Metabolomics in Infectious Diseases and Vaccine Response: Insights into Neglected Tropical and Non-Neglected Pathogens

To end the neglect of neglected tropical diseases

World Health Organization statistics show that deaths worldwide from chronic noncommunicable diseases (CNCDs) now exceed those from infectious diseases [1]. The major CNCDs causing the greatest share of deaths and disability worldwide include cardiovascular conditions (mainly heart disease and stroke), some cancers, chronic respiratory conditions, and type 2 diabetes [2]. Together they account for 60% of all deaths worldwide [2]. Approximately 80% of the CNCD deaths occur in low-income and middle-income countries [2]. Most of the factors contributing to such large numbers of deaths, a large proportion of which are premature, are similar to those in developed countries. They include increasing tobacco use, diminished physical activity and lack of exercise, and the consumption of unhealthy foods [2]. CNCDs are defined as diseases or conditions that affect individuals over an extensive period of time and for which there are no known causative agents that are transmitted from one affected individual to another [2]. More than any other type of infection, the neglected tropical diseases (NTDs) most closely resemble the CNCDs. The characteristic feature of the NTDs are their chronic and insidious clinical manifestations, and the resulting long-term disability [3],[4]. An impoverished person suffering from a NTD will typically have the condition for years, sometimes decades, and sometimes their entire life [3],[4]. Indeed, except for the fact that we know their causative agents, the NTDs for the most part meet CNCD-defining criteria. Shown in Table 1 are the major chronic disease syndromes that result from NTDs. Chagas disease is a leading cause of chronic cardiovascular disease in Latin America, often resulting in severe cardiomyopathy [5], while Loa loa and other parasitic infections have been identified as possible etiologies of endomyocardial fibrosis in sub-Saharan Africa [6]. Urinary schistosomiasis is a leading cause of bladder cancer in Africa and the Middle East (causing a unique squamous cell carcinoma) [7],[8], while opisthorchiasis and clonorchiasis, both causes of oriental liver fluke infection, cause bile duct carcinoma in Southeast Asia and China [9]. Worldwide, trichuriasis causes more inflammatory bowel disease than either Crohn disease or ulcerative colitis [10], and schistosomiasis is a leading cause of chronic renal disease and failure in Africa and the Middle East [7],[8],[11]. In Asia, paragonomiasis ranks with tuberculosis and lung cancer as a leading cause of hemoptysis [12], and toxocariasis is emerging as an important cause of asthma [13]. Table 1 CNCD-Like Syndromes Caused by the NTDs. Anemia is one of the best documented examples of a chronic condition in which a single NTD, such as hookworm infection, accounts for a significant percentage of the attributable risk [14]–[17], or in which multiple NTD coinfections and polyparasitism make a significant contribution [18]–[23]. Another is cancer—urinary schistosomiasis was shown to account for 28% of the bladder cancer in Bulawayo, Zimbabwe [24], and 0.1% of the world's cancer burden [25], while liver flukes (e.g., Clonorchis sinensis and Opisthorchis spp.) account for an estimated 0.02% of all cancers [25]. Van der Werf et al. determined that Schistosoma haematobium was responsible for 10 million cases of hydronephrosis in sub-Saharan Africa, and S. mansoni was associated with 8.5 million cases of hepatomegaly in the region [11]. It has been further estimated that approximately 5.4 million people will develop chronic Chagas heart disease, while 900,000 will develop severe enlargement of the digestive tract (megacolon and megaesophagus) [26]. However, the full extent to which the NTDs listed in Table 1 contribute to the other CNCDs requires active investigation. Among the bottom billion living in the poorest areas of the developing world, the underlying causes of chronic cardiovascular, renal, hepatic, and gastrointestinal disease, as well as cancer, are frequently neglected and unstudied. Because they are so common in low-income and middle-income countries, it is of critical importance to determine how the NTDs contribute significantly to the CNCD burden in such regions. Such an evidence base is critical for informing new policies for tackling chronic disease in developing countries. The new Grand Challenges in CNCDs initiative [2] is an ambitious effort to raise public awareness of these conditions in the developing world, enhance economic, legal, and environmental policies, modify risk factors, mitigate the health impacts of poverty and urbanization, engage the community, and reorient health systems away from treatment towards prevention [2]. Wherever the NTDs geographically overlap with the CNCDs, there is a need to assess the contribution of the former, and to recognize that when it comes to NTDs, the distinction between noncommunicable and communicable diseases can be murky.

