Meeting Report: WHO Workshop on modelling global mortality and aetiology estimates of enteric pathogens in children under five. Cape Town, 28-29th November 2018.

Investment in vaccine product development should be guided by up-to-date and transparent global burden of disease estimates, which are also fundamental to policy recommendation and vaccine introduction decisions. For low- and middle-income countries (LMICs), vaccine prioritization is primarily driven by the number of deaths caused by different pathogens. Enteric diseases are known to be a major cause of death in LMICs. The two main modelling groups providing mortality estimates for enteric diseases are the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, Seattle and the Maternal Child Epidemiology Estimation (MCEE) group, led by Johns Hopkins Bloomberg School of Public Health. Whilst previous global diarrhoea mortality estimates for under five-year-olds from these two groups were closely aligned, more recent estimates for 2016 have diverged, particularly with respect to numbers of deaths attributable to different enteric pathogens. This has impacted prioritization and investment decisions for vaccines in the development pipeline. The mission of the Product Development for Vaccines Advisory Committee (PDVAC) at the World Health Organisation (WHO) is to accelerate product development of vaccines and technologies that are urgently needed and ensure they are appropriately targeted for use in LMICs. At their 2018 meeting, PDVAC recommended the formation of an independent working group of subject matter experts to explore the reasons for the difference between the IHME and MCEE estimates, and to assess the respective strengths and limitations of the estimation approaches adopted, including a review of the data on which the estimates are based. Here, we report on the proceedings and recommendations from a consultation with the working group of experts, the IHME and MCEE modelling groups, and other key stakeholders. We briefly review the methodological approaches of both groups and provide a series of proposals for investigating the drivers for the differences in enteric disease burden estimates

Influence of degree of specific allergic sensitivity on severity of rhinitis and asthma in Chinese allergic patients

<p>Abstract</p> <p>Background</p> <p>The association between sensitizations and severity of allergic diseases is controversial.</p> <p>Objective</p> <p>This study was to investigate the association between severity of asthma and rhinitis and degree of specific allergic sensitization in allergic patients in China.</p> <p>Method</p> <p>A cross-sectional survey was performed in 6304 patients with asthma and/or rhinitis from 4 regions of China. Patients completed a standardized questionnaire documenting their respiratory and allergic symptoms, their impact on sleep, daily activities, school and work. They also underwent skin prick tests with 13 common aeroallergens. Among the recruited subjects, 2268 provided blood samples for serum measurement of specific IgE (sIgE) against 16 common aeroallergens.</p> <p>Results</p> <p>Significantly higher percentage of patients with moderate-severe intermittent rhinitis were sensitized to outdoor allergens while percentage of patients sensitized to indoor allergens was increased with increasing severity of asthma. Moderate-severe intermittent rhinitis was associated with the skin wheal size and the level of sIgE to <it>Artemisia vulgaris </it>and <it>Ambrosia artemisifolia </it>(p < 0.001). Moderate-severe asthma was associated with increasing wheal size and sIgE response to <it>Dermatophagoides </it>(<it>D</it>.) <it>pteronyssinus </it>and <it>D. farinae </it>(p < 0.001). Moderate-severe rhinitis and asthma were also associated with increase in number of positive skin prick test and sIgE.</p> <p>Conclusions</p> <p><it>Artemisia vulgaris </it>and <it>Ambrosia artemisifolia </it>sensitizations are associated with the severity of intermittent rhinitis and <it>D. pteronyssinus </it>and <it>D. farinae </it>sensitizations are associated with increasing severity of asthma in China. Increase in number of allergens the patients are sensitized to may also increase the severity of rhinitis and asthma.</p

Asthma in changing environments - chances and challenges of international research collaborations between South America and Europe - study protocol and description of the data acquisition of a case-control-study

<p>Abstract</p> <p>Background</p> <p>Asthma in children is an emerging public health problem in South America. So far, research in this part of the world is limited. This paper presents the methodology and description of the data acquisition of an asthma case-control study conducted in the Central South of Chile.</p> <p>Methods/Design</p> <p>A hospital-based case-control study about asthma (188 cases, 294 controls) in children (6-15 years) was carried out in Valdivia, Chile between November 2008 and December 2009. Data on asthma risk factors were collected by computer-assisted personal interview using validated questions from e.g. ISAAC phase II. Data on household dust exposure (endotoxin, allergen analyses), skin prick tests to most common allergens, stool examinations for parasitic infection, and blood samples (total IgE, genetics) were collected. Additionally, 492 randomly chosen blood donors were recruited in order to assess allele frequencies in the population of Valdivia.</p> <p>Discussion</p> <p>Overall 1,173 participants were contacted. Response was 82% among cases and 65% among controls. Atopic sensitization was high (78% among cases, 47% among controls). Cases had a statistically significantly (p < .0001) increased self-reported 12-month prevalence of symptoms of rhinitis (82% vs. 51%) and wheeze (68% vs. 16%). The study is well placed to address current hypotheses about asthma and its correlates in the South American context. Results of this study might help develop novel, innovative and individualized prevention strategies in countries in transition with respect to the South American context.</p

