• Aetiology and Outcomes of Suspected Infections of the Central Nervous System in Children in Mbarara, Uganda

      Page, A; Boum Ii, Y; Kemigisha, E; Salez, N; Nanjebe, D; Langendorf, C; Aberrane, S; Nyehangane, D; Nackers, F; Baron, E; et al. (Nature Publishing Group, 2017-06-02)
      Infections of the central nervous system (CNS) are severe conditions, leading to neurological sequelae or death. Knowledge of the causative agents is essential to develop guidelines for case management in resource-limited settings. Between August 2009 and October 2012, we conducted a prospective descriptive study of the aetiology of suspected CNS infections in children two months to 12 years old, with fever and at least one sign of CNS involvement in Mbarara Hospital, Uganda. Children were clinically evaluated on admission and discharge, and followed-up for 6 months for neurological sequelae. Pathogens were identified from cerebrospinal fluid (CSF) and blood using microbiological and molecular methods. We enrolled 459 children. Plasmodium falciparum (36.2%) and bacteria in CSF (13.3%) or blood (3.3%) were the most detected pathogens. Viruses were found in 27 (5.9%) children. No pathogen was isolated in 207 (45.1%) children. Patterns varied by age and HIV status. Eighty-three (18.1%) children died during hospitalisation, and 23 (5.0%) during follow-up. Forty-one (13.5%) children had neurological sequelae at the last visit. While malaria remains the main aetiology in children with suspected CNS infections, no pathogen was isolated in many children. The high mortality and high rate of neurological sequelae highlight the need for efficient diagnosis.
    • Brain injury: Iraq's unseen burden of wounded civilians

      Guerrier, Gilles; Baron, Emmanuel; Fakri, Rasheed; Mouniaman, Isabelle; Epicentre, Paris, France; Médecins Sans Frontières, Amman, Jordan; Médecins Sans Frontières, Paris, France (Nature Publishing Group, 2011-10-27)
      The burden of war-related mental disorders is well documented among US veterans (Nature 477, 390–393; 2011), but not among civilians in Iraq. This oversight must be rectified so that adequate medical support can be provided to the Iraqi people. US combat troops will soon depart Iraq, leaving Iraqis to cope with the consequences of the 2003 invasion. Although the number of violent deaths is falling, civilians have been killed almost every day this year, most of them in coordinated bomb attacks. Roadside blasts cause long-term disabilities and societal effects among injured civilians. However, these have been largely neglected by the media and no systematic surveillance has been undertaken.
    • Disseminated Tuberculosis Among Hospitalised HIV Patients in South Africa: A Common Condition that Can Be Rapidly Diagnosed Using Urine-Based Assays

      Kerkhoff, A; Barr, D; Schutz, C; Burton, R; Nicol, M; Lawn, S; Meintjes, G (Nature Publishing Group, 2017-09-07)
      HIV-associated disseminated TB (tuberculosis) has been under-recognised and poorly characterised. Blood culture is the gold-standard diagnostic test, but is expensive, slow, and may under-diagnose TB dissemination. In a cohort of hospitalised HIV patients, we aimed to report the prevalence of TB-blood-culture positivity, performance of rapid diagnostics as diagnostic surrogates, and better characterise the clinical phenotype of disseminated TB. HIV-inpatients were systematically investigated using sputum, urine and blood testing. Overall, 132/410 (32.2%) patients had confirmed TB; 41/132 (31.1%) had a positive TB blood culture, of these 9/41 (22.0%) died within 90-days. In contrast to sputum diagnostics, urine Xpert and urine-lipoarabinomannan (LAM) combined identified 88% of TB blood-culture-positive patients, including 9/9 who died within 90-days. For confirmed-TB patients, half the variation in major clinical variables was captured on two principle components (PCs). Urine Xpert, urine LAM and TB-blood-culture positive patients clustered similarly on these axes, distinctly from patients with localised disease. Total number of positive tests from urine Xpert, urine LAM and MTB-blood-culture correlated with PCs (p < 0.001 for both). PC1&PC2 independently predicted 90-day mortality (ORs 2.6, 95%CI = 1.3-6.4; and 2.4, 95%CI = 1.3-4.5, respectively). Rather than being a non-specific diagnosis, disseminated TB is a distinct, life-threatening condition, which can be diagnosed using rapid urine-based tests, and warrants specific interventional trials.
    • Genomic Insights into the 2016-2017 Cholera Epidemic in Yemen

