Prevalence of fever of unidentified aetiology in East African adolescents and adults: a systematic review and meta-analysis.

BACKGROUND: Primary health care settings and hospitals of low- and middle-income countries have few accessible diagnostic tools and limited laboratory and human resources capacity to identify multiple pathogens with high accuracy. In addition, there is a paucity of information on fever and its underlying aetiology in the adolescent and adult population in East Africa. The purpose of this study was to estimate the pooled prevalence of fever of unidentified aetiology among adolescent and adult febrile patients seeking health care in East Africa. METHODS: We pursued a systematic review using readily available electronic databases (i.e. PubMed, Cumulative Index to Nursing & Allied Health Literature, Scopus, Cochrane Library and Web of Science) without language restriction from inception date of the respective databases to October 31, 2022. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Identified studies were screened for relevance. Further analyses based on pre-set eligibility criteria were carried out for final inclusion. Two reviewers independently screened and extracted data. Risk of study bias was assessed. Meta-analysis of the prevalence of fever of unidentified aetiology was performed. RESULTS: We identified 14,029 articles of which 25 were eligible for inclusion, reporting data from 8538 participants. The pooled prevalence of febrile cases with unidentified aetiology was 64% [95% confidence interval (CI): 51-77%, I2 = 99.6%] among febrile adolescents and adults in East Africa. For the proportion of patients with identified aetiology, the studies documented bacterial pathogens (human bloodstream infections), bacterial zoonotic pathogens and arboviruses as the main non-malarial causative agents in East Africa. CONCLUSIONS: Our study provides evidence that almost two-thirds of adolescent and adult febrile patients attending health care facilities in East Africa might receive inappropriate treatments due to unidentified potential life-threatening fever aetiology. Hence, we call for a comprehensive fever syndromic surveillance to broaden a consequential differential diagnosis of syndromic fever and to considerably improve the course of patients' disease and treatment outcomes.

More than seven decades of Acta Tropica: Looking back to move into the future.

Acta Tropica is an international, peer-reviewed journal advancing scientific research in the fields of tropical medicine and parasitology. This article elucidates the rich history of the journal and speculates about its future. Acta Tropica was launched in 1944 and formed an integral part of the establishment and running of the Swiss Tropical Institute in Basel. After two distinct periods of relatively small publication activities (1944-1976 and 1977-1988), in 1989, Acta Tropica was transferred to the Dutch publisher Elsevier. Subsequently, the annual number of publications steadily increased and the scope of the journal broadened to the biology of pathogens and their vectors, to genetics, host-parasite relationships, mechanisms of pathogenicity, diagnostics, and treatment of tropical diseases. The body of published articles contributed to an improved understanding of the prevention, surveillance, control, and elimination of diseases that are intimately linked to poverty, such as malaria and neglected tropical diseases. In recent years, the scope of Acta Tropica was widening to target emerging and re-emerging infectious diseases, epidemics and pandemics, interrelations of microbes, viruses, and parasites, co-dependencies of epidemiology, ecology, environment, and climate change. Importantly, non-communicable diseases are gaining interest in low- and middle-income countries due to urbanization, globalization, and rapidly changing life styles, and hence, these issues receive growing prominence. Acta Tropica continues to embrace inter- and, indeed, transdisciplinary research to address pressing global health issues and sustainable development.

More than seven decades of Acta Tropica: Partnership to advance the 2030 Agenda for Sustainable Development.

The inaugural issue of Acta Tropica has been published in 1944, at a time of utmost international isolation and uncertainty due to World War II. Now, more than seven decades later, Acta Tropica is a trusted outlet to communicate and disseminate scientific advances in the fields of parasitology and tropical medicine. As a scholarly, peer-reviewed journal, Acta Tropica contributes to the 2030 Agenda for Sustainable Development, particularly the Sustainable Development Goal (SDG) 3, that is "Ensure healthy lives and promote well-being for all of all ages". This article explores how Acta Tropica has evolved over time. Our analysis is based on a systematic review of keywords derived from all issues published in a specific year, arbitrarily selected at decadal snapshots (1950, 1960, 1970, 1980, 1990, 2000, 2010, and 2020). Results indicate a decrease in interdisciplinarity in favour of more specialised expertise in various fields of infectious diseases research and public health with a particular emphasis on low- and middle-income countries. Yet, by examining first and last authors' institutional affiliations and classifying countries by the Human Development Index (HDI), we find that most authors are affiliated with institutions in high- and very high-HDI countries. Over time, the mean number of authors on a paper has increased severalfold (from 1.35 in 1950 to 7.51 in 2020). Taken together, Acta Tropica has become increasingly globally anchored and contributes not only to SDG 3, but increasingly also to SDG 17, that is "Revitalize the global partnership for sustainable development".