Anti-tumor necrosis factor-Α antibody treatment reduces pulmonary inflammation and methacholine hyper-responsiveness in a murine asthma model induced by house dust

Background/Aims Recent studies documented that sensitization and exposure to cockroach allergens significantly increase children's asthma morbidity as well as severity, especially among inner city children. TNF-Α has been postulated to be a critical mediator directly contributing to the bronchopulmonary inflammation and airway hyper-responsiveness in asthma. This study investigated whether an anti-TNF-Α antibody would inhibit pulmonary inflammation and methacholine (Mch) hyper-responsiveness in a mouse model of asthma induced by a house dust extract containing both endotoxin and cockroach allergens. Methods A house dust sample was extracted with phosphate-buffered saline and then used for immunization and two additional pulmonary challenges of BALB/c mice. Mice were treated with an intravenous injection of anti-TNF-Α antibody or control antibody 1  h before each pulmonary challenge. Results In a kinetic study, TNF-Α levels within the bronchoalveolar lavage (BAL) fluid increased quickly peaking at 2 h while BAL levels of IL-4, IL-5, and IL-13 peaked at later time-points. Mch hyper-responsiveness was measured 24 h after the last challenge, and mice were killed 24 h later. TNF inhibition resulted in an augmentation of these Th2 cytokines. However, the allergic pulmonary inflammation was significantly reduced by anti-TNF-Α antibody treatment as demonstrated by a substantial reduction in the number of BAL eosinophils, lymphocytes, macrophages, and neutrophils compared with rat IgG-treated mice. Mch hyper-responsiveness was also significantly reduced in anti-TNF-Α antibody-treated mice and the pulmonary histology was also significantly improved. Inhibition of TNF significantly reduced eotaxin levels within the lung, suggesting a potential mechanism for the beneficial effects. These data indicate that anti-TNF-Α antibody can reduce the inflammation and pathophysiology of asthma in a murine model of asthma induced by a house dust extract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73609/1/j.1365-2222.2005.02407.x.pd

The clinical presentation of culture-positive and culture-negative, qPCR-attributable shigellosis in the Global Enteric Multicenter Study and derivation of a Shigella severity score: implications for pediatric Shigella vaccine trials

BACKGROUND: Shigella is a leading cause of childhood diarrhea and target for vaccine development. Microbiologic and clinical case definitions are needed for pediatric field vaccine efficacy trials. METHODS: We compared characteristics of moderate to severe diarrhea (MSD) cases in the Global Enteric Multicenter Study (GEMS) between children with culture positive Shigella to those with culture-negative, qPCR-attributable Shigella (defined by an ipaH gene cycle threshold <27.9). Among Shigella MSD cases, we determined risk factors for death and derived a clinical severity score. RESULTS: Compared to culture-positive Shigella MSD cases (n=745), culture-negative/qPCR-attributable Shigella cases (n=852) were more likely to be under 12 months, stunted, have a longer duration of diarrhea, and less likely to have high stool frequency or a fever. There was no difference in dehydration, hospitalization, or severe classification from a modified Vesikari score. Twenty-two (1.8%) Shigella MSD cases died within the 14-days after presentation to health facilities, and 59.1% of these deaths were in culture-negative cases. Age < 12 months, diarrhea duration prior to presentation, vomiting, stunting, wasting, and hospitalization were associated with mortality. A model-derived score assigned points for dehydration, hospital admission, and longer diarrhea duration but was not significantly better at predicting 14-day mortality than a modified Vesikari score. CONCLUSIONS: A composite severity score consistent with severe disease or dysentery may be a pragmatic clinical endpoint for severe shigellosis in vaccine trials. Reliance on culture for microbiologic confirmation may miss a substantial number of Shigella cases but is currently required to measure serotype specific immunity

