Sören L. Becker

New diagnostic tools in schistosomiasis

Schistosomiasis is a water-based parasitic disease that affects over 250 million people. Control efforts have long been in vain, which is one reason why schistosomiasis is considered a neglected tropical disease. However, since the new millennium, interventions against schistosomiasis are escalating. The initial impetus stems from a 2001 World Health Assembly resolution, urging member states to scale-up deworming of school-aged children with the anthelminthic drug praziquantel. Because praziquantel is safe, efficacious and inexpensive when delivered through the school platform, diagnosis before drug intervention was deemed unnecessary and not cost-effective. Hence, there was little interest in research and development of novel diagnostic tools. With the recent publication of the World Health Organization (WHO) Roadmap to overcome the impact of neglected tropical diseases in 2020, we have entered a new era. Elimination of schistosomiasis has become the buzzword and this has important ramifications for diagnostic tools. Indeed, measuring progress towards the WHO Roadmap and whether local elimination has been achieved requires highly accurate diagnostic assays. Here, we introduce target product profiles for diagnostic tools that are required for different stages of a schistosomiasis control programme. We provide an update of the latest developments in schistosomiasis diagnosis, including microscopic techniques, rapid diagnostic tests for antigen detection, polymerase chain reaction (PCR) assays and proxy markers for morbidity assessments. Particular emphasis is placed on challenges and solutions for new technologies to enter clinical practice.

Persistent digestive disorders in the tropics: causative infectious pathogens and reference diagnostic tests

BackgroundPersistent digestive disorders account for considerable disease burden in the tropics. Despite advances in understanding acute gastrointestinal infections, important issues concerning epidemiology, diagnosis, treatment and control of most persistent digestive symptomatologies remain to be elucidated. Helminths and intestinal protozoa are considered to play major roles, but the full extent of the aetiologic spectrum is still unclear. We provide an overview of pathogens causing digestive disorders in the tropics and evaluate available reference tests.MethodsWe searched the literature to identify pathogens that might give rise to persistent diarrhoea, chronic abdominal pain and/or blood in the stool. We reviewed existing laboratory diagnostic methods for each pathogen and stratified them by (i) microscopy; (ii) culture techniques; (iii) immunological tests; and (iv) molecular methods. Pathogen-specific reference tests providing highest diagnostic accuracy are described in greater detail.ResultsOver 30 pathogens may cause persistent digestive disorders. Bacteria, viruses and parasites are important aetiologic agents of acute and long-lasting symptomatologies. An integrated approach, consisting of stool culture, microscopy and/or specific immunological techniques for toxin, antigen and antibody detection, is required for accurate diagnosis of bacteria and parasites. Molecular techniques are essential for sensitive diagnosis of many viruses, bacteria and intestinal protozoa, and are increasingly utilised as adjuncts for helminth identification.ConclusionsDiagnosis of the broad spectrum of intestinal pathogens is often cumbersome. There is a need for rapid diagnostic tests that are simple and affordable for resource-constrained settings, so that the management of patients suffering from persistent digestive disorders can be improved.

Diagnosis and treatment of schistosomiasis in children in the era of intensified control

In the current era of intensified and integrated control against schistosomiasis and other neglected tropical diseases, there is a need to carefully rethink and take into consideration disease-specific issues pertaining to the diagnosis, prevention, control and local elimination. Here, we present a comprehensive overview about schistosomiasis including recent trends in the number of people treated with praziquantel and the latest developments in diagnosis and control. Particular emphasis is placed on children. Identified research needs are offered for consideration; namely, expanding our knowledge about schistosomiasis in preschool-aged children, assessing and quantifying the impact of schistosomiasis on infectious and noncommunicable diseases, developing new antischistosomal drugs and child-friendly formulations, designing and implementing setting-specific control packages and developing highly sensitive, but simple diagnostic tools that are able to detect very light infections in young children and in people living in areas targeted for schistosomiasis elimination.

