Investigating the epidemiology of trypanosomiasis in domestic livestock at the micro-scale in Busia, Kenya

Trypanosomiasis in Kenya is no longer viewed as a public health issue, as only sporadic sleeping sickness cases are reported from historic foci such as Busia. Trypanosomiasis is thus mainly perceived as a constraint on livestock production. The responsibility for tsetse and trypanosomiasis control in Kenya has therefore increasingly shifted from the state to individual livestock owners; this drastically reduced the scale of control approaches. This thesis examines the epidemiology of both animal infective and zoonotic trypanosome species in a range of domestic livestock at the micro-scale, in Busia, Kenya. The work is based on a unique crosssectional census data set of the entire livestock population in two study sites in Busia, employing sensitive molecular tools (PCR) to detect trypanosome infections.Cattle were the largest reservoir of trypanosomes with an infection prevalence of 20.1%, followed by pigs (11.5%). A low prevalence of infection was detected in small ruminants (3.3%). Human infective trypanosomes (71 b. rhodesiense) were detected at a low prevalence in cattle (1.5%) and pigs (2.9%). Key clinical signs for trypanosomiasis infection (anaemia & poor body condition) were only observed in a minority of infected cattle (<20%). Confinement of livestock to the homesteads, instead of grazing in communal grounds and watering at the river did not provide protection from trypanosome infections. An investigation of the micro-geographic variation in the distribution of trypanosome infections over the study population, revealed significant clustering in one of the two study sites. However, there was no significant effect of distance to water features on trypanosomiasis risk at the herd level. A convenience sampling protocol was shown to give a good estimate of overall trypanosomiasis in cattle, but failed to detect the low prevalence of T. b. rhodesiense.The sustainability of small-scale trypanosomiasis control based on trypanocide treatment of visibly diseased cattle is appraised and the feasibility of additional vector control is discussed. Furthermore, the potential human health implications of a livestock reservoir of T. b. rhodesiense to the local population are examined

Moving epidemic method (MEM) applied to virology data as a novel real time tool to predict peak in seasonal influenza healthcare utilisation. The Scottish experience of the 2017/18 season to date

Scotland observed an unusual influenza A(H3N2)- dominated 2017/18 influenza season with healthcare services under significant pressure. We report the application of the moving epidemic method (MEM) to virology data as a tool to predict the influenza peak activity period and peak week of swab positivity in the current season. This novel MEM application has been successful locally and is believed to be of potential use to other countries for healthcare planning and building wider community resilience

Vaccine effectiveness of live attenuated and trivalent inactivated influenza vaccination in 2010/11 to 2015/16:the SIVE II record linkage study

Background: There is good evidence of vaccine effectiveness in healthy individuals but less robust evidence for vaccine effectiveness in the populations targeted for influenza vaccination. The live attenuated influenza vaccine (LAIV) has recently been recommended for children in the UK. The trivalent influenza vaccine (TIV) is recommended for all people aged≥65 years and for those aged<65 years who are at an increased risk of complications from influenza infection (e.g. people with asthma). Objective: To examine the vaccine effectiveness of LAIV and TIV. Design: Cohort study and test-negative designs to estimate vaccine effectiveness. A self-case series study to ascertain adverse events associated with vaccination. Setting: A national linkage of patient-level general practice (GP) data from 230 Scottish GPs to the Scottish Immunisation & Recall Service, Health Protection Scotland virology database, admissions to Scottish hospitals and the Scottish death register. Participants: A total of 1,250,000 people. Interventions: LAIV for 2- to 11-year-olds and TIV for older people (aged≥65 years) and those aged<65 years who are at risk of diseases, from 2010/11 to 2015/16. Main outcome measures: The main outcome measures include vaccine effectiveness against laboratory-confirmed influenza using real-time reverse-transcription polymerase chain reaction (RT-PCR), influenza-related morbidity and mortality, and adverse events associated with vaccination. Results: Two-fifths (40%) of preschool-aged children and three-fifths (60%) of primary school-aged children registered in study practices were vaccinated. Uptake varied among groups [e.g. most affluent vs. most deprived in 2- to 4-year-olds, odds ratio 1.76, 95% confidence interval (CI) 1.70 to 1.82]. LAIV-adjusted vaccine effectiveness among children (aged 2-11 years) for preventing RT-PCR laboratoryconfirmed influenza was 21% (95% CI -19% to 47%) in 2014/15 and 58% (95% CI 39% to 71%) in 2015/16. No significant adverse events were associated with LAIV. Among at-risk 18- to 64-year-olds, significant trivalent influenza vaccine effectiveness was found for four of the six seasons, with the highest vaccine effectiveness in 2010/11 (53%, 95% CI 21% to 72%). The seasons with non-significant vaccine effectiveness had low levels of circulating influenza virus (2011/12, 5%; 2013/14, 9%). Among those people aged≥65 years, TIV effectiveness was positive in all six seasons, but in only one of the six seasons (2013/14) was significance achieved (57%, 95% CI 20% to 76%). Conclusions: The study found that LAIV was safe and effective in decreasing RT-PCR-confirmed influenza in children. TIV was safe and significantly effective in most seasons for 18- to 64-year-olds, with positive vaccine effectiveness in most seasons for those people aged≥65 years (although this was significant in only one season). Future work: The UK Joint Committee on Vaccination and Immunisation has recommended the use of adjuvanted injectable vaccine for those people aged≥65 years from season 2018/19 onwards. A future study will be required to evaluate this vaccine. Trial registration: Current Controlled Trials ISRCTN88072400

