• The case for improved diagnostic tools to control Ebola Virus Disease in West Africa and how to get there

      Chua, Arlene C; Cunningham, Jane; Moussy, Francis; Perkins, Mark D; Formenty, Pierre (Public Library of Science, 2015-06-11)
    • Challenges in Preparing and Implementing a Clinical Trial at Field Level in an Ebola Emergency: A Case Study in Guinea, West Africa

      Carazo Perez, S; Folkesson, E; Anglaret, X; Beavogui, A; Berbain, E; Camara, A; Depoortere, E; Lefevre, A; Maes, P; Malme, K; et al. (Public Library of Science, 2017-06-22)
      During the large Ebola outbreak that affected West Africa in 2014 and 2015, studies were launched to evaluate potential treatments for the disease. A clinical trial to evaluate the effectiveness of the antiviral drug favipiravir was conducted in Guinea. This paper describes the main challenges of the implementation of the trial in the Ebola treatment center of Guéckédou. Following the principles of the Good Clinical Research Practices, we explored the aspects of the community's communication and engagement, ethical conduct, trial protocol compliance, informed consent of participants, ongoing benefit/risk assessment, record keeping, confidentiality of patients and study data, and roles and responsibilities of the actors involved. We concluded that several challenges have to be addressed to successfully implement a clinical trial during an international medical emergency but that the potential for collaboration between research teams and humanitarian organizations needs to be highlighted.
    • Cholera Rapid Test with Enrichment Step Has Diagnostic Performance Equivalent to Culture

      Ontweka, LN; Deng, LO; Rauzier, J; Debes, AK; Tadesse, F; Parker, LA; Wamala, JF; Bior, BK; Lasuba, M; But, AB; et al. (Public Library of Science, 2016-12-19)
      Cholera rapid diagnostic tests (RDT) could play a central role in outbreak detection and surveillance in low-resource settings, but their modest performance has hindered their broad adoption. The addition of an enrichment step may improve test specificity. We describe the results of a prospective diagnostic evaluation of the Crystal VC RDT (Span Diagnostics, India) with enrichment step and of culture, each compared to polymerase chain reaction (PCR), during a cholera outbreak in South Sudan. RDTs were performed on alkaline peptone water inoculated with stool and incubated for 4-6 hours at ambient temperature. Cholera culture was performed from wet filter paper inoculated with stool. Molecular detection of Vibrio cholerae O1 by PCR was done from dry Whatman 903 filter papers inoculated with stool, and from wet filter paper supernatant. In August and September 2015, 101 consecutive suspected cholera cases were enrolled, of which 36 were confirmed by PCR. The enriched RDT had 86.1% (95% CI: 70.5-95.3) sensitivity and 100% (95% CI: 94.4-100) specificity compared to PCR as the reference standard. The sensitivity of culture versus PCR was 83.3% (95% CI: 67.2-93.6) for culture performed on site and 72.2% (95% CI: 54.8-85.8) at the international reference laboratory, where samples were tested after an average delay of two months after sample collection, and specificity was 98.5% (95% CI: 91.7-100) and 100% (95% CI: 94.5-100), respectively. The RDT with enrichment showed performance comparable to that of culture and could be a sustainable alternative to culture confirmation where laboratory capacity is limited.
    • Clinical Features and Risk Factors of Oedematous Mycobacterium ulcerans Lesions in an Australian Population: Beware Cellulitis in an Endemic Area

      O'Brien, Daniel P; Friedman, N Deborah; McDonald, Anthony; Callan, Peter; Hughes, Andrew; Athan, Eugene (Public Library of Science, 2014)
      Oedematous lesions are a less common but more severe form of Mycobacterium ulcerans disease. Misdiagnosis as bacterial cellulitis can lead to delays in treatment. We report the first comprehensive descriptions of the clinical features and risk factors of patients with oedematous disease from the Bellarine Peninsula of south-eastern Victoria, Australia.
    • Cryptococcal antigen screening by lay cadres using a rapid test at the point of care: A feasibility study in rural Lesotho