StrongNet: An International Network to Improve Diagnostics and Access to Treatment for Strongyloidiasis Control

Strongyloidiasis is a disease caused by an infection with a soil-transmitted helminth that affects, according to largely varying estimates, between 30 million and 370 million people worldwide [1,2]. Not officially listed as a neglected tropical disease (NTD), strongyloidiasis stands out as particularly overlooked [3]. Indeed, there is a paucity of research and public health efforts pertaining to strongyloidiasis. Hence, clinical, diagnostic, epidemiologic, treatment, and control aspects are not adequately addressed to allow for an effective management of the disease, both in clinical medicine and in public health programs [4]. The manifold signs and symptoms caused by Strongyloides stercoralis infection, coupled with the helminth’s unique potential to cause lifelong, persistent infection, make strongyloidiasis relevant beyond tropical and subtropical geographic regions, where, however, most of the disease burden is concentrated. Indeed, strongyloidiasis is acquired through contact with contaminated soil, and the infection is, thus, primarily transmitted in areas with poor sanitation, inadequate access to clean water, and lack of hygiene. While the actual morbidity of chronically infected, immunocompetent individuals is subtle and difficult to appreciate [5], the particular importance of this parasitic worm is linked to its potential for maintaining lifelong autoinfections and causing a life-threatening hyperinfection syndrome in immunocompromised individuals [6]. Lack of point-of-care (POC) diagnostics and poor availability of, and access to, ivermectin (the current treatment of choice) are the two most significant bottlenecks that hinder effective management of the disease both in clinical and in public health settings. Examples of the management and importance of strongyloidiasis in two clinical contexts (in a tropical setting and a high-income country) and from a public health perspective are given in Boxes 1–3. Box 1. Individual Living in an Endemic Area with Diarrhea, Abdominal Pain, Pruritus, and Significant Dermatological Manifestations [10] A 43-year-old male farmer, living in the rural eastern part of Preah Vihear province, northern Cambodia, was diagnosed with a heavy Strongyloides stercoralis infection (924 and 478 larvae present in two Baermann examinations). Additionally, larvae and adult S. stercoralis were detected in Koga agar plate culture examinations of the stools. The patient was co-infected with hookworm and presented with abdominal pain, diarrhea, nausea, vomiting, fever, and a pronounced and persistent skin rash, which had been present with extensive itching for more than two years. The rash was observed on the back, chest, abdomen, and extremities and, due to frequent and intense scratching, showed signs of focal infection. Three weeks after treatment with a single oral dose of ivermectin (200 μg/kg) and a single oral dose of mebendazole, the patient’s rash had almost disappeared, and he was free of episodes of intensive itching.

The use of portable ultrasound devices in low- and middle-income countries: a systematic review of the literature.

To review the scientific literature pertaining to the use of hand‐carried and hand‐held ultrasound devices in low‐ and middle‐income countries (LMIC), with a focus on clinical applications, geographical areas of use, the impact on patient management and technical features of the devices used.

Clinical implications of Mycobacterium chimaera detection in thermoregulatory devices used for extracorporeal membrane oxygenation (ECMO), Germany, 2015 to 2016

Mycobacterium chimaera, a non-tuberculous mycobacterium, was recently identified as causative agent of deep-seated infections in patients who had previously undergone open-chest cardiac surgery. Outbreak investigations suggested an aerosol-borne pathogen transmission originating from water contained in heater-cooler units (HCUs) used during cardiac surgery. Similar thermoregulatory devices are used for extracorporeal membrane oxygenation (ECMO) and M. chimaera might also be detectable in ECMO treatment settings. We performed a prospective microbiological study investigating the occurrence of M. chimaera in water from ECMO systems and in environmental samples, and a retrospective clinical review of possible ECMO-related mycobacterial infections among patients in a pneumological intensive care unit. We detected M. chimaera in 9 of 18 water samples from 10 different thermoregulatory ECMO devices; no mycobacteria were found in the nine room air samples and other environmental samples. Among 118 ECMO patients, 76 had bronchial specimens analysed for mycobacteria and M. chimaera was found in three individuals without signs of mycobacterial infection at the time of sampling. We conclude that M. chimaera can be detected in water samples from ECMO-associated thermoregulatory devices and might potentially pose patients at risk of infection. Further research is warranted to elucidate the clinical significance of M. chimaera in ECMO treatment settings.