Insects dispersing taeniid eggs: Who and how?

Taeniosis/cysticercosis and echinococcosis are neglected zoonotic helminth infections with high disease burden caused by tapeworms which circulate between definitive and intermediate host reflecting a predator-prey interaction. Taeniid eggs can remain vital for months, allowing arthropods to mechanically transport them to intermediate hosts. However, the multiple routes that arthropods provide as carriers of taeniid eggs are still often unregarded or not considered. This review focuses on the prevalence and importance of arthropods as carriers and spreaders of taeniid eggs in the epidemiology of taeniosis/cysticercosis and echinococcosis. Current scientific knowledge showed a relevant role of houseflies (Muscidae), blowflies (Calliphoridae), dung beetles (Scarabaeoidea), darkling beetles (Tenebrionidae), ground beetles (Carabidae) and skin beetles (Dermestidae) in the spread of taeniid eggs in the environment, which may favor the infection of new hosts through the direct ingestion of an insect or of contaminated food and water. At last, key research challenges are highlighted, illustrating that further knowledge on the topic is needed to develop and improve guidelines and actions to prevent taeniid infections worldwide.

Galectins from Onchocerca ochengi and O. volvulus and their immune recognition by Wistar rats, Gudali zebu cattle and human hosts.

BACKGROUND: During the last two decades research on animal filarial parasites, especially Onchocerca ochengi, infecting cattle in savanna areas of Africa revealed that O. ochengi as an animal model has biological features that are similar to those of O. volvulus, the aetiological agent of human onchocerciasis. There is, however, a paucity of biochemical, immunological and pathological data for O. ochengi. Galectins can be generated by parasites and their hosts. They are multifunctional molecules affecting the interaction between filarial parasites and their mammalian hosts including immune responses. This study characterized O. ochengi galectin, verified its immunologenicity and established its immune reactivity and that of Onchocerca volvulus galectin. RESULTS: The phylogenetic analysis showed the high degree of identity between the identified O. ochengi and the O. volvulus galectin-1 (ß-galactoside-binding protein-1) consisting only in one exchange of alanine for serine. O. ochengi galectin induced IgG antibodies during 28 days after immunization of Wistar rats. IgG from O. ochengi-infected cattle and O. volvulus-infected humans cross-reacted with the corresponding galectins. Under the applied experimental conditions in a cell proliferation test, O. ochengi galectin failed to significantly stimulate peripheral blood mononuclear cells (PBMCs) from O. ochengi-infected cattle, regardless of their parasite load. CONCLUSION: An O. ochengi galectin gene was identified and the recombinantly expressed protein was immunogenic. IgG from Onchocerca-infected humans and cattle showed similar cross-reaction with both respective galectins. The present findings reflect the phylogenetic relationship between the two parasites and endorse the appropriateness of the cattle O. ochengi model for O. volvulus infection research.

Impact of environmental changes on infectious diseases: Key findings from an international conference in Trieste, Italy in May 2017.

Elsevier's 2nd conference on "Impact of Environmental Changes on Infectious Diseases" (IECID), convened in May 2017 in Trieste, Italy, brought together some 120 researchers from more than 20 countries. They presented the latest findings and discussed the impact of current and predicted future environmental changes on infectious disease dynamics in humans, livestock and wildlife in different parts of the world. Particular emphasis was placed on food-, vector- and water-borne diseases within the general theme of infectious diseases of poverty and emerging and re-emerging diseases. The potential impact of mobility, travel, population growth, trade and globalization on infectious disease dynamics against the background of a changing climate, land use, air quality and urbanization on individual, population, ecosystem and planetary health were addressed. Speakers at the conference were encouraged to put forth their talks into stand-alone manuscripts, which resulted in a unique collection of 13 articles, now brought together into a thematic issue of Acta Tropica. In this umbrella piece, we synthesize key findings from the published articles and highlight potential actions that might be taken forward to prevent and mitigate the impact of environmental change on infectious diseases. The work presented is salient in the current era of the Sustainable Development Goals.