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Neglected Tropical Diseases focuses its scope on the ''neglected'' communicable diseases of developing countries, diseases that do not receive attention from the developed world.The list of neglected tropical diseases (NTDs) is mainly comprised of helminths, protozoa, and many tropical bacterial species that currently do not receive sufficient priority in international public health programs and research agendas.In a practical sense, these very prevalent diseases of underdevelopment are seen as neglected because they are outside the purview of the Global Fund and its related programs, which

The Gulf of Mexico: a "hot zone" for neglected tropical diseases?

Neglected tropical diseases (NTDs) exist and persist for social and economic reasons that enable the vectors and pathogens to take advantage of changes in the behavioral and physical environment. Persistent poverty at household, community, and national levels, and inequalities within and between sectors, contribute to the perpetuation and re-emergence of NTDs. Changes in production and habitat affect the physical environment, so that agricultural development, mining and forestry, rapid industrialization, and urbanization all result in changes in human uses of the environment, exposure to vectors, and vulnerability to infection. Concurrently, political instability and lack of resources limit the capacity of governments to manage environments, control disease transmission, and ensure an effective health system. Social, cultural, economic, and political factors interact and influence government capacity and individual willingness to reduce the risks of infection and transmission, and to recognize and treat disease. Understanding the dynamic interaction of diverse factors in varying contexts is a complex task, yet critical for successful health promotion, disease prevention, and disease control. Many of the research techniques and tools needed for this purpose are available in the applied social sciences. In this article we use this term broadly, and so include behavioral, population and economic social sciences, social and cultural epidemiology, and the multiple disciplines of public health, health services, and health policy and planning. These latter fields, informed by foundational social science theory and methods, include health promotion, health communication, and heath education.