Application in Europe of a urine-based rapid diagnostic test for confirmation of Schistosoma mansoni infection in migrants from endemic areas.

In February 2015, a male patient from Eritrea with persistent abdominal pain and rectal bleeding was diagnosed with Schistosoma mansoni infection upon examination of a rectal biopsy. In May 2015, repeated stool microscopy identified S. mansoni infection in another Eritrean patient with abdominal pain and considerable eosinophilia (34%). Use of point-of-care circulating cathodic antigen (POC-CCA) tests on urine confirmed S. mansoni infection in both patients. Wider application of non-invasive POC-CCA urine tests will improve schistosomiasis diagnosis and clinical management in migrants.

Experiences and Lessons from a Multicountry NIDIAG Study on Persistent Digestive Disorders in the Tropics.

Persistent digestive disorders can be defined as any diarrhea (i.e., three or more loose stools per day) lasting for at least two weeks and/or abdominal pain that persists for two weeks or longer [1–3]. These disorders cause considerable morbidity and human suffering, and hence, are reasons why people might seek primary health care. However, in resource-constrained settings of the tropics and subtropics, accurate point-of-care diagnostics are often lacking and treatment is empiric, particularly in remote rural areas with no laboratory infrastructure. As a result, the relative contribution of selected pathogens to the syndrome of persistent digestive disorders is poorly understood, and evidence-based guidelines for patient management in different social-ecological settings are scarce [4–6]. In order to improve the clinical management of patients with disorders caused by neglected tropical diseases (NTDs), the European Commission (EC) funded a five-year study—the Neglected Infectious diseases DIAGnosis (NIDIAG) research consortium. The overarching goal of the NIDIAG consortium is to develop and validate patient-centered diagnosis–treatment guidelines for use at the primary health care level in low- and middle-income countries (http://www.nidiag.org) [3,7–9]. Emphasis is placed on three syndromes: (i) persistent digestive disorders described here; (ii) persistent fever; and (iii) neurological disorders, the latter two of which are detailed in companion pieces published in the same issue of PLOS Neglected Tropical Diseases. With regard to the study on persistent digestive disorders, the main aims are (i) to identify the most important NTDs and other infectious agents that give rise to this clinical syndrome, including their relative frequency; (ii) to assess and compare the accuracy of different diagnostic methods; and (iii) to determine clinical responses to commonly employed empiric treatment options for persistent digestive disorders [9]. To this end, a case–control study has been implemented in four countries: Cote d’Ivoire and Mali in West Africa and Indonesia and Nepal in Asia. An integral part of the NIDIAG consortium is to ensure that good clinical practice (GCP) and good clinical laboratory practice (GCLP) are adhered to while conducting the studies [10,11]. A quality assurance system, which included the development and implementation of a set of standard operating procedures (SOPs), along with on-the-spot staff training and internal and external quality control activities, has been developed at the project level and introduced at each study site. The development of, and adherence to, SOPs within harmonized study protocols were considered crucial steps for maximizing the integrity of laboratory and clinical data across study settings. They also provided the basis on which quality control activities could be performed. For Which Procedures Have SOPs Been Developed? For the study on persistent digestive disorders, 33 specific SOPs have been developed (Supporting Information). As summarized in Table 1, detailed steps on clinical and laboratory procedures, data management, and quality assurance were described. With regard to clinical investigations, SOPs on history taking and clinical examination, assessing inclusion and exclusion criteria, patient recruitment, and study flow were developed (S1-S6). Detailed instructions on how to perform a set of laboratory diagnostic techniques for the detection of helminth and intestinal protozoa infections were included in the laboratory SOPs. Different conventional stool microscopy techniques were combined with more recent rapid antigen detection tests to encompass a broad spectrum of potentially implicated pathogens with high diagnostic accuracy (S7-S20). An overview of the employed diagnostic methods is provided in Table 2. Pertaining to data management, SOPs on completion of case report forms (CRFs) and on various activities (such as data entry, data cleaning, querying, database locking, and backing up data) were also included. To ensure quality control, SOPs on internal quality control activities, external monitoring, and laboratory supervision visits were jointly developed for the three syndromes (S21-S33). Table 1 Set of standard operating procedures (SOPs) used in the NIDIAG study on persistent digestive disorders. Table 2 Laboratory diagnostic techniques used and internally compared in the NIDIAG study on persistent digestive disorders. Of note, all SOPs were developed in English (for use in Nepal) and subsequently translated into French (for use in Cote d’Ivoire and Mali) and Bahasa Indonesia (for use in Indonesia). This comprehensive set of closely interconnected SOPs—which provides guidance on all essential procedures from the first presentation of an individual at a health care center until the final processing of all patient and laboratory data—is displayed in Fig 1. Fig 1 Principal elements of the NIDIAG digestive study and the respective standard operating procedures (SOPs) used. How Was the Development of SOPs Coordinated, and Which Quality Control Measures Were Adopted? The development and harmonization of the various SOPs was coordinated by the quality assurance group of the NIDIAG consortium and the trial management group (TMG) of the digestive syndrome study and followed a standard template and consortium-wide guidelines stipulated in the SOP entitled “SOP on SOP” (S24). This allowed different authors with varied background and writing styles to convey key messages and pass on their expert knowledge in a systematic, standardized manner for the benefit of the end user of all the SOPs. In addition, it provided clear instructions on how the SOPs should be numbered, reviewed, and approved to allow for strict version control. The authors of the SOPs were chosen from within the NIDIAG consortium, and allocation of topics was based on expertise and track record in the clinical, laboratory, data management, and quality assurance components of the study. Experts in the field, at the bench, and at the bedside carefully reviewed and revised the draft SOPs. Before the start of recruitment, local clinical and laboratory teams were trained on the set of SOPs through two hands-on workshops lasting three days each that were conducted on site by relevant experts of the NIDIAG consortium. During these workshops, feedback from the local partners was incorporated to refine the already developed SOPs, and additional SOPs were jointly developed to meet specific demands of local clinical, epidemiologic, and laboratory conditions. For example, in Indonesia, where Kinyoun staining was not available, an SOP pertaining to a slightly modified acid-fast staining technique was developed for the local team instead. Finally, once an SOP was finalized, a member of the TMG would approve it. A quality assurance member of the NIDIAG consortium was tasked to compile and keep updated the final set of SOPs and ensure that the latest versions were available on the NIDIAG intranet for distribution among the different country partners.