      Rick, F; Niyibizi, AA; Shroufi, A; Onami, K; Steele, SJ; Kuleile, M; Muleya, I; Chiller, T; Walker, T; Van Cutsem, G (Public Library of Science, 2017-09-06)
      Cryptococcal meningitis is one of the leading causes of death among people with HIV in Africa, primarily due to delayed presentation, poor availability and high cost of treatment. Routine cryptococcal antigen (CrAg) screening of patients with a CD4 count less than 100 cells/mm3, followed by pre-emptive therapy if positive, might reduce mortality in high prevalence settings. Using the cryptococcal antigen (CrAg) lateral flow assay (LFA), screening is possible at the point of care (POC). However, critical shortages of health staff may limit adoption. This study investigates the feasibility of lay counsellors conducting CrAg LFA screening in rural primary care clinics in Lesotho.
    • Cryptococcal Meningitis: A Neglected NTD?

      Molloy, S; Chiller, T; Greene, G; Burry, J; Govender, N; Kanyama, C; Mfinanga, S; Lesikari, S; Mapoure, Y; Kouanfack, C; et al. (Public Library of Science, 2017-06-29)
    • Descriptive Epidemiology of Typhoid Fever during an Epidemic in Harare, Zimbabwe, 2012

      Polonsky, Jonathan A; Martínez-Pino, Isabel; Nackers, Fabienne; Chonzi, Prosper; Manangazira, Portia; Van Herp, Michel; Maes, Peter; Porten, Klaudia; Luquero, Francisco J (Public Library of Science, 2014-12-08)
      Typhoid fever remains a significant public health problem in developing countries. In October 2011, a typhoid fever epidemic was declared in Harare, Zimbabwe - the fourth enteric infection epidemic since 2008. To orient control activities, we described the epidemiology and spatiotemporal clustering of the epidemic in Dzivaresekwa and Kuwadzana, the two most affected suburbs of Harare.
    • Development of Diagnostics for Chagas Disease: Where Should We Put Our Limited Resources?

      Picado, A; Angheben, A; Marchiol, A; Alarcón de Noya, B; Flevaud, L; Pinazo, MJ; Gállego, M; Meymandi, S; Moriana, S (Public Library of Science, 2017-01-05)
    • Drivers for Rift Valley fever emergence in Mayotte: A Bayesian modelling approach

      Métras, R; Fournié, G; Dommergues, L; Camacho, A; Cavalerie, L; Mérot, P; Keeling, MJ; Cêtre-Sossah, C; Cardinale, E; Edmunds, WJ (Public Library of Science, 2017-07-21)
      Rift Valley fever (RVF) is a major zoonotic and arboviral hemorrhagic fever. The conditions leading to RVF epidemics are still unclear, and the relative role of climatic and anthropogenic factors may vary between ecosystems. Here, we estimate the most likely scenario that led to RVF emergence on the island of Mayotte, following the 2006-2007 African epidemic. We developed the first mathematical model for RVF that accounts for climate, animal imports and livestock susceptibility, which is fitted to a 12-years dataset. RVF emergence was found to be triggered by the import of infectious animals, whilst transmissibility was approximated as a linear or exponential function of vegetation density. Model forecasts indicated a very low probability of virus endemicity in 2017, and therefore of re-emergence in a closed system (i.e. without import of infected animals). However, the very high proportion of naive animals reached in 2016 implies that the island remains vulnerable to the import of infectious animals. We recommend reinforcing surveillance in livestock, should RVF be reported is neighbouring territories. Our model should be tested elsewhere, with ecosystem-specific data.
    • Early onset of neurological features differentiates two outbreaks of Lassa fever in Ebonyi state, Nigeria during 2017-2018.