In a previous article, we outlined the efforts of the Neglected Tropical Diseases (NTD) lobby to overcome the diseases' snub in the 2000 Millennium Development Goals (MDGs) and to campaign for inclusion in the post-2015 development agenda [1]. In doing so, we noted the extraordinary achievements made by the lobby despite its view from outside of the MDG juggernaut, which singled out just three for special consideration (HIV/AIDS, Malaria, and, latterly, Tuberculosis), leaving a group of previously disparate to be formulated within a plan for inclusion. The plan resulted in a three-pronged attack forged on advocacy, policy, and science. The NTD lobby has grown significantly since the original 2003 WHO/Deutsche Gesellschaft fur Technische Zusammenarbeit (GTZ) meetings were convened to float the idea that the NTDs should be reconceptualised and tackled as a group moving forward. The original core group—Peter J. Hotez, David Molyneux, and Alan Fenwick (along with WHO’s Lorenzo Savioli and others)—has since been joined by representation from academia (e.g., PLOS Neglected Tropical Diseases), the third sector (e.g., the Global Network, the Neglected Tropical Disease Non-Governmental Development Organization Network), the pharmaceutical industry, donor agencies, and the philanthropic sector (cf. Uniting to Combat NTDs). The lobby is also formally supported by the World Health Organisation (through the WHO Roadmap [2] and WHA Resolution 66.12 [3]) and by the disease endemic country governments that have signed the Addis Ababa NTD Commitment. Yet, despite boasting swelling ranks and a number of sizeable achievements in the intervening period—for instance the landmark London Declaration—the NTD lobby has remained interested in the more mainstream development agenda. The advocacy goal has always been the formal inclusion of NTDs in the successor framework to the Millennium Development Goals: the post-2015 Sustainable Development Agenda. On 1 January 2016, the Sustainable Development Goals (SDGs or Global Goals) came into force. The particulars of the goals were finalised at the United Nations summit in September 2015, and, as hoped, NTDs gained a special mention in goal 3.3: By 2030, end the epidemics of AIDS, tuberculosis, malaria, and neglected tropical and combat hepatitis, waterborne diseases, and other communicable diseases (p 16) [4]. But what is this mention worth and what are its implications? The SDGs are similar to the MDGs in that they represent time-bound targets and retain a focus on ending world poverty, but they break with the original eight MDGs in terms of their colossal scope. Composed of 17 goals and 169 targets, the SDGs are the result of an extensive three-year consultation involving multiple perspectives from government, civil society, expert groups, the private sector, and individuals. The MDGs were regularly critiqued as restricted in focus and top-down, something which cannot be levelled against the SDGs. But might the warning of the High-Level Panel that originally drafted the framework document have been ignored—The international community will need to ensure that a single, sustainable framework agenda is not overloaded with too many priorities. A product of compromise rather than decisions…? (p 14) [5]. The post-2015 vision—as articulated through the SDGs—is to create a single universal agenda in which the social, economic, and environmental dimensions of sustainability are integrated. Whereas the MDGs were criticised for targeting the low-hanging fruit, the post-2015 agenda is underpinned by the tenet “leave no one behind.” As the UN summit drew closer in 2015, we noted how this principle, coupled with the post-2015 focus on environmental issues, provided a number of advocacy issues behind which the NTD lobby began to position itself: equity, poverty, water sanitation and hygiene (WASH), climate change, quality education, NTD-related disability, and nutrition. In this paper, we reflect on the NTD lobby’s efforts to gain traction in the wide-ranging post-2015 agenda by making the case that NTDs are crosscutting and by lobbying for NTD indicators.

Proteomics‐Based Investigations of Neglected and Tropical Diseases

BackgroundThe burden of neglected tropical diseases (NTDs), HIV/AIDS, tuberculosis, and malaria pose significant public health challenges in Ethiopia. This study aimed to the explore service availability and readiness for NTD care among Ethiopian health facilities treating tuberculosis (TB), HIV/AIDS, and/or malaria.MethodsThis study utilized secondary data from the Ethiopian Service Provision Assessment 2021–22 survey. The availability of services was calculated as the percentage of HIV/AIDS, tuberculosis, or malaria facilities providing NTD services. Facilities were considered highly prepared to manage any type of NTD if they scored at least half (> 50%) of the tracer items listed in each of the three domains (staff training and guidelines, equipment, and essential medicines). Descriptive statistics and logistic regression models were employed to present the study findings and analyze factors influencing facility readiness, respectively.ResultsOut of 403 health facilities providing NTD care nationally, 179, 183, and 197 also offer TB, HIV/AIDS, and malaria services, respectively. The majority of TB (90.1%), HIV/AIDS (89.6%), and malaria (90.9%) facilities offer soil-transmitted helminth services, followed by trachoma (range 87–90%). The percentages of the aforementioned facilities with at least one trained staff member for any type of NTD were 87.2%, 88.4%, and 82.1%, respectively. The percentage of facilities with guidelines for any type of NTD was relatively low (range 3.7–4.1%). Mebendazole was the most widely available essential medicine, ranging from 69 to 70%. The overall readiness analysis indicated that none of the included facilities (TB = 11.9%; HIV/AIDS = 11.6%; and malaria = 10.6%) were ready to offer NTD care. Specifically, a higher level of readiness was observed only in the domain of medicines across these facilities. Hospitals had better readiness to offer NTD care than did health centers and clinics. Furthermore, a significant associations were observed between facility readiness and factors such as facility type, region, presence of routine management meetings, types of NTD services provided, and fixed costs for services.ConclusionsEthiopian health facilities treating TB, HIV/AIDS, and malaria had an unsatisfactory overall service availability and a lack of readiness to provide NTD care. Given the existing epidemiological risks and high burden of TB, HIV/AIDS, malaria, and NTDs in Ethiopia, there is an urgent need to consider preparing and implementing a collaborative infectious disease care plan to integrate NTD services in these facilities.