Reply: Epidemiologic studies need asymptomatic controls

S. L. Becker, F. Chappuis, K. Polman, E. K. N’Goran, L. von Muller and J. Utzinger 1) Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, 2) University of Basel, Basel, Switzerland, 3) Institute of Medical Microbiology and Hygiene, Saarland University Medical Center, Homburg/Saar, Germany, 4) Division of Tropical and Humanitarian Medicine, Geneva University Hospitals, Geneva, Switzerland, 5) Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium, 6) Departement Environnement et Sante, Centre Suisse de Recherches Scientifiques en Cote d’Ivoire and 7) Unite de Formation et de Recherche Biosciences, Universite Felix Houphouet-Boigny, Abidjan, Cote d’Ivoire

Epidemiology of community-onset bloodstream infections in Bouaké, central Côte d’Ivoire

Bacterial bloodstream infections (BSI) account for considerable morbidity worldwide, but epidemiological data from resource-constrained tropical settings are scarce. We analysed 293 blood cultures from patients presenting to a regional referral hospital in Bouaké, central Côte d’Ivoire, to determine the aetiology of community-onset BSI. The prevalence of bacteraemia was 22.5%, with children being most commonly affected. Enterobacteriaceae (predominantly Klebsiella pneumoniae and Salmonella enterica) accounted for 94% of BSI. Staphylococcus aureus was the only relevant Gram-positive pathogen. Clinical signs and symptoms were not significantly associated with blood culture positivity after controlling for malaria.