Onchocerciasis (river blindness) - more than a century of research and control.

This review summarises more than a century of research on onchocerciasis, also known as river blindness, and its control. River blindness is an infection caused by the tissue filaria Onchocerca volvulus affecting the skin, subcutaneous tissue and eyes and leading to blindness in a minority of infected persons. The parasite is transmitted by its intermediate hosts Simulium spp. which breed in rivers. Featured are history and milestones in onchocerciasis research and control, state-of-the-art data on the parasite, its endobacteria Wolbachia, on the vectors, previous and current prevalence of the infection, its diagnostics, the interaction between the parasite and its host, immune responses and the pathology of onchocerciasis. Detailed information is documented on the time course of control programmes in the afflicted countries in Africa and the Americas, a long road from previous programmes to current successes in control of the transmission of this infectious disease. By development, adjustment and optimization of the control measures, transmission by the vector has been interrupted in foci of countries in the Americas, in Uganda, in Sudan and elsewhere, followed by onchocerciasis eliminations. The current state and future perspectives for control, elimination and eradication within the next 20-30 years are described and discussed. This review contributes to a deeper comprehension of this disease by a tissue-dwelling filaria and it will be helpful in efforts to control and eliminate other filarial infections.

Helminthiases in the People's Republic of China: Status and prospects.

Helminth infections, many of them listed as neglected tropical diseases by the World Health Organization, remain a public health issue in many parts of the world. The People's Republic of China (P.R. China) stands out due to impressive progress in the control and local elimination of helminth infections. An important contextual factor is P.R. China's sustained social and economic development that allowed implementation of health-related poverty alleviation, improving water, sanitation and hygiene, enhancing information, education and communication, coupled with major engineering and infrastructure development and intersectoral collaboration. Nonetheless, food-borne trematodiases, soil-transmitted helminthiases, echinococcosis, cysticercosis/taeniasis and schistosomiasis still exert a considerable burden in P.R. China, even though the numbers of infected people have decreased substantially since the new millennium. This special issue of Acta Tropica provides a comprehensive update of the current knowledge of the main helminth infections in P.R. China, summarises progress in research and discusses future prospects for gaining and sustaining control towards the final goal of breaking transmission and hence, eliminating helminthiases. It consists of 34 articles with a wide coverage that can be grouped into six domains: (i) epidemiological assessment and disease burden estimates; (ii) diagnostics and antigen characterisation; (iii) drug and vaccine development; (iv) host-parasite interactions and snail genetics; (v) surveillance and public health response; and (vi) capacity building and international cooperation. The control and elimination of helminthiases not only furthers the health and wellbeing of the Chinese people, but also provides innovative approaches, tools and strategies, which can be adopted and applied in other countries and regions of the world where helminthiases still prevail.

Onchocerca - infected cattle produce strong antibody responses to excretory-secretory proteins released from adult male Onchocerca ochengi worms.

BACKGROUND: The front line molecules from filarial worms and other nematodes or helminthes are their Excretory-Secretory (ES) products. Their interaction with the host cells, proteins and immune system accounts for the skin and eye pathology or hyposensitivity observed in human onchocerciasis. ES products and adult worms' crude extracts from Onchocerca ochengi, a filarial nematode that infects the African zebu cattle, were utilized in the present study as a model for studying Onchocerca volvulus that causes river blindness in man. METHODS: The ES products were generated from adult male and female worms in vitro and analyzed with poly acrylamide gel electrophoresis (PAGE) and enzyme-linked immunosorbent assay (ELISA) using sera from Onchocerca-infected cattle and humans. The cattle sera were collected from a herd that had been exposed for six years to natural transmission of Onchocerca spp. The expressed reactivity was evaluated and differences analyzed statistically using Kruskal-Wallis rank and Chi-square tests. RESULTS: The gel electrophoretic analyses of 156 ES products from O. ochengi female and male worms and of two somatic extracts from three females and 25 males revealed differences in the protein pattern showing pronounced bands at 15, 30-50 and 75 kDa for male ES proteins and 15, 25 and 40-75 kDa for somatic extracts, respectively and less than 100 kDa for female worms. Proteins in the ES products and somatic extracts from female and male Onchocerca ochengi worms were recognized by IgG in sera from both Onchocerca-exposed cattle and humans. Bovine serum antibodies reacted more strongly with proteins in the somatic extracts than with those in the ES products. Interestingly, the reaction was higher with male ES products than with ES products from female worms, suggesting that the males which migrate from one nodule to another are more exposed to the host immune system than the females which remain encapsulated in intradermal nodules. CONCLUSIONS: This study demonstrates that O. ochengi ES products and, in particular, extracts from male filariae may represent a good source of immunogenic proteins and potential vaccine candidates.

Ecohealth research in Africa: Where from-Where to?

Epidemiological mapping and risk profiling build on the idea that diseases are tied to social-ecological systems that govern the distribution and abundance of transmissible pathogens, vectors and hosts. This is the heart of the emerging field of ecohealth, which examines how biological, cultural, demographic, economic, physical, political and social environments change and how these changes affect the health and wellbeing of humans, animals and ecosystems and the services they provide. This paper is an overview of a special issue of Acta Tropica, whose 15 publications reflect a geographically and epidemiologically diverse landscape of ecohealth. Nowhere is an ecohealth approach better suited than in Africa and its myriad of landscapes that include contexts varying from profuse expanses of tropical rain forests to the world's greatest desert. The publication of African ecohealth-related projects displays a biological, cultural and social diversity in health system contexts and a wide variety of contributions pertaining to different, often neglected, tropical diseases, including brucellosis, Buruli ulcer, fascioliasis, malaria, Q fever, rabies, Rift Valley fever and schistosomiasis. Pursuing an ecohealth approach provides a platform that brings together community members, decision makers, scientists and other stakeholders with a view to understand how ecosystem changes affect health conditions. Taken together, the presentation of this variety of papers dealing with environmental variables associated with health inaugurates the vital concept of ecohealth. By emphasizing that all organisms are part of social-ecological systems, the long-term wellbeing of both people and animals depending on healthy and productive ecosystems is highlighted.

Multifunctional Thioredoxin-Like Protein from the Gastrointestinal Parasitic Nematodes Strongyloides ratti and Trichuris suis Affects Mucosal Homeostasis.

The cellular redox state is important for the regulation of multiple functions and is essential for the maintenance of cellular homeostasis and antioxidant defense. In the excretory/secretory (E/S) products of Strongyloides ratti and Trichuris suis sequences for thioredoxin (Trx) and Trx-like protein (Trx-lp) were identified. To characterize the antioxidant Trx-lp and its interaction with the parasite's mucosal habitat, S. ratti and T. suis Trx-lps were cloned and recombinantly expressed. The primary antioxidative activity was assured by reduction of insulin and IgM. Further analysis applying an in vitro mucosal 3D-cell culture model revealed that the secreted Trx-lps were able to bind to monocytic and intestinal epithelial cells and induce the time-dependent release of cytokines such as TNF-α, IL-22, and TSLP. In addition, the redox proteins also possessed chemotactic activity for monocytic THP-1 cells and fostered epithelial wound healing activity. These results confirm that the parasite-secreted Trx-lps are multifunctional proteins that can affect the host intestinal mucosa.

SPARC (secreted protein acidic and rich in cysteine) of the intestinal nematode Strongyloides ratti is involved in mucosa-associated parasite-host interaction.

The secreted protein acidic and rich in cysteine (SPARC), found in the excretory/secretory products of Strongyloides ratti, is most strongly expressed in parasitic females. Since SPARC proteins are involved in the modulation of cell-matrix interactions, a role of the secreted S. ratti SPARC (Sr-SPARC) in the manifestation of the parasite in the host's intestine is postulated. The full-length cDNA of Sr-SPARC was identified and the protein was recombinantly expressed. The purified protein was biologically active, able to bind calcium, and to attach to mucosa-associated human cells. Addition of Sr-SPARC to an in vitro mucosal three-dimensional-cell culture model led to a time-dependent release of the cytokines TNF-α, IL-22, IL-10 and TSLP. Of importance, exposure with Sr-SPARC fostered wound closure in an intestinal epithelial cell model. Here, we demonstrate for the first time that SPARC released from the nematode is a multifunctional protein affecting the mucosal immune system.

