed the 1999-2021 frequency and distribution of RVFV outbreaks among humans, animals, and vectors to identify potential locations and population targets for a human RVFV vaccine efficacy trial. It focuses on current understanding of RVFV epidemiology and the identification of gaps that pose critical barriers to controlling expansion of RVFV and implementing new protective measures including human vaccination.

Elimination of schistosomiasis as a public health problem among all disease-endemic countries in 2030 is an ambitious goal. Recent achievements resulting from mass drug administration (MDA) with praziquantel is promising but may need to be complemented with also other means. Schistosomiasis was highly prevalent in China before the initiation of the national schistosomiasis control program in the mid-1950s, and, at that time, the country bore the world’s highest burden of schistosomiasis. The concerted control efforts, upheld without interruption for more than a half century, have resulted in elimination of the disease as a public health problem in China as of 2015. Here, we describe the current status of schistosomiasis in China, analyze the potential challenges affecting schistosomiasis elimination, and propose the future research needs and priorities for the country, aiming to provide more universal insights into the structures needed for a global schistosomiasis elimination encompassing also other endemic regions.

Background: World Health Organization (WHO) guidelines for measuring global progress in schistosomiasis control classify individuals withSchistosomaspp. infections based on the concentration of excreted eggs. We assessed the associations between WHO infection intensity categories and morbidity prevalence for selectedS.haematobiumandS.mansonimorbidities in school-age children.Methodology: A total of 22,488 children aged 6–15 years from monitoring and evaluation cohorts in Burkina Faso, Mali, Niger, Uganda, Tanzania, and Zambia from 2003–2008 were analyzed using Bayesian logistic regression. Models were utilized to evaluate associations between intensity categories and the prevalence of any urinary bladder lesion, any upper urinary tract lesion, microhematuria, and pain while urinating (forS.haematobium) and irregular hepatic ultrasound image pattern (C-F), enlarged portal vein, laboratory-confirmed diarrhea, and self-reported diarrhea (forS.mansoni) across participants with infection and morbidity data.Principal findings: S.haematobiuminfection intensity categories possessed consistent morbidity prevalence across surveys for multiple morbidities and participants with light infections had elevated morbidity levels, compared to negative participants. Conversely,S.mansoniinfection intensity categories lacked association with prevalence of the morbidity measures assessed.Conclusions/significance: Current status infection intensity categories forS.haematobiumwere associated with morbidity levels in school-age children, suggesting urogenital schistosomiasis morbidity can be predicted by an individual’s intensity category. Conversely,S.mansoniinfection intensity categories were not consistently indicative of childhood morbidity at baseline or during the first two years of a preventive chemotherapy control program.

Throughout the last decade, chikungunya virus (CHIKV) and Zika virus (ZIKV) infections have spread globally, causing a spectrum of disease that ranges from self-limited febrile illness to permanent severe disability, congenital anomalies, and early death. Nevertheless, estimates of their aggregate health impact are absent from the literature and are currently omitted from the Global Burden of Disease (GBD) reports. We systematically reviewed published literature and surveillance records to evaluate the global burden caused by CHIKV and ZIKV between 2010 and 2019, to calculate estimates of their disability-adjusted life year (DALY) impact. Extracted data on acute, chronic, and perinatal outcomes were used to create annualized DALY estimates, following techniques outlined in the GBD framework. This study is registered with PROSPERO (CRD42020192502). Of 7,877 studies identified, 916 were screened in detail, and 21 were selected for inclusion. Available data indicate that CHIKV and ZIKV caused the average yearly loss of over 106,000 and 44,000 DALYs, respectively, between 2010 and 2019. Both viruses caused substantially more burden in the Americas than in any other World Health Organization (WHO) region. This unequal distribution is likely due to a combination of limited active surveillance reporting in other regions and the lack of immunity that left the previously unexposed populations of the Americas susceptible to severe outbreaks during the last decade. Long-term rheumatic sequelae provided the largest DALY component for CHIKV, whereas congenital Zika syndrome (CZS) contributed most significantly for ZIKV. Acute symptoms and early mortality accounted for relatively less of the overall burden. Suboptimal reporting and inconsistent diagnostics limit precision when determining arbovirus incidence and frequency of complications. Despite these limitations, it is clear from our assessment that CHIKV and ZIKV represent a significant cause of morbidity that is not included in current disease burden reports. These results suggest that transmission-blocking strategies, including vector control and vaccine development, remain crucial priorities in reducing global disease burden through prevention of potentially devastating arboviral outbreaks.