Seasonal influenza vaccine effectiveness in people with asthma: a national test-negative design case-control study

Financial support. The work was funded by the Chief Scientist Office of the Scottish Government under the grant (AUKCAR/14/03) and the NIHR–Health Technology Assessment (HTA) Programme (13/34/14) for the Seasonal Influenza Vaccination Effectiveness II (SIVE II) study. As principal investigator, C. R. S. received a grant for the SIVE-II project from the NIHR HTA. This work was carried out with the support of the Asthma UK Centre for Applied Research (AUK-AC-2012-01), the Farr Institute (MR/M501633/2), Health Data Research UK (an initiative funded by UK Research and Innovation, Department of Health and Social Care England and the devolved administrations and leading medical research charities), the European Union’s Horizon 2020 research and innovation programme (under grant agreement No 634446) and European Centre for Disease Prevention and Control (Influenza-Monitoring Vaccine Effectiveness). Acknowledgments. The authors thank and acknowledge all colleagues at the Asthma UK Centre for Applied Research for their support in this study. Disclaimer. The funding bodies had no role in the design of the study, review process, analysis, interpretation, or reporting of data. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Health Technology Assessment Programme, National Institute for Health Research (NIHR), National Health Service, or the Department of Health. Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.Peer reviewedPublisher PDFPublisher PD

Evaluating the effectiveness, impact and safety of live attenuated and seasonal inactivated influenza vaccination: protocol for the Seasonal Influenza Vaccination Effectiveness II (SIVE II) study

Funding This project was funded by the National Institute for Health Research Health Technology Assessment Programme (project number 13/34/14). EV was supported by the Chief Scientist Office of the Scottish Government under grant (AUKCAR/14/03). This work is carried out with the support of the Asthma UK Centre for Applied Research (AUK-AC-2012–2001) and the Farr Institute.Peer reviewedPublisher PD

Evaluating the impact of targeting livestock for the prevention of human and animal trypanosomiasis, at village level, in districts newly affected with T. b. rhodesiense in Uganda