The genomic basis of parasitism in the Strongyloides clade of nematodes.

Soil-transmitted nematodes, including the Strongyloides genus, cause one of the most prevalent neglected tropical diseases. Here we compare the genomes of four Strongyloides species, including the human pathogen Strongyloides stercoralis, and their close relatives that are facultatively parasitic (Parastrongyloides trichosuri) and free-living (Rhabditophanes sp. KR3021). A significant paralogous expansion of key gene families--families encoding astacin-like and SCP/TAPS proteins--is associated with the evolution of parasitism in this clade. Exploiting the unique Strongyloides life cycle, we compare the transcriptomes of the parasitic and free-living stages and find that these same gene families are upregulated in the parasitic stages, underscoring their role in nematode parasitism.

DNA vaccine encoding the moonlighting protein Onchocerca volvulus glyceraldehyde-3-phosphate dehydrogenase (Ov-GAPDH) leads to partial protection in a mouse model of human filariasis.

River blindness, caused by the filarial parasite Onchocerca volvulus, is a major socio-economic and public health problem in Sub-Saharan Africa. In January 2015, The Onchocerciasis Vaccine for Africa (TOVA) Initiative has been launched with the aim of providing new tools to complement mass drug administration (MDA) of ivermectin, thereby promoting elimination of onchocerciasis in Africa. In this context we here present Onchocerca volvulus glyceraldehyde-3-phosphate dehydrogenase (Ov-GAPDH) as a possible DNA vaccine candidate. We report that in a laboratory model for filariasis, immunization with Ov-GAPDH led to a significant reduction of adult worm load and microfilaraemia in BALB/c mice after challenge infection with the filarial parasite Litomosoides sigmodontis. Mice were either vaccinated with Ov-GAPDH.DNA plasmid (Ov-pGAPDH.DNA) alone or in combination with recombinantly expressed Ov-GAPDH protein (Ov-rGAPDH). During the following challenge infection of immunized and control mice with L. sigmodontis, those formulations which included the DNA plasmid, led to a significant reduction of adult worm loads (up to 57% median reduction) and microfilaraemia (up to 94% reduction) in immunized animals. In a further experiment, immunization with a mixture of four overlapping, synthetic Ov-GAPDH peptides (Ov-GAPDHpept), with alum as adjuvant, did not significantly reduce worm loads. Our results indicate that DNA vaccination with Ov-GAPDH has protective potential against filarial challenge infection in the mouse model. This suggests a transfer of the approach into the cattle Onchocerca ochengi model, where it is possible to investigate the effects of this vaccination in the context of a natural host-parasite relationship.

Progress in research, control and elimination of helminth infections in Asia.

Global health has substantially improved over the past 20 years. In low- and middle-income countries, in particular, great strives have been made in the control of communicable diseases, including helminth infections. Nevertheless, the most marginalised communities still suffer from infectious diseases that are intimately connected with poverty and lack of access to essential commodities and services, such as clean water, improved sanitation and sufficient food. A two-pronged approach is thus necessary: (i) intensifying control in remaining high-endemicity areas and pockets of high transmission; and (ii) moving from morbidity control to interruption of disease transmission in low-endemicity areas with the goal of local elimination. The latter will require new tools and strategies, going hand-in-hand with strong partnerships and new strategic alliances. In this special issue of Acta Tropica, 35 articles are featured that, together, provide an up-to-date overview of the latest progress made in research, control and elimination of helminth infections in East and Southeast Asia. The first 12 articles expound tools and approaches for improved detection, surveillance and monitoring of helminth infections. Control and elimination approaches for the most important helminth infections are revisited in the next 20 articles. The three remaining articles are cross-cutting pieces examining the interface of agriculture, environment and helminth infections and providing a rationale for integrated, multi-sectorial control approaches that are necessary for sustaining helminthiasis control and progressively moving towards elimination. An interesting aspect revealed through an in-depth analysis of the provenance of the 35 contributions is that the People's Republic of China emerges as a key player in global health, which is documented through its prominent role in research and control of helminth infection and networking throughout Asia. Policy implications are discussed and will hopefully shape the future agenda for the control and elimination of helminth infections the world over.