Background: Schistosomiasis is one of the most prevalent neglected tropical diseases (NTDs) with an estimated 229 million people requiring preventive treatment worldwide. Recommendations for preventive chemotherapy strategies have been made by the World Health Organization (WHO) whereby the frequency of treatment is determined by the settings prevalence. Despite recent progress, many countries still need to scale up treatment and important questions remain regarding optimal control strategies. This paper presents a systematic review of the economic evaluations of human schistosomiasis interventions. Methods: A systematic review of the literature was conducted on 22nd August 2019 using the PubMed (MEDLINE) and ISI Web of Science electronic databases. The focus was economic evaluations of schistosomiasis interventions, such as cost-effectiveness and cost-benefit analyses. No date or language stipulations were applied to the searches. Results: We identified 53 relevant health economic analyses of schistosomiasis interventions. Most studies related to Schistosoma japonicum followed by S. haematobium. Several studies also included other NTDs. In Africa, most studies evaluated preventive chemotherapy, whereas in China they mostly evaluated programmes using a combination of interventions (such as chemotherapy, snail control and health education). There was wide variation in the methodology and epidemiological settings investigated. A range of effectiveness metrics were used by the different studies. Conclusions: Due to the variation across the identified studies, it was not possible to make definitive policy recommendations. Although, in general, the current WHO recommended preventive chemotherapy approach to control schistosomiasis was found to be cost-effective. This finding has important implications for policymakers, advocacy groups and potential funders. However, there are several important inconsistencies and research gaps (such as how the health benefits of interventions are quantified) that need to be addressed to identify the resources required to achieve schistosomiasis control and elimination.

Background: Iron deficiency may impair adaptive immunity and is common among African infants at time of vaccination. Whether iron deficiency impairs vaccine response and whether iron supplementation improves humoral vaccine response is uncertain. Methods: We performed two studies in southern coastal Kenya. In a birth cohort study, we followed infants to age 18 mo and assessed whether anemia or iron deficiency at time of vaccination predicted vaccine response to three-valent oral polio, diphtheria-tetanus-whole cell pertussis-Haemophilus influenzae type b vaccine, ten-valent pneumococcal-conjugate vaccine and measles vaccine. Primary outcomes were anti-vaccine-IgG and seroconversion at age 24 wk and 18 mo. In a randomized trial cohort follow-up, children received a micronutrient powder (MNP) with 5 mg iron daily or a MNP without iron for 4 mo starting at age 7.5 mo and received measles vaccine at 9 and 18 mo; primary outcomes were anti-measles IgG, seroconversion and avidity at age 11.5 mo and 4.5 y. Findings: In the birth cohort study, 573 infants were enrolled and 303 completed the study. Controlling for sex, birthweight, anthropometric indices and maternal antibodies, hemoglobin at time of vaccination was the strongest positive predictor of: (A) anti-diphtheria and anti-pertussis-IgG at 24 wk (p = 0.0071, p = 0.0339) and 18 mo (p = 0.0182, p = 0.0360); (B) anti-pertussis filamentous hemagglutinin-IgG at 24 wk (p = 0.0423); and (C) anti-pneumococcus 19 IgG at 18 mo (p = 0.0129). Anemia and serum transferrin receptor at time of vaccination were the strongest predictors of seroconversion against diphtheria (p = 0.0484, p = 0.0439) and pneumococcus 19 at 18 mo (p = 0.0199, p = 0.0327). In the randomized trial, 155 infants were recruited, 127 and 88 were assessed at age 11.5 mo and 4.5 y. Compared to infants that did not receive iron, those who received iron at time of vaccination had higher anti-measles-IgG (p = 0.0415), seroconversion (p = 0.0531) and IgG avidity (p = 0.0425) at 11.5 mo. Interpretation: In Kenyan infants, anemia and iron deficiency at time of vaccination predict decreased response to diphtheria, pertussis and pneumococcal vaccines. Primary response to measles vaccine may be increased by iron supplementation at time of vaccination. These findings argue that correction of iron deficiency during early infancy may improve vaccine response.