      Weill, FX; Domman, D; Njamkepo, E; Almesbahi, AA; Naji, M; Nasher, SS; Rakesh, A; Assiri, AM; Sharma, NC; Kariuki, S; et al. (Nature Publishing Group, 2019-01-02)
      Yemen is currently experiencing, to our knowledge, the largest cholera epidemic in recent history. The first cases were declared in September 2016, and over 1.1 million cases and 2,300 deaths have since been reported1. Here we investigate the phylogenetic relationships, pathogenesis and determinants of antimicrobial resistance by sequencing the genomes of Vibrio cholerae isolates from the epidemic in Yemen and recent isolates from neighbouring regions. These 116 genomic sequences were placed within the phylogenetic context of a global collection of 1,087 isolates of the seventh pandemic V. cholerae serogroups O1 and O139 biotype El Tor2-4. We show that the isolates from Yemen that were collected during the two epidemiological waves of the epidemic1-the first between 28 September 2016 and 23 April 2017 (25,839 suspected cases) and the second beginning on 24 April 2017 (more than 1 million suspected cases)-are V. cholerae serotype Ogawa isolates from a single sublineage of the seventh pandemic V. cholerae O1 El Tor (7PET) lineage. Using genomic approaches, we link the epidemic in Yemen to global radiations of pandemic V. cholerae and show that this sublineage originated from South Asia and that it caused outbreaks in East Africa before appearing in Yemen. Furthermore, we show that the isolates from Yemen are susceptible to several antibiotics that are commonly used to treat cholera and to polymyxin B, resistance to which is used as a marker of the El Tor biotype.
    • Global Phylogeography and Evolutionary History of Shigella Dysenteriae Type 1

      Njamkepo, E; Fawal, N; Tran-Dien, A; Hawkey, J; Strockbine, N; Jenkins, C; Talukder, KA; Bercion, R; Kuleshov, K; Kolínská, R; et al. (Nature Publishing Group, 2016-03-21)
      Together with plague, smallpox and typhus, epidemics of dysentery have been a major scourge of human populations for centuries(1). A previous genomic study concluded that Shigella dysenteriae type 1 (Sd1), the epidemic dysentery bacillus, emerged and spread worldwide after the First World War, with no clear pattern of transmission(2). This is not consistent with the massive cyclic dysentery epidemics reported in Europe during the eighteenth and nineteenth centuries(1,3,4) and the first isolation of Sd1 in Japan in 1897(5). Here, we report a whole-genome analysis of 331 Sd1 isolates from around the world, collected between 1915 and 2011, providing us with unprecedented insight into the historical spread of this pathogen. We show here that Sd1 has existed since at least the eighteenth century and that it swept the globe at the end of the nineteenth century, diversifying into distinct lineages associated with the First World War, Second World War and various conflicts or natural disasters across Africa, Asia and Central America. We also provide a unique historical perspective on the evolution of antibiotic resistance over a 100-year period, beginning decades before the antibiotic era, and identify a prevalent multiple antibiotic-resistant lineage in South Asia that was transmitted in several waves to Africa, where it caused severe outbreaks of disease.
    • Higher risk Sexual Behaviour is associated with Unawareness of HIV-positivity and lack of Viral Suppression - implications for Treatment as Prevention

