Epidemiology of infections and co-infections: Impact on survival and growth of zebu cattle under one year

In any host population, individuals may be infected with multiple pathogens concurrently or in sequence. The direction and strength of pathogen-pathogen interactions are often unknown and dependent on the mechanism of interaction. This thesis is concerned with the epidemiology of infections and coinfections in zebu cattle during their first year of life, and the consequences they have for hosts’ survival probabilities and growth rates. Specifically, the study aims to: a) identify the many different pathogen infections occurring in zebu cattle under one year old, b) identify the main causes of mortality and reduced growth rates, c) test for evidence of effects of pathogen-pathogen interactions on mortality and growth, and d) determine the risk factors for infections with pathogens associated with increased mortality and reduced growth rates in zebu calves. To achieve these aims data collected from an epidemiological follow-up study of a cohort of 548 indigenous zebu cattle, recruited at birth and followed for the entire first year of life was used. Growth rates were enormously variable (52 to 704% of birth-weight) and 88 (16%) of the calves died during the first year, most from infectious disease. In total, 25,104 calf weeks of observation and data from 5,337 individual calf visits were analysed. Over 50 different pathogens were identified in the cohort. The thesis begins by providing an overview of zebu cattle and the importance of cattle diseases relevant to Sub-Saharan Africa, emphasising the importance of epidemiological studies taking into account co-infections, which are common in the natural populations, as opposed to a single-pathogen focus. A detailed description of the study design, data collection and descriptive analysis of non-infectious factors, including management and environmental factors, and a descriptive analysis of all pathogens screened for in the study are provided. Using Cox proportional models with frailty terms, the study then identifies infectious and non-infectious risk factors associated with mortality. Further, the role co-infections play in decreasing survival probabilities are investigated, revealing that the hazard for death from East Coast Fever (ECF) - the single most important disease associated with 40% of all deaths - increases 10 times in animals co-infected with Trypanosoma species, and 1.3 times for every 1000 eggs per gram faeces increase in strongyle egg count. Mixed-effect models are used to study growth rates and the impact of coinfections, revealing both synergistic interactions (lower host growth rates) of T. parva and A. marginale co-infections, and antagonistic interactions (relatively higher host growth rates) of T. parva and T. mutans co-infections compared to single infections with T. parva. Further, this work shows that helminth infections can have a strong negative effect on the growth rates but this is burden-dependent. These findings provide baseline epidemiological data on the diseases with greatest impact on health and performance of young zebu cattle, information that is valuable in the prioritisation and control of diseases. Additionally, they provide evidence of co-infections affecting host growth and survival, and have important implications on disease control strategies, suggesting benefits of aan integrated approach to control of worm, tick and tsetse-borne diseases

A hundred years of rabies in Kenya and the strategy for eliminating dog-mediated rabies by 2030

Background: Rabies causes an estimated 59,000 human deaths annually. In Kenya, rabies was first reported in a dog in 1912, with the first human case reported in 1928. Here we examine retrospective rabies data in Kenya for the period 1912 – 2017 and describe the spatial and temporal patterns of rabies occurrence in the country. Additionally, we detail Kenya’s strategy for the elimination of dog-mediated human rabies by 2030. Methods: Data on submitted samples and confirmed cases in humans, domestic animals and wildlife were obtained from Kenya’s Directorate of Veterinary Services. These data were associated with the geographical regions where the samples originated, and temporal and spatial trends examined. Results: Between 1912 and the mid 1970’s, rabies spread across Kenya gradually, with fewer than 50 cases reported per year and less than half of the 47 counties affected. Following an outbreak in the mid 1970’s, rabies spread rapidly to more than 85% of counties, with a 4 fold increase in the percent positivity of samples submitted and number of confirmed rabies cases. Since 1958, 7,584 samples from domestic animals (93%), wildlife (5%), and humans (2%) were tested. Over two-thirds of all rabies cases came from six counties, all in close proximity to veterinary diagnostic laboratories, highlighting a limitation of passive surveillance. Conclusions: Compulsory annual dog vaccinations between 1950’s and the early 1970’s slowed rabies spread. The rapid spread with peak rabies cases in the 1980’s coincided with implementation of structural adjustment programs privatizing the veterinary sector leading to breakdown of rabies control programs. To eliminate human deaths from rabies by 2030, Kenya is implementing a 15-year step-wise strategy based on three pillars: a) mass dog vaccination, b) provision of post-exposure prophylaxis and public awareness and c) improved surveillance for rabies in dogs and humans with prompt responses to rabies outbreaks

Parasite co-infections show synergistic and antagonistic interactions on growth performance of East African zebu cattle under one year

The co-occurrence of different pathogen species and their simultaneous infection of hosts are common, and may affect host health outcomes. Co-infecting pathogens may interact synergistically (harming the host more) or antagonistically (harming the host less) compared with single infections. Here we have tested associations of infections and their co-infections with variation in growth rate using a subset of 455 animals of the Infectious Diseases of East Africa Livestock (IDEAL) cohort study surviving to one year. Data on live body weight, infections with helminth parasites and haemoparasites were collected every 5 weeks during the first year of life. Growth of zebu cattle during the first year of life was best described by a linear growth function. A large variation in daily weight gain with a range of 0·03–0·34 kg, and a mean of 0·135 kg (0·124, 0·146; 95% CI) was observed. After controlling for other significant covariates in mixed effects statistical models, the results revealed synergistic interactions (lower growth rates) with Theileria parva and Anaplasma marginale co-infections, and antagonistic interactions (relatively higher growth rates) with T. parva and Theileria mutans co-infections, compared with infections with T. parva only. Additionally, helminth infections can have a strong negative effect on the growth rates but this is burden-dependent, accounting for up to 30% decrease in growth rate in heavily infected animals. These findings present evidence of pathogen–pathogen interactions affecting host growth, and we discuss possible mechanisms that may explain observed directions of interactions as well as possible modifications to disease control strategies when co-infections are present.This work was supported by the Wellcome Trust (grant No. 079445).http://www.parasitesandvectors.com/am2014ab201

Mortality in East African shorthorn zebu cattle under one year : predictors of infectious-disease mortality

BACKGROUND: