Non-malarial febrile illness: a systematic review of published aetiological studies and case reports from China, 1980-2015.

BACKGROUND: Rapid point-of-care tests for malaria are now widely used in many countries to guide the initial clinical management of patients presenting with febrile illness. With China having recently achieved malaria elimination, better understanding regarding the identity and distribution of major non-malarial causes of febrile illnesses is of particular importance to inform evidence-based empirical treatment policy. METHODS: A systematic review of published literature was undertaken to characterise the spectrum of pathogens causing non-malaria febrile illness in China (1980-2015). Literature searches were conducted in English and Chinese languages in six databases: Ovid MEDLINE, Global Health, EMBASE, Web of Science™ - Chinese Science Citation Database SM, The China National Knowledge Infrastructure (CNKI), and WanFang Med Online. Selection criteria included reporting on an infection or infections with a confirmed diagnosis, defined as pathogens detected in or cultured from samples from normally sterile sites, or serological evidence of current or past infection. The number of published articles, reporting a given pathogen were presented, rather than incidence or prevalence of infection. RESULTS: A total of 57,181 records from 13 provinces of China where malaria used to be endemic were screened, of which 392 met selection criteria and were included in this review. The review includes 60 (15.3%) records published from 1980 to 2000, 211 (53.8%) from 2001 to 2010 and 121 (30.9%) from 2011 to 2015;. Of the 392 records, 166 (42.3%) were from the eastern region of China, 120 (30.6%) were from the south-west, 102 (26.0%) from south-central, and four (1.0%) were multi-regional studies. Bacterial infections were reported in 154 (39.3%) records, viral infections in 219 (55.9%), parasitic infections in four (1.0%), fungal infections in one (0.3%), and 14 (3.6%) publications reported more than one pathogen group. Participants of all ages were included in 136 (34.7%) studies, only adults in 75 (19.1%), only children in 17 (4.3%), only neonates in two (0.5%) and the age distribution was not specified in 162 (41.3%) records. The most commonly reported bacterial pathogens included Typhoidal Salmonella (n = 30), Orientia/ Rickettsia tsutsugamushi (n = 31), Coxiella burnetii (n = 17), Leptospira spp. (n = 15) and Brucella spp. (n = 15). The most commonly reported viral pathogens included Hantavirus/Hantaan virus (n = 89), dengue virus (DENV) (n = 76 including those with unknown serovars), Japanese encephalitis virus (n = 21), and measles virus (n = 15). The relative lack of data in the western region of the country, as well as in in neonates and children, represented major gaps in the understanding of the aetiology of fever in China. CONCLUSIONS: This review presents a landscape of non-malaria pathogens causing febrile illness in China over 36 years as the country progressed toward malaria elimination. These findings can inform guidelines for clinical management of fever cases and infection surveillance and prevention, and highlight the need to standardize operational and reporting protocols for better understanding of fever aetiology in the country.

Non-malarial febrile illness: a systematic review of published aetiological studies and case reports from Southern Asia and South-eastern Asia, 1980-2015.

BACKGROUND: In the absence of definitive diagnosis, healthcare providers are likely to prescribe empirical antibacterials to those who test negative for malaria. This problem is of critical importance in Southern Asia (SA) and South-eastern Asia (SEA) where high levels of antimicrobial consumption and high prevalence of antimicrobial resistance have been reported. To improve management and guide further diagnostic test development, better understanding is needed of the true causative agents of fever and their geographical variability. METHODS: We conducted a systematic review of published literature (1980-2015) to characterise the spectrum of pathogens causing non-malarial febrile illness in SA and SEA. We searched six databases in English and French languages: MEDLINE, EMBASE, Global Health (CABI) database, WHO Global Health Library, PASCAL, and Bulletin de la Société Française de Parasitologie (BDSP). Selection criteria included reporting on an infection or infections with a confirmed diagnosis, defined as pathogens detected in or cultured from samples from normally sterile sites, or serological evidence of current or past infection. RESULTS: A total of 29,558 records from 19 countries in SA and SEA were screened, of which 2410 (8.1%) met the selection criteria. Bacterial aetiologies were reported in 1235 (51.2%) articles, viral in 846 (35.1%), parasitic in 132 (5.5%), and fungal in 54 (2.2%), and 143 (6.0%) articles reported more than one pathogen group. In descending order of frequency, Salmonella Typhi, Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, and coagulase negative Staphylococcus were the commonly reported bacteria, while dengue virus, chikungunya virus, Japanese encephalitis virus, hepatitis B virus, and hepatitis C virus were common viral pathogens reported. Reports of rarely reported or emerging pathogens included a case report of Borrelia burgdorferi (Lyme disease) in India in 2010 and reports of Nipah virus in Singapore and India. CONCLUSIONS: This review summarises the reported non-malaria pathogens that may cause febrile illness in SA and SEA. The findings emphasise the need of standardising the reporting of aetiological studies to develop effective, evidence-based fever management and improved surveillance. Research and development of diagnostic tools would benefit from up-to-date epidemiological reporting of the regional diversities of non-malaria fever aetiologies. TRIAL REGISTRATION: PROSPERO registration, CRD42016049281.

Non-malarial febrile illness: a systematic review of published aetiological studies and case reports from Africa, 1980-2015.

BACKGROUND: The availability of reliable point-of-care tests for malaria has heralded a paradigm shift in the management of febrile illnesses away from presumptive antimalarial therapy. In the absence of a definitive diagnosis, health care providers are more likely to prescribe empirical antimicrobials to those who test negative for malaria. To improve management and guide further test development, better understanding is needed of the true causative agents and their geographic variability. METHODS: A systematic review of published literature was undertaken to characterise the spectrum of pathogens causing non-malaria febrile illness in Africa (1980-2015). Literature searches were conducted in English and French languages in six databases: MEDLINE, EMBASE, Global Health (CABI), WHO Global Health Library, PASCAL, and Bulletin de la Société Française de Parasitologie (BDSP). Selection criteria included reporting on an infection or infections with a confirmed diagnosis, defined as pathogens detected in or cultured from samples from normally sterile sites, or serological evidence of current or past infection. A number of published articles (rather than incidence or prevalence) reporting a given pathogen were presented. RESULTS: A total of 16,523 records from 48 African countries were screened, of which 1065 (6.4%) met selection criteria. Bacterial infections were reported in 564 (53.0%) records, viral infections in 374 (35.1%), parasitic infections in 47 (4.4%), fungal infections in nine (0.8%), and 71 (6.7%) publications reported more than one pathogen group. Age range of the study population was not specified in 233 (21.9%) publications. Staphylococcus aureus (18.2%), non-typhoidal Salmonella (17.3%), and Escherichia coli (15.4%) were the commonly reported bacterial infections whereas Rift Valley fever virus (7.4%), yellow fever virus (7.0%), and Ebola virus (6.7%) were the most commonly reported viral infections. Dengue virus infection, previously not thought to be widespread in Africa, was reported in 54 (5.1%) of articles. CONCLUSIONS: This review summarises the published reports of non-malaria pathogens that may cause febrile illness in Africa. As the threat of antimicrobial resistance looms, knowledge of the distribution of infectious agents causing fever should facilitate priority setting in the development of new diagnostic tools and improved antimicrobial stewardship. TRIAL REGISTRATION: PROSPERO, CRD42016049281.

An online mapping database of molecular markers of drug resistance in Plasmodium falciparum: the ACT Partner Drug Molecular Surveyor.