Background: Uganda has suffered from a series of epidemics of Human African Trypanosomiasis (HAT), a tsetse transmitted disease, also known as sleeping sickness. The area affected by acute Trypanosoma brucei rhodesiense HAT (rHAT) has been expanding, driven by importation of infected cattle into regions previously free of the disease. These regions are also affected by African Animal Trypanosomiasis (AAT) demanding a strategy for integrated disease control.Methods: In 2008, the Public Private Partnership, Stamp Out Sleeping Sickness (SOS) administered a single dose of trypanocide to 31 486 head of cattle in 29 parishes in Dokolo and Kaberamaido districts. This study examines the impact of this intervention on the prevalence of rHAT and AAT trypanosomes in cattle from villages that had (HAT+ve) or had not (HAT-ve) experienced a recent case of rHAT. Cattle herds from 20 villages were sampled and screened by PCR, pre-intervention and 6-months post-intervention, for the presence or absence of: Trypanosoma brucei s.l.; human infective T. b. rhodesiense; Trypanosoma vivax; and Trypanosoma congolense savannah.Results: Post-intervention, there was a significant decrease in the prevalence of T. brucei s.l. and the human infective sub-species T. b. rhodesiense in village cattle across all 20 villages. The prevalence of T. b. rhodesiense was reduced from 2.4% to 0.74% (P < 0.0001), with the intervention showing greater impact in HAT-ve villages. The number of villages containing cattle harbouring human infective parasites decreased from 15/20 to 8/20, with T. b. rhodesiense infection mainly persisting within cattle in HAT+ve villages (six/eight). The proportion of T. brucei s.l. infections identified as human infective T. b. rhodesiense decreased after the intervention from 8.3% (95% CI = 11.1–5.9%) to 4.1% (95% CI = 6.8–2.3%). Villages that had experienced a recent human case (HAT+ve villages) showed a significantly higher prevalence for AAT both pre- and post-intervention. For AAT the prevalence of T. vivax was significantly reduced from 5.9% to 0.05% post-intervention while the prevalence of T. congolense increased from 8.0% to 12.2%.Conclusions: The intervention resulted in a significant decrease in the prevalence of T. brucei s.l., human infective T. b. rhodesiense and T. vivax infection in village cattle herds. The proportion of T. brucei s.l. that were human infective, decreased from 1:12 T. brucei s.l. infections before the intervention to 1:33 post-intervention. It is clearly more difficult to eliminate T. b. rhodesiense from cattle in villages that have experienced a human case. Evidence of elevated levels of AAT in livestock within village herds is a useful indicator of risk for rHAT in Uganda. Integrated veterinary and medical surveillance is key to successful control of zoonotic rHAT

No Gold Standard Estimation of the Sensitivity and Specificity of Two Molecular Diagnostic Protocols for Trypanosoma brucei spp. in Western Kenya

African animal trypanosomiasis is caused by a range of tsetse transmitted protozoan parasites includingTrypanosoma vivax, Trypanosoma congolense and Trypansoma brucei. In Western Kenya and other parts of East Africa two subspecies of T. brucei, T.b. brucei and the zoonoticT.b. rhodesiense, co-circulate in livestock. A range of polymerase chain reactions (PCR) have been developed as important molecular diagnostic tools for epidemiological investigations of T. brucei s.l. in the animal reservoir and of its zoonotic potential. Quantification of the relative performance of different diagnostic PCRs is essential to ensure comparability of studies. This paper describes an evaluation of two diagnostic test systems for T. brucei using a T. brucei s.l. specific PCR [1] and a single nested PCR targeting the Internal Transcribed Spacer (ITS) regions of trypanosome ribosomal DNA [2]. A Bayesian formulation of the Hui-Walter latent class model was employed to estimate their test performance in the absence of a gold standard test for detecting T.brucei s.l. infections in ear-vein blood samples from cattle, pig, sheep and goat populations in Western Kenya, stored on Whatman FTA cards. The results indicate that the system employing the T. brucei s.l. specific PCR (Se1 = 0.760) had a higher sensitivity than the ITS-PCR (Se2 = 0.640); both have high specificity (Sp1 = 0.998; Sp2 = 0.997). The true prevalences for livestock populations were estimated (pcattle = 0.091, ppigs = 0.066, pgoats = 0.005, psheep = 0.006), taking into account the uncertainties in the specificity and sensitivity of the two test systems. Implications of test performance include the required survey sample size; due to its higher sensitivity and specificity, the T. brucei s.l. specific PCR requires a consistently smaller sample size than the ITS-PCR for the detection of T. brucei s.l. However the ITS-PCR is able to simultaneously screen samples for other pathogenic trypanosomes and may thus be, overall, a better choice of test in multi-organism studies

Informing prevention of stillbirth and preterm birth in Malawi:development of a minimum dataset for health facilities participating in the DIPLOMATIC collaboration