      Chika-Igwenyi, NM; Harrison, RE; Psarra, C; Gil Cuesta, J; Gulamhusein, M; Onwe, EO; Onoh, RC; Unigwe, US; Ajayi, NA; Nndadozie, UU; et al. (Public Library of Science, 2021-03-08)
      Lassa fever (LF) is an acute viral haemorrhagic illness with various non-specific clinical manifestations. Neurological symptoms are rare at the early stage of the disease, but may be seen in late stages, in severely ill patients.The aim of this study was to describe the epidemiological evolution, socio-demographic profiles, clinical characteristics, and outcomes of patients seen during two Lassa fever outbreaks in Ebonyi State, between December 2017 and December 2018. Routinely collected clinical data from all patients admitted to the Virology Centre of the hospital during the period were analysed retrospectively. Out of a total of 83 cases, 70(84.3%) were RT-PCR confirmed while 13 (15.7%) were probable cases. Sixty-nine (83.1%) patients were seen in outbreak 1 of whom 53.6% were urban residents, while 19%, 15%, and 10% were farmers, students and health workers respectively. There were 14 (16.8%) patients, seen in second outbreak with 92.9% rural residents. There were differences in clinical symptoms, signs and laboratory findings between the two outbreaks. The case fatality rates were 29.9% in outbreak 1 and 85.7% for outbreak 2. Neurological features and abnormal laboratory test results were associated with higher mortality rate, seen in outbreak 2. This study revealed significant differences between the two outbreaks. Of particular concern was the higher case fatality during the outbreak 2 which may be from a more virulent strain of the Lassa virus. This has important public health implications and further molecular studies are needed to better define its characteristics.
    • Ebola Management Centre Proximity Associated With Reduced Delays of Healthcare of Ebola Virus Disease (EVD) Patients, Tonkolili, Sierra Leone, 2014-15

      Theocharopoulos, G; Danis, K; Greig, J; Hoffmann, A; De Valk, H; Jimissa, A; Tejan, S; Sankoh, M; Kleijer, K; Turner, W; et al. (Public Library of Science, 2017-05-01)
      Between August-December 2014, Ebola Virus Disease (EVD) patients from Tonkolili District were referred for care to two Médecins Sans Frontières (MSF) Ebola Management Centres (EMCs) outside the district (distant EMCs). In December 2014, MSF opened an EMC in Tonkolili District (district EMC). We examined the effect of opening a district-based EMC on time to admission and number of suspect cases dead on arrival (DOA), and identified factors associated with fatality in EVD patients, residents in Tonkolili District. Residents of Tonkolili district who presented between 12 September 2014 and 23 February 2015 to the district EMC and the two distant EMCs were identified from EMC line-lists. EVD cases were confirmed by a positive Ebola PCR test. We calculated time to admission since the onset of symptoms, case-fatality and adjusted Risk Ratios (aRR) using Binomial regression. Of 249 confirmed Ebola cases, 206 (83%) were admitted to the distant EMCs and 43 (17%) to the district EMC. Of them 110 (45%) have died. Confirmed cases dead on arrival (n = 10) were observed only in the distant EMCs. The median time from symptom onset to admission was 6 days (IQR 4,8) in distant EMCs and 3 days (IQR 2,7) in the district EMC (p<0.001). Cases were 2.0 (95%CI 1.4-2.9) times more likely to have delayed admission (>3 days after symptom onset) in the distant compared with the district EMC, but were less likely (aRR = 0.8; 95%CI 0.6-1.0) to have a high viral load (cycle threshold ≤22). A fatal outcome was associated with a high viral load (aRR 2.6; 95%CI 1.8-3.6) and vomiting at first presentation (aRR 1.4; 95%CI 1.0-2.0). The opening of a district EMC was associated with earlier admission of cases to appropriate care facilities, an essential component of reducing EVD transmission. High viral load and vomiting at admission predicted fatality. Healthcare providers should consider the location of EMCs to ensure equitable access during Ebola outbreaks.
    • Ebola Virus Disease Outbreak in Isiro, Democratic Republic of the Congo, 2012: Signs and Symptoms, Management and Outcomes