      Huerga, H; Venables, E; Ben-Farhat, J; van Cutsem, G; Ellman, T; Kenyon, C (Nature Publishing Group, 2017-11-23)
      Efficacy of Treatment as Prevention Strategy depends on a variety of factors including individuals' likelihood to test and initiate treatment, viral load and sexual behaviour. We tested the hypothesis that people with higher risk sexual behaviour are less likely to know their HIV-positive status and be virologically suppressed. A cross-sectional population-based survey of individuals aged 15-59 years old was conducted in 2013 in KwaZulu-Natal, South Africa. A two-stage cluster probability sampling was used. After adjustment for age and sex, lack of awareness of HIV-positivity was strongly associated with having more than one sexual partner in the preceding year (aOR: 2.1, 95%CI: 1.5-3.1). Inconsistent condom use was more common in individuals with more than one sexual partner (aOR: 16.6, 95%CI: 7.6-36.7) and those unaware (aOR: 3.7, 95%CI: 2.6-5.4). Among people aware of their HIV-positivity, higher risk sexual behaviour was associated with lack of viral suppression (aOR: 2.2, 95%CI: 1.1-4.5). Risky sexual behaviour seems associated with factors linked to poor health-seeking behaviour which may have negative implications for HIV testing and Treatment as Prevention. Innovative strategies, driven by improved epidemiological and anthropological understanding, are needed to enable comprehensive approaches to HIV prevention.
    • Immune Responses to an Oral Cholera Vaccine in Internally Displaced Persons in South Sudan

      Iyer, AS; Bouhenia, M; Rumunu, J; Abubakar, A; Gruninger, RJ; Pita, J; Lino, RL; Deng, LL; Wamala, JF; Ryan, ET; et al. (Nature Publishing Group, 2016-10-24)
      Despite recent large-scale cholera outbreaks, little is known about the immunogenicity of oral cholera vaccines (OCV) in African populations, particularly among those at highest cholera risk. During a 2015 preemptive OCV campaign among internally displaced persons in South Sudan, a year after a large cholera outbreak, we enrolled 37 young children (1-5 years old), 67 older children (6-17 years old) and 101 adults (≥18 years old), who received two doses of OCV (Shanchol) spaced approximately 3 weeks apart. Cholera-specific antibody responses were determined at days 0, 21 and 35 post-immunization. High baseline vibriocidal titers (>80) were observed in 21% of the participants, suggesting recent cholera exposure or vaccination. Among those with titers ≤80, 90% young children, 73% older children and 72% adults seroconverted (≥4 fold titer rise) after the 1(st) OCV dose; with no additional seroconversion after the 2(nd) dose. Post-vaccination immunological endpoints did not differ across age groups. Our results indicate Shanchol was immunogenic in this vulnerable population and that a single dose alone may be sufficient to achieve similar short-term immunological responses to the currently licensed two-dose regimen. While we found no evidence of differential response by age, further immunologic and epidemiologic studies are needed.
    • Molecular epidemiology of hepatitis C virus in Cambodia during 2016-2017.

      Nouhin, J; Iwamoto, M; Prak, S; Dousset, JP; Phon, K; Heng, S; Kerleguer, A; Le Paih, M; Dussart, P; Maman, D; et al. (Nature Publishing Group, 2019-05-13)
      In Cambodia, little epidemiological data of hepatitis C virus (HCV) is available. All previous studies were limited to only small or specific populations. In the present study, we performed a characterization of HCV genetic diversity based on demography, clinical data, and phylogenetic analysis of HCV non-structural 5B (NS5B) sequences belonging to a large cohort of patients (n = 3,133) coming from majority part of Cambodia between September 2016 and December 2017. The phylogenetic analysis revealed that HCV genotype 1 and 6 were the most predominant and sharing equal proportions (46%). The remaining genotypes were genotype 2 (4.3%) and unclassified variants (3.6%). Among genotype 1, subtype 1b was the most prevalent subtype accounting for 94%. Within genotype 6, we observed a high degree of diversity and the most common viral subtypes were 6e (44%) and 6r (23%). This characteristic points to the longstanding history of HCV in Cambodia. Geographic specificity of viral genotype was not observed. Risks of HCV infection were mainly associated with experience of an invasive medical procedure (64.7%), having partner with HCV (19.5%), and blood transfusion (9.9%). In addition, all of these factors were comparable among different HCV genotypes. All these features define the specificity of HCV epidemiology in Cambodia.
    • Mycobacterium Tuberculosis Lineage 4 Comprises Globally Distributed and Geographically Restricted Sublineages