BackgroundThis study investigates the impact of the COVID-19 pandemic on the prevalence, management, and control of the neglected tropical diseases (NTDs) highlighting the current or prospective impact of COVID-19 on research and development funding for, and execution of, NTD programmes. This review was conducted to determine if, and how, NTDs were affected by COVID-19, and whether those effects will delay the elimination goals of the Sustainable Development goals.MethodsUsing open-source available data from policy and documentation from official websites of the relevant stakeholders including but not limited to World Health Organization (WHO) documents and policies, government foreign aid documents, and the Policy Cures G-Finder reports, this scoping review explored ongoing challenges to supporting research and development (R&D) for the NTDs and in maintaining NTD control programs; examined the constraints posed for NTD management by the pandemic from disruptions to healthcare services, reduction of finance and explored the potential long-term implications and consequences for those poorer, neglected populations in low and middle income-countries (LMICs). This was done by a scoping review literature search, publications were subject to an initial practical screening step to ensure the most relevant publications were selected for full screening, with the focus on scoping the designated topic of the impact of COVID-19 on NTDs. We further undertook an evaluation of the socio-economic factors exacerbating the impact of COVID-19 on NTD burden.ResultsMultiple disruptions and setbacks, likely to affect NTD programmes and progress towards their elimination targets were identified in this study. R&D funding for the NTDs and AIDs and TB has declined since the funding high point of 2019, and for malaria since the high point of 2018. Significant changes in allocation of R&D funding within the NTDs are observed post pandemic, likely because of prioritization among donors. Diseases for which the least R&D investment was reported in place, prior to the pandemic (mycetoma, taeniasis/cysticercosis, trachoma and Buruli ulcer) have been particularly impacted post pandemic. We identified specific NTDs including schistosomiasis, leprosy, and rabies that have been affected by the COVID-19 pandemic and disruptions caused to on ongoing NTD control and elimination programs. Pandemic restrictions disrupted essential medical supply manufacturing and distribution impacting immunization programs and hindered efforts to control the spread of infectious diseases. NTD programmes have experienced numerous setbacks including delays in mass drug administration programs (e.g. for schistosomiasis), cancelled or delayed vaccination programs (e.g. for rabies) and closure of testing facilities has resulted in reduced diagnosis, treatment, and disease elimination for all NTDs. Lockdowns and clinic closures causing disruption to essential healthcare services restricted NTD surveillance and treatment programs. Community fears around contracting COVID-19 exacerbated the constraints to service delivery. Disparities in global vaccine distribution have widened with LMICs facing limited access to vaccines and disruption to immunization programs. Finally, the pandemic has led to increased poverty with poor and marginalized communities, impacting nutrition, healthcare access and education all of which have long term implications for NTD management and control.ConclusionsThe COVID-19 pandemic profoundly impacted global health research and global health equity. Attention and funding were diverted from all sectors, significantly affecting research and development efforts set out in the World Health Organization’s NTD elimination Roadmaps. Ongoing changes to funding, economic crises, logistics and supply chain disruptions as well as deepening poverty has put a strain on already weak healthcare systems and exacerbated LMIC healthcare challenges. In particular, the delays and constraints to NTD management and elimination programs will have long-reaching consequences highlighting the need for global cooperation and renewed investment to put the NTD roadmap back on track. Targets and milestones are unlikely to be met without significant investment for recovery, in place.Graphical