Diet and asthma: looking back, moving forward

Asthma is an increasing global health burden, especially in the western world. Public health interventions are sought to lessen its prevalence or severity, and diet and nutrition have been identified as potential factors. With rapid changes in diet being one of the hallmarks of westernization, nutrition may play a key role in affecting the complex genetics and developmental pathophysiology of asthma. The present review investigates hypotheses about hygiene, antioxidants, lipids and other nutrients, food types and dietary patterns, breastfeeding, probiotics and intestinal microbiota, vitamin D, maternal diet, and genetics. Early hypotheses analyzed population level trends and focused on major dietary factors such as antioxidants and lipids. More recently, larger dietary patterns beyond individual nutrients have been investigated such as obesity, fast foods, and the Mediterranean diet. Despite some promising hypotheses and findings, there has been no conclusive evidence about the role of specific nutrients, food types, or dietary patterns past early childhood on asthma prevalence. However, diet has been linked to the development of the fetus and child. Breastfeeding provides immunological protection when the infant's immune system is immature and a modest protective effect against wheeze in early childhood. Moreover, maternal diet may be a significant factor in the development of the fetal airway and immune system. As asthma is a complex disease of gene-environment interactions, maternal diet may play an epigenetic role in sensitizing fetal airways to respond abnormally to environmental insults. Recent hypotheses show promise in a biological approach in which the effects of dietary factors on individual physiology and immunology are analyzed before expansion into larger population studies. Thus, collaboration is required by various groups in studying this enigma from epidemiologists to geneticists to immunologists. It is now apparent that this multidisciplinary approach is required to move forward and understand the complexity of the interaction of dietary factors and asthma

Effects of chronic ascariasis and trichuriasis on cytokine production and gene expression in human blood: a cross-sectional study.

Background Chronic soil-transmitted helminth (STH) infections are associated with effects on systemic immune responses that could be caused by alterations in immune homeostasis. To investigate this, we measured the impact in children of STH infections on cytokine responses and gene expression in unstimulated blood. Methodology/Principal Findings Sixty children were classified as having chronic, light, or no STH infections. Peripheral blood mononuclear cells were cultured in medium for 5 days to measure cytokine accumulation. RNA was isolated from peripheral blood and gene expression analysed using microarrays. Different infection groups were compared for the purpose of analysis: STH infection (combined chronic and light vs. uninfected groups) and chronic STH infection (chronic vs. combined light and uninfected groups). The chronic STH infection effect was associated with elevated production of GM-CSF (P = 0.007), IL-2 (P = 0.03), IL-5 (P = 0.01), and IL-10 (P = 0.01). Data reduction suggested that chronic infections were primarily associated with an immune phenotype characterized by elevated IL-5 and IL-10, typical of a modified Th2-like response. Chronic STH infections were associated with the up-regulation of genes associated with immune homeostasis (IDO, P = 0.03; CCL23, P = 0.008, HRK, P = 0.005), down-regulation of microRNA hsa-let-7d (P = 0.01) and differential regulation of several genes associated with granulocyte-mediated inflammation (IL-8, down-regulated, P = 0.0002; RNASE2, up-regulated, P = 0.009; RNASE3, up-regulated, p = 0.03). Conclusions/Significance Chronic STH infections were associated with a cytokine response indicative of a modified Th2 response. There was evidence that STH infections were associated with a pattern of gene expression suggestive of the induction of homeostatic mechanisms, the differential expression of several inflammatory genes and the down-regulation of microRNA has-let-7d. Effects on immune homeostasis and the development of a modified Th2 immune response during chronic STH infections could explain the systemic immunologic effects that have been associated with these infections such as impaired immune responses to vaccines and the suppression of inflammatory diseases

Unexpected differential metabolic responses of Campylobacter jejuni to the abundant presence of glutamate and fucose

Introduction: Campylobacter jejuni is the leading cause of foodborne bacterial enteritis in humans, and yet little is known in regard to how genetic diversity and metabolic capabilities among isolates affect their metabolic phenotype and pathogenicity. Objectives: For instance, the C. jejuni 11168 strain can utilize both l-fucose and l-glutamate as a carbon source, which provides the strain with a competitive advantage in some environments and in this study we set out to assess the metabolic response of C. jejuni 11168 to the presence of l-fucose and l-glutamate in the growth medium. Methods: To achieve this, untargeted hydrophilic liquid chromatography coupled to mass spectrometry was used to obtain metabolite profiles of supernatant extracts obtained at three different time points up to 24 h. Results: This study identified both the depletion and the production and subsequent release of a multitude of expected and unexpected metabolites during the growth of C. jejuni 11168 under three different conditions. A large set of standards allowed identification of a number of metabolites. Further mass spectrometry fragmentation analysis allowed the additional annotation of substrate-specific metabolites. The results show that C. jejuni 11168 upon l-fucose addition indeed produces degradation products of the fucose pathway. Furthermore, methionine was faster depleted from the medium, consistent with previously-observed methionine auxotrophy. Conclusions: Moreover, a multitude of not previously annotated metabolites in C. jejuni were found to be increased specifically upon l-fucose addition. These metabolites may well play a role in the pathogenicity of this C. jejuni strain.</p