      Stucki, D; Brites, D; Jeljeli, L; Coscolla, M; Liu, Q; Trauner, A; Fenner, L; Rutaihwa, L; Borrell, S; Luo, T; et al. (Nature Publishing Group, 2016-12-01)
      Generalist and specialist species differ in the breadth of their ecological niches. Little is known about the niche width of obligate human pathogens. Here we analyzed a global collection of Mycobacterium tuberculosis lineage 4 clinical isolates, the most geographically widespread cause of human tuberculosis. We show that lineage 4 comprises globally distributed and geographically restricted sublineages, suggesting a distinction between generalists and specialists. Population genomic analyses showed that, whereas the majority of human T cell epitopes were conserved in all sublineages, the proportion of variable epitopes was higher in generalists. Our data further support a European origin for the most common generalist sublineage. Hence, the global success of lineage 4 reflects distinct strategies adopted by different sublineages and the influence of human migration.
    • Predictive Modeling Targets Thymidylate Synthase ThyX in Mycobacterium Tuberculosis

      Djaout, K; Singh, V; Boum, Y; Katawera, V; Becker, H F; Bush, N G; Hearnshaw, S J; Pritchard, J E; Bourbon, P; Madrid, P B; et al. (Nature Publishing Group, 2016-06-10)
      There is an urgent need to identify new treatments for tuberculosis (TB), a major infectious disease caused by Mycobacterium tuberculosis (Mtb), which results in 1.5 million deaths each year. We have targeted two essential enzymes in this organism that are promising for antibacterial therapy and reported to be inhibited by naphthoquinones. ThyX is an essential thymidylate synthase that is mechanistically and structurally unrelated to the human enzyme. DNA gyrase is a DNA topoisomerase present in bacteria and plants but not animals. The current study set out to understand the structure-activity relationships of these targets in Mtb using a combination of cheminformatics and in vitro screening. Here, we report the identification of new Mtb ThyX inhibitors, 2-chloro-3-(4-methanesulfonylpiperazin-1-yl)-1,4-dihydronaphthalene-1,4-dione) and idebenone, which show modest whole-cell activity and appear to act, at least in part, by targeting ThyX in Mtb.
    • Sustainable HIV Treatment in Africa Through Viral-Load-Informed Differentiated Care

      Phillips, A; Shroufi, A; Vojnov, L; Cohn, J; Roberts, T; Ellman, T; Bonner, K; Rousseau, C; Garnett, G; Cambiano, V; et al. (Nature Publishing Group, 2015-12-03)
      There are inefficiencies in current approaches to monitoring patients on antiretroviral therapy in sub-Saharan Africa. Patients typically attend clinics every 1 to 3 months for clinical assessment. The clinic costs are comparable with the costs of the drugs themselves and CD4 counts are measured every 6 months, but patients are rarely switched to second-line therapies. To ensure sustainability of treatment programmes, a transition to more cost-effective delivery of antiretroviral therapy is needed. In contrast to the CD4 count, measurement of the level of HIV RNA in plasma (the viral load) provides a direct measure of the current treatment effect. Viral-load-informed differentiated care is a means of tailoring care so that those with suppressed viral load visit the clinic less frequently and attention is focussed on those with unsuppressed viral load to promote adherence and timely switching to a second-line regimen. The most feasible approach to measuring viral load in many countries is to collect dried blood spot samples for testing in regional laboratories; however, there have been concerns over the sensitivity and specificity of this approach to define treatment failure and the delay in returning results to the clinic. We use modelling to synthesize evidence and evaluate the cost-effectiveness of viral-load-informed differentiated care, accounting for limitations of dried blood sample testing. We find that viral-load-informed differentiated care using dried blood sample testing is cost-effective and is a recommended strategy for patient monitoring, although further empirical evidence as the approach is rolled out would be of value. We also explore the potential benefits of point-of-care viral load tests that may become available in the future.
    • Thymus size in children with moderate malnutrition: a cohort study from Burkina Faso