BACKGROUND: Prior to this project, only a handful of online visualizations existed for exploring the published literature on molecular markers of antimalarial drug resistance, and none specifically for the markers associated with Plasmodium falciparum resistance to the partner drugs in artemisinin-based combination therapy (ACT). Molecular information is collected in studies with different designs, using a variety of molecular methodologies and data analysis strategies, making it difficult to compare across studies. The purpose of this project was to develop a free online tool, which visualizes the widely published data on molecular markers of antimalarial drug resistance, starting with the two genes pfcrt and pfmdr-1, associated with resistance to the three most common partner drugs; amodiaquine, lumefantrine and mefloquine. METHODS: A literature review was conducted, and a standardized method was used to extract data from publications, and critical decisions on visualization were made. A global geospatial database was developed of specific pfmdr1 and pfcrt single nucleotide polymorphisms and pfmdr1 copy number variation. An informatics framework was developed that allowed flexibility in development of the tool over time and efficient adaptation to different source data. RESULTS: The database discussed in this paper has pfmdr1 and pfcrt marker prevalence information, from 579 geographic sites in 76 different countries, including results from over 86,000 samples from 456 articles published January 2001-May 2017. The ACT Partner Drugs Molecular Surveyor was launched by the WorldWide Antimalarial Resistance Network (WWARN) in March 2015 and it has attracted over 3000 unique visitors since then. Presented here is a demonstration of how the Surveyor database can be explored to monitor local, temporal changes in the prevalence of molecular markers. Here publications up to May 2017 were included, however the online ACT partner drug Molecular Surveyor is continuously updated with new data and relevant markers. CONCLUSIONS: The WWARN ACT Partner Drugs Molecular Surveyor summarizes data on resistance markers in the pfmdr1 and pfcrt genes. The database is fully accessible, providing users with a rich resource to explore and analyze, and thus utilize a centralized, standardized database for different purposes. This open-source software framework can be adapted to other data, as demonstrated by the subsequent launch of the Artemisinin Molecular Surveyor and the Vivax Surveyor.

An inventory of supranational antimicrobial resistance surveillance networks involving low- and middle-income countries since 2000.

Low- and middle-income countries (LMICs) shoulder the bulk of the global burden of infectious diseases and drug resistance. We searched for supranational networks performing antimicrobial resistance (AMR) surveillance in LMICs and assessed their organization, methodology, impacts and challenges. Since 2000, 72 supranational networks for AMR surveillance in bacteria, fungi, HIV, TB and malaria have been created that have involved LMICs, of which 34 are ongoing. The median (range) duration of the networks was 6 years (1-70) and the number of LMICs included was 8 (1-67). Networks were categorized as WHO/governmental (n = 26), academic (n = 24) or pharma initiated (n = 22). Funding sources varied, with 30 networks receiving public or WHO funding, 25 corporate, 13 trust or foundation, and 4 funded from more than one source. The leading global programmes for drug resistance surveillance in TB, malaria and HIV gather data in LMICs through periodic active surveillance efforts or combined active and passive approaches. The biggest challenges faced by these networks has been achieving high coverage across LMICs and complying with the recommended frequency of reporting. Obtaining high quality, representative surveillance data in LMICs is challenging. Antibiotic resistance surveillance requires a level of laboratory infrastructure and training that is not widely available in LMICs. The nascent Global Antimicrobial Resistance Surveillance System (GLASS) aims to build up passive surveillance in all member states. Past experience suggests complementary active approaches may be needed in many LMICs if representative, clinically relevant, meaningful data are to be obtained. Maintaining an up-to-date registry of networks would promote a more coordinated approach to surveillance.

Scrub typhus ecology: a systematic review of Orientia in vectors and hosts.

Scrub typhus, caused by Orientia tsutsugamushi, is an important and neglected vector-borne zoonotic disease with an expanding known distribution. The ecology of the disease is complex and poorly understood, impairing discussion of public health interventions. To highlight what we know and the themes of our ignorance, we conducted a systematic review of all studies investigating the pathogen in vectors and non-human hosts. A total of 276 articles in 7 languages were included, with 793 study sites across 30 countries. There was no time restriction for article inclusion, with the oldest published in 1924. Seventy-six potential vector species and 234 vertebrate host species were tested, accounting for over one million trombiculid mites ('chiggers') and 83,000 vertebrates. The proportion of O. tsutsugamushi positivity was recorded for different categories of laboratory test and host species. Vector and host collection sites were geocoded and mapped. Ecological data associated with these sites were summarised. A further 145 articles encompassing general themes of scrub typhus ecology were reviewed. These topics range from the life-cycle to transmission, habitats, seasonality and human risks. Important gaps in our understanding are highlighted together with possible tools to begin to unravel these. Many of the data reported are highly variable and inconsistent and minimum data reporting standards are proposed. With more recent reports of human Orientia sp. infection in the Middle East and South America and enormous advances in research technology over recent decades, this comprehensive review provides a detailed summary of work investigating this pathogen in vectors and non-human hosts and updates current understanding of the complex ecology of scrub typhus. A better understanding of scrub typhus ecology has important relevance to ongoing research into improving diagnostics, developing vaccines and identifying useful public health interventions to reduce the burden of the disease.