      Kratz, Thomas; Roddy, Paul; Tshomba Oloma, Antoine; Jeffs, Benjamin; Pou Ciruelo, Diana; de la Rosa, Olimpia; Borchert, Matthias (Public Library of Science, 2015-06-24)
      Data collected during the 2012 Ebola virus disease (EVD) epidemic in the Democratic Republic of the Congo were analysed for clinical signs, symptoms and case fatality of EVD caused by Bundibugyo virus (BDBV), establishment of differential diagnoses, description of medical treatment and evaluation of the quality of clinical documentation. In a quantitative observational prospective study, global epidemiological data from 52 patients (34 patients within the community, 18 patients treated in the Ebola Treatment Centre) were entered anonymously into a database, subsequently matched and analysed. Relevant findings include an over-representation of females among community EVD cases (85.3%) and of community EVD cases in the age group of 15-54 years (82.4%). All ETC patients had fever (55.6% of all 18 ETC patients during their hospital stay) or self-reported fever (88.2% upon admission) at some point of time during their illness. Major symptoms of ETC patients during hospital stay included asthenia (82.4%), anorexia (82.4%), myalgia (70.6%), sore throat/difficulty swallowing (70.6%), arthralgia (76.5%) and nausea (70.6%). Gastrointestinal signs and symptoms (nausea, diarrhoea, vomiting) (76.4%) as well as general pain (94.1%) were frequent in ETC patients. The median duration of EVD was 18 days, while the mean incubation period was 11.3 days. Differential diagnosis of EVD included malaria (28.3%), intestinal parasitosis (10.9%), and infectious syndrome (10.9%). There was also an important variation in clinical evolvement. Quality of documentation was adversely affected by the way patient file contents were transferred from inside to outside the high-risk zone, entailing a mean mismatch value of 27.3% between patient file contents inside vs. outside the high-risk zone. This study adds further description of EVD (frequently non-specific signs and symptoms, non frequent bleeding, a long incubation period, long duration of disease) and emphasizes the need for improving clinical monitoring and documentation in EVD outbreak settings.
    • The Ebola-effect in Guinea 2014-15: Tangled trends of malaria care in children under-five

      Kolie, D; Camara, BS; Delamou, A; Béavogui, AH; Hermans, V; Edwards, JK; Benedetti, G; Muller, CP; Griensven, JV; Zachariah, R (Public Library of Science, 2018-02-28)
      The 2014-15 Ebola outbreak in West Africa was disruptive for the general health services in the affected countries. This study assessed the impact of the outbreak on the reported number and management of malaria in children under-five in rural Guinea.
    • Estimating the Number of Secondary Ebola Cases Resulting From an Unsafe Burial and Risk Factors for Transmission During the West Africica Ebola Epidemic

      Tiffany, A; Dalziel, B; Kagume N; Johnson, G; Nugba Ballah, R; James, D; Wone, A; Bedford, J; McClelland, A (Public Library of Science, 2017-06-22)
      Safely burying Ebola infected individuals is acknowledged to be important for controlling Ebola epidemics and was a major component of the 2013-2016 West Africa Ebola response. Yet, in order to understand the impact of safe burial programs it is necessary to elucidate the role of unsafe burials in sustaining chains of Ebola transmission and how the risk posed by activities surrounding unsafe burials, including care provided at home prior to death, vary with human behavior and geography.
    • Evaluation of a Rapid Test for the Diagnosis of Cholera in the Absence of a Gold Standard

      Page, Anne-Laure; Alberti, Kathryn P.; Mondonge, Vital; Rauzier, Jean; Quilici, Marie-Laure; Guerin, Philippe J.; Bhutta, Zulfiqar A.; Epicentre, Paris, France; Ministry of Health, Kinshasa, Democratic Republic of Congo; Institut Pasteur, Unité des Bactéries Pathogènes Entériques, Centre National de Référence des Vibrions et du Choléra, Paris, France; Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, Centre for Clinical Vaccinology and Tropical Medicine (CCVTM), University of Oxford, Oxford, United Kingdom (Public Library of Science, 2012-05-30)
      Early detection and confirmation of cholera outbreaks are crucial for rapid implementation of control measures. Because cholera frequently affects regions with limited laboratory resources, rapid diagnostic tests (RDT) designed for field conditions are important to enhance rapid response. Stool culture remains the ‘‘gold standard’’ for cholera diagnosis; however, its lack of sensitivity may lead to underestimation of test specificity. We evaluated the Crystal VCH immunochromatographic test (Span Diagnostics, India) for cholera diagnosis using a modified reference standard that combines culture-dependent and independent assays, or a Bayesian latent class model (LCM) analysis. The study was conducted during a cholera epidemic in 2008, in Lubumbashi, Democratic Republic of Congo. Stools collected from 296 patients were used to perform the RDT on site and sent to Institut Pasteur, Paris, for bacterial culture. In comparison with culture as the gold standard, the RDT showed good sensitivity (92.2%; 95% CI: 86.8%–95.9%) but poor specificity when used by a trained laboratory technician (70.6%; 95% CI: 60.7%–79.2%) or by clinicians with no specific test training (60.4%, 95% CI: 50.2%–70.0%). The specificity of the test performed by the laboratory technician increased to 88.6% (95% CI: 78.7–94.9) when PCR was combined with culture results as the reference standard, and to 85.0% (95% CI: 70.4–99.2), when the Bayesian LCM analysis was used for performance evaluation. In both cases, the sensitivity remained high. Using an improved reference standard or appropriate statistical methods for diagnostic test evaluations in the absence of a gold standard, we report better performance of the Crystal VCH RDT than previously published. Our results confirm that this test can be used for early outbreak detection or epidemiological surveillance, key components of efficient global cholera control. Our analysis also highlights the importance of improving evaluations of RDT when no reliable gold standard is available.
    • Experimental Treatment of Ebola Virus Disease with Brincidofovir