OBJECTIVE: The global research group, DIPLOMATIC (Using eviDence, Implementation science, and a clinical trial PLatform to Optimise MATernal and newborn health in low Income Countries), aims to reduce stillbirths and preterm births and optimise outcomes for babies born preterm. Minimum datasets for routine data collection in healthcare facilities participating in DIPLOMATIC (initially in Malawi) were designed to assist understanding of baseline maternal and neonatal care processes and outcomes, and facilitate evaluation of improvement interventions and pragmatic clinical trials. DESIGN: Published and grey literature was reviewed alongside extensive in-country consultation to define relevant clinical best practice guidance, and the existing local data and reporting infrastructure, to identify requirements for the minimum datasets. Data elements were subjected to iterative rounds of consultation with topic experts in Malawi and Scotland, the relevant Malawian professional bodies and the Ministry of Health in Malawi to ensure relevance, validity and feasibility. SETTING: Antenatal, maternity and specialist neonatal care in Malawi. RESULTS: The resulting three minimum datasets cover the maternal and neonatal healthcare journey for antenatal, maternity and specialist neonatal care, with provision for effective linkage of records for mother/baby pairs. They can facilitate consistent, precise recording of relevant outcomes (stillbirths, preterm births, neonatal deaths), risk factors and key care processes. CONCLUSIONS: Poor quality routine data on care processes and outcomes constrain healthcare system improvement. The datasets developed for implementation in DIPLOMATIC partner facilities reflect, and hence support delivery of, internationally agreed best practice for maternal and newborn care in low-income settings. Informed by extensive consultation, they are designed to integrate with existing local data infrastructure and reporting as well as meeting research data needs. This work provides a transferable example of strengthening data infrastructure to underpin a learning healthcare system approach in low-income settings.DIPLOMATIC is funded by the UK National Institute for Health Research

Effectiveness of influenza vaccines in asthma: a systematic review and meta-analysis

There is uncertainty about the effectiveness of influenza vaccination in people with asthma and its impact on asthma outcomes, which may contribute to the sub-optimal vaccination rates in people with asthma. This systematic review and meta-analysis involved searching 12 international databases for randomized controlled trials (RCTs) and high quality quasi-experimental and epidemiological studies (1970 to 2016). The risk of bias was low for three included RCTs. The quality of three included observational studies was moderate. The quality of evidence was very low for all study outcomes. Pooled vaccine effectiveness in 1,825 people with asthma from two test-negative design case-control studies was 45% (95% CI 31 to 56) for laboratory-confirmed influenza. Pooled efficacy of live vaccines in reducing influenza was 81% (95% CI 33 to 94). Live vaccine reduced febrile illness by 72% (95% CI 20 to 90). Influenza vaccine prevented 59-78% of asthma attacks leading to emergency visits and/or hospitalizations. For people with asthma influenza vaccination may be effective in both reducing influenza infection and asthma attacks

Quantifying the Association between Bovine and Human Trypanosomiasis in Newly Affected Sleeping Sickness Areas of Uganda

BACKGROUND: Uganda has active foci of both chronic and acute HAT with the acute zoonotic form of disease classically considered to be restricted to southeast Uganda, while the focus of the chronic form of HAT was confined to the northwest of the country. Acute HAT has however been migrating from its traditional disease focus, spreading rapidly to new districts, a spread linked to movement of infected cattle following restocking. Cattle act as long-term reservoirs of human infective T. b. rhodesiense showing few signs of morbidity, yet posing a significant risk to human health. It is important to understand the relationship between infected cattle and infected individuals so that an appropriate response can be made to the risk posed to the community from animals infected with human pathogens in a village setting. METHODOLOGY/PRINCIPAL FINDINGS: This paper examines the relationship between human T. b. rhodesiense infection and human infective and non-human T. brucei s.l. circulating in cattle at village level in Kaberamaido and Dokolo Districts, Uganda. The study was undertaken in villages that had reported a case of sleeping sickness in the six months prior to sample collection and those villages that had never reported a case of sleeping sickness. CONCLUSIONS AND SIGNIFICANCE: The sleeping sickness status of the villages had a significant effect with higher odds of infection in cattle from case than from non-case villages for T. brucei s.l. (OR: 2.94, 95%CI: 1.38-6.24). Cattle age had a significant effect (p<0.001) on the likelihood of T. brucei s.l. infection within cattle: cattle between 18-36 months (OR: 3.51, 95%CI: 1.63-7.51) and cattle over 36 months (OR: 4.20, 95%CI: 2.08-8.67) had significantly higher odds of T. brucei s. l. infection than cattle under 18 months of age. Furthermore, village human sleeping sickness status had a significant effect (p<0.05) on the detection of T. b. rhodesiense in the village cattle herd, with significantly higher likelihood of T. b. rhodesiense in the village cattle of case villages (OR: 25, 95%CI: 1.2-520.71). Overall a higher than average T. brucei s.l. prevalence (>16.3%) in a village herd over was associated with significantly higher likelihood of T. b. rhodesiense being detected in a herd (OR: 25, 95%CI: 1.2-520.71)