Infectious diseases have influenced the biological, historical, and political development of the human species more than any other factor: from the outcome of wars to the success of empires, from the pace of technological advance to the structure of society [1]. Dracunculiasis (Guinea worm disease) was considered a mild affliction not warranting a widespread public health campaign. However, examination of the benefits of eradicating Guinea worm disease (GWD) reveals the effort is contributing to development, including contributions to certain Millennium Development Goals (MDGs) [2]. Given the use of the MDGs in the development of global health agendas, it is timely to consider the contributions of neglected tropical disease (NTD) programs, such as the Guinea Worm Eradication Program (GWEP), toward the achievement of the MDGs. The prevention of NTDs, and their cost-effective interventions, fuels long-term economic growth and development, and human advancement [3]. The effort to eradicate GWD is considered one of the most cost-effective health interventions available [2,4,5]. The authors provide evidence that concentrated efforts on eradication, elimination, and control of some NTDs can yield far-reaching results, and given these results, stimulate increased efforts toward NTD eradication, elimination, and control among public health advocates, global health entities, and donors. GWD is a disease of the poor, debilitating many in the most remote and disadvantaged communities in parts of sub-Saharan Africa, where potable water is limited and health care and education are lacking [6]. Endemic GWD transmission is an indicator of extreme poverty [6,7]. GWD is a preventable, painful, and incapacitating waterborne helminthic disease, which harms health, agriculture, school attendance, and overall quality of life for individuals and communities [7–9]. GWD is transmitted when humans drink water, usually from stagnant water sources, containing tiny copepods that have ingested larvae of the parasite. Once consumed, the digestive juices in the human stomach kill the copepods, allowing the larvae to be released and move to the intestinal wall where they migrate to connective tissues of the thorax. Male and female larvae mature and mate 60–90 days after infection. Symptoms appear 10–14 months later when the gravid adult female(s), measuring up to 70–100 cm long, emerges from the skin, causing a painful lesion [10]. When the emerging worm is exposed to water, she ejects hundreds of thousands of larvae into the water to continue the cycle. During emergence, an infected person can be incapacitated for an average of 8.5 weeks [10,11]. Although rarely fatal, GWD inflicts devastating pain and infection resulting in immobility [8,12]. The pain is so long-lasting that infected individuals may be incapacitated for up to three months during and after the Guinea worm (GW) emerges [11,13–15]. Other symptoms include nausea, vomiting, diarrhea, and dizziness; secondary bacterial infections can also occur and can lead to arthritis, tetanus, and permanent crippling [8]. There is no cure, vaccine, or immunity after infection [11]. Since there is no evidence that animals are reservoir hosts, the disease is deemed a good candidate for eradication [8]. The global eradication campaign began at the United States Centers for Disease Control and Prevention (CDC) in 1980 and was then adopted as a subgoal of the United Nations International Drinking-Water Supply and Sanitation Decade (1981–1990). In that same year, the decision-making body of the World Health Organization (WHO) adopted a resolution (WHA 34.25) recognizing the decade could be an opportunity to eliminate GWD. Since 1986, The Carter Center (TCC) has led the effort, with the help of the CDC, WHO, United Nations Children’s Fund (UNICEF), and many other donors and nongovernmental organizations, to assist national eradication efforts by governments of the countries where GWD is endemic [11]. The GWEP assists ministries of health (MOH) in each endemic country to provide GWD interventions. The GWEP is an eradication effort that relies heavily on behavioral change via health education and interventions. The GWEP has demonstrated that when people are given the proper tools and health education, cases decrease dramatically [16]. The most effective and cost-efficient way to prevent GWD is the promotion of its health campaign coupled with proper and consistent use of filters to remove the copepods from drinking water, case containment, and the application of ABATE, a safe chemical larvicide, to control the copepods [4,17–19]. GWD is an infectious disease categorized as a neglected tropical disease (NTD) [20]. NTDs are among the most common infectious diseases of the world’s poorest people [21,22]. An estimated 1.2 billion people are infected with one or more NTDs [23]. These individuals are among the billion people living on less than $1 per day, a population identified as the ‘‘bottom billion’’ [23]. NTDs are a group of parasitic, bacterial, and viral diseases that cause

Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa do Timo. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Ciências Biomédicas. Programa de Pós-Graduação em Biologia Celular e do Desenvolvimento. Rio de Janeiro, RJ, Brasil.

Two birds with one stone