The implications of three major new trials for the effect of water, sanitation and hygiene on childhood diarrhea and stunting: a consensus statement

BACKGROUND: Three large new trials of unprecedented scale and cost, which included novel factorial designs, have found no effect of basic water, sanitation and hygiene (WASH) interventions on childhood stunting, and only mixed effects on childhood diarrhea. Arriving at the inception of the United Nations' Sustainable Development Goals, and the bold new target of safely managed water, sanitation and hygiene for all by 2030, these results warrant the attention of researchers, policy-makers and practitioners. MAIN BODY: Here we report the conclusions of an expert meeting convened by the World Health Organization and the Bill and Melinda Gates Foundation to discuss these findings, and present five key consensus messages as a basis for wider discussion and debate in the WASH and nutrition sectors. We judge these trials to have high internal validity, constituting good evidence that these specific interventions had no effect on childhood linear growth, and mixed effects on childhood diarrhea. These results suggest that, in settings such as these, more comprehensive or ambitious WASH interventions may be needed to achieve a major impact on child health. CONCLUSION: These results are important because such basic interventions are often deployed in low-income rural settings with the expectation of improving child health, although this is rarely the sole justification. Our view is that these three new trials do not show that WASH in general cannot influence child linear growth, but they do demonstrate that these specific interventions had no influence in settings where stunting remains an important public health challenge. We support a call for transformative WASH, in so much as it encapsulates the guiding principle that - in any context - a comprehensive package of WASH interventions is needed that is tailored to address the local exposure landscape and enteric disease burden

Helminth-induced Th2 cell dysfunction is distinct from exhaustion and is maintained in the absence of antigen

T cell-intrinsic regulation, such as anergy, adaptive tolerance and exhaustion, is central to immune regulation. In contrast to Type 1 and Type 17 settings, knowledge of the intrinsic fate and function of Th2 cells in chronic Type 2 immune responses is lacking. We previously showed that Th2 cells develop a PD-1/PD-L2-dependent intrinsically hypo-responsive phenotype during infection with the filarial nematode Litomosoides sigmodontis, denoted by impaired functionality and parasite killing. This study aimed to elucidate the transcriptional changes underlying Th2 cell-intrinsic hypo-responsiveness, and whether it represents a unique and stable state of Th2 cell differentiation. We demonstrated that intrinsically hypo-responsive Th2 cells isolated from L. sigmodontis infected mice stably retained their dysfunctional Th2 phenotype upon transfer to naïve recipients, and had a divergent transcriptional profile to classical Th2 cells isolated prior to hypo-responsiveness and from mice exposed to acute Type 2 stimuli. Hypo-responsive Th2 cells displayed a distinct transcriptional profile to exhausted CD4+ T cells, but upregulated Blimp-1 and the anergy/regulatory-associated transcription factors Egr2 and c-Maf, and shared characteristics with tolerised T cells. Hypo-responsive Th2 cells increased mRNA expression of the soluble regulatory factors Fgl2, Cd38, Spp1, Areg, Metrnl, Lgals3, and Csf1, and a subset developed a T-bet+IFN-γ+ Th2/Th1 hybrid phenotype, indicating that they were not functionally inert. Contrasting with their lost ability to produce Th2 cytokines, hypo-responsive Th2 cells gained IL-21 production and IL-21R blockade enhanced resistance to L. sigmodontis. IL-21R blockade also increased the proportion of CD19+PNA+ germinal centre B cells and serum levels of parasite specific IgG1. This indicates a novel regulatory role for IL-21 during filarial infection, both in controlling protection and B cell responses. Thus, Th2 cell-intrinsic hypo-responsiveness is a distinct and stable state of Th2 cell differentiation associated with a switch from a classically active IL-4+IL-5+ Th2 phenotype, to a non-classical dysfunctional and potentially regulatory IL-21+Egr2+c-Maf+Blimp-1+IL-4loIL-5loT-bet+IFN-γ+ Th2 phenotype. This divergence towards alternate Th2 phenotypes during chronicity has broad implications for the outcomes and treatment of chronic Type 2-related infections and diseases