      Dunning, J; Kennedy, SB; Antierens, A; Whitehead, J; Ciglenecki, I; Carson, G; Kanapathipillai, R; Castle, L; Howell-Jones, R; Pardinaz-Solis, R; et al. (Public Library of Science, 2016-09-09)
      The nucleotide analogue brincidofovir was developed to prevent and treat infections caused by double-stranded DNA viruses. Based on in vitro data suggesting an antiviral effect against Ebola virus, brincidofovir was included in the World Health Organisation list of agents that should be prioritised for clinical evaluation in patients with Ebola virus disease (EVD) during the West African epidemic.
    • Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea

      Sissoko, D; Laouenan, C; Folkesson, E; M'Lebing, AB; Beavogui, AH; Baize, S; Camara, AM; Maes, P; Shepherd, S; Danel, C; et al. (Public Library of Science, 2016-03-01)
      Ebola virus disease (EVD) is a highly lethal condition for which no specific treatment has proven efficacy. In September 2014, while the Ebola outbreak was at its peak, the World Health Organization released a short list of drugs suitable for EVD research. Favipiravir, an antiviral developed for the treatment of severe influenza, was one of these. In late 2014, the conditions for starting a randomized Ebola trial were not fulfilled for two reasons. One was the perception that, given the high number of patients presenting simultaneously and the very high mortality rate of the disease, it was ethically unacceptable to allocate patients from within the same family or village to receive or not receive an experimental drug, using a randomization process impossible to understand by very sick patients. The other was that, in the context of rumors and distrust of Ebola treatment centers, using a randomized design at the outset might lead even more patients to refuse to seek care. Therefore, we chose to conduct a multicenter non-randomized trial, in which all patients would receive favipiravir along with standardized care. The objectives of the trial were to test the feasibility and acceptability of an emergency trial in the context of a large Ebola outbreak, and to collect data on the safety and effectiveness of favipiravir in reducing mortality and viral load in patients with EVD. The trial was not aimed at directly informing future guidelines on Ebola treatment but at quickly gathering standardized preliminary data to optimize the design of future studies.
    • Factors Affecting Perceived Stigma in Leprosy Affected Persons in Western Nepal