      Rytter, MJ; Cichon, B; Fabiansen, C; Yameogo, CW; Windinmi, SZ; Michaelsen, KF; Filteau, S; Jeppesen, DL; Friis, H; Briend, A; et al. (Nature Publishing Group, 2020-07-20)
      Background: Moderate acute malnutrition (MAM) affects millions of children, increasing their risk of dying from infections. Thymus atrophy may be a marker of malnutrition-associated immunodeficiency, but factors associated with thymus size in children with MAM are unknown, as is the effect of nutritional interventions on thymus size. Methods: Thymus size was measured by ultrasound in 279 children in Burkina Faso with MAM, diagnosed by low mid-upper arm circumference (MUAC) and/or low weight-for-length z-score (WLZ), who received 12 weeks treatment with different food supplements as part of a randomized trial. Correlates of thymus size and of changes in thymus size after treatment, and after another 12 weeks of follow-up were identified. Results: Thymus size correlated positively with age, anthropometry and blood haemoglobin, and was smaller in children with malaria. Children with malnutrition diagnosed using MUAC had a smaller thymus than children diagnosed based on WLZ. Thymus size increased during and after treatment, similarly across the different food supplement groups. Conclusions: In children with MAM, the thymus is smaller in children with anaemia or malaria, and grows with recovery. Assuming that thymus size reflects vulnerability, low MUAC seems to identify more vulnerable children than low WLZ in children with MAM. Impact: Thymus atrophy is known to be a marker of the immunodeficiency associated with malnutrition in children.In children with moderate malnutrition, we found the thymus to be smaller in children with anaemia or malaria.Assuming that thymus size reflects vulnerability, low MUAC seems to identify more vulnerable children than low weight for length.Thymus atrophy appears reversible with recovery from malnutrition, with similar growth seen in children randomized to treatment with different nutritional supplements.
    • Unique Human Immune Signature of Ebola Virus Disease in Guinea

      Ruibal, P; Oestereich, L; Lüdtke, A; Becker-Ziaja, B; Wozniak, DM; Kerber, R; Korva, M; Cabeza-Cabrerizo, M; Bore, JA; Koundouno, FR; et al. (Nature Publishing Group, 2016-05-05)
      Despite the magnitude of the Ebola virus disease (EVD) outbreak in West Africa, there is still a fundamental lack of knowledge about the pathophysiology of EVD. In particular, very little is known about human immune responses to Ebola virus. Here we evaluate the physiology of the human T cell immune response in EVD patients at the time of admission to the Ebola Treatment Center in Guinea, and longitudinally until discharge or death. Through the use of multiparametric flow cytometry established by the European Mobile Laboratory in the field, we identify an immune signature that is unique in EVD fatalities. Fatal EVD was characterized by a high percentage of CD4(+) and CD8(+) T cells expressing the inhibitory molecules CTLA-4 and PD-1, which correlated with elevated inflammatory markers and high virus load. Conversely, surviving individuals showed significantly lower expression of CTLA-4 and PD-1 as well as lower inflammation, despite comparable overall T cell activation. Concomitant with virus clearance, survivors mounted a robust Ebola-virus-specific T cell response. Our findings suggest that dysregulation of the T cell response is a key component of EVD pathophysiology.