      Adhikari, Bipin; Kaehler, Nils; Chapman, Robert S.; Raut, Shristi; Roche, Paul; Akogun, Oladele B. (Public Library of Science, 2014-06-05)
      Background There are various factors which construct the perception of stigma in both leprosy affected persons and unaffected persons. The main purpose of this study was to determine the level of perceived stigma and the risk factors contributing to it among leprosy affected person attending the Green Pastures Hospital, Pokhara municipality of western Nepal. Methods A cross-sectional study was conducted among 135 people affected by leprosy at Green Pastures Hospital and Rehabilitation Centre. Persons above the age of 18 were interviewed using a set of questionnaire form and Explanatory Model Interview Catalogue (EMIC). In addition, two sets of focused group discussions each containing 10 participants from the ward were conducted with the objectives of answering the frequently affected EMIC items. Results Among 135 leprosy affected persons, the median score of perceived stigma was 10 while it ranged from 0–34. Higher perceived stigma score was found in illiterate persons (p = 0.008), participants whose incomes were self-described as inadequate (p = 0.014) and who had changed their occupation due to leprosy (p = 0.018). Patients who lacked information on leprosy (p = 0.025), knowledge about the causes (p = 0.02) and transmission of leprosy (p = 0.046) and those who had perception that leprosy is a severe disease (p<0.001) and is difficult to treat (p<0.001) had higher perceived stigma score. Participants with disfigurement or deformities (p = 0.014), ulcers (p = 0.022) and odorous ulcers (p = 0.043) had higher perceived stigma score. Conclusion The factors associated with higher stigma were illiteracy, perceived economical inadequacy, change of occupation due to leprosy, lack of knowledge about leprosy, perception of leprosy as a severe disease and difficult to treat. Similarly, visible deformities and ulcers were associated with higher stigma. There is an urgent need of stigma reduction strategies focused on health education and health awareness programs in addition to the necessary rehabilitation support.
    • First external Quality Assurance Program for bloodstream Real-Time PCR monitoring of treatment response in clinical trials of Chagas disease

      Ramírez, JC; Parrado, R; Sulleiro, E; de la Barra, A; Rodríguez, M; Villarroel, S; Irazu, L; Alonso-Vega, C; Alves, F; Curto, MA; et al. (Public Library of Science, 2017-11-27)
      Real-Time PCR (qPCR) testing is recommended as both a diagnostic and outcome measurement of etiological treatment in clinical practice and clinical trials of Chagas disease (CD), but no external quality assurance (EQA) program provides performance assessment of the assays in use. We implemented an EQA system to evaluate the performance of molecular biology laboratories involved in qPCR based follow-up in clinical trials of CD. An EQA program was devised for three clinical trials of CD: the E1224 (NCT01489228), a pro-drug of ravuconazole; the Sampling Study (NCT01678599), that used benznidazole, both conducted in Bolivia; and the CHAGASAZOL (NCT01162967), that tested posaconazole, conducted in Spain. Four proficiency testing panels containing negative controls and seronegative blood samples spiked with 1, 10 and 100 parasite equivalents (par. eq.)/mL of four Trypanosoma cruzi stocks, were sent from the Core Lab in Argentina to the participating laboratories located in Bolivia and Spain. Panels were analyzed simultaneously, blinded to sample allocation, at 4-month intervals. In addition, 302 random blood samples from both trials carried out in Bolivia were sent to Core Lab for retesting analysis. The analysis of proficiency testing panels gave 100% of accordance (within laboratory agreement) and concordance (between laboratory agreement) for all T. cruzi stocks at 100 par. eq./mL; whereas their values ranged from 71 to 100% and from 62 to 100% at 1 and 10 par. eq./mL, respectively, depending on the T. cruzi stock. The results obtained after twelve months of preparation confirmed the stability of blood samples in guanidine-EDTA buffer. No significant differences were found between qPCR results from Bolivian laboratory and Core Lab for retested clinical samples. This EQA program for qPCR analysis of CD patient samples may significantly contribute to ensuring the quality of laboratory data generated in clinical trials and molecular diagnostics laboratories of CD.
    • Geographic Distribution and Mortality Risk Factors during the Cholera Outbreak in a Rural Region of Haiti, 2010-2011

      Page, Anne-Laure; Ciglenecki, Iza; Jasmin, Ernest Robert; Desvignes, Laurence; Grandesso, Francesco; Polonsky, Jonathan; Nicholas, Sarala; Alberti, Kathryn P; Porten, Klaudia; Luquero, Francisco J (Public Library of Science, 2015-03-26)
      In 2010 and 2011, Haiti was heavily affected by a large cholera outbreak that spread throughout the country. Although national health structure-based cholera surveillance was rapidly initiated, a substantial number of community cases might have been missed, particularly in remote areas. We conducted a community-based survey in a large rural, mountainous area across four districts of the Nord department including areas with good versus poor accessibility by road, and rapid versus delayed response to the outbreak to document the true cholera burden and assess geographic distribution and risk factors for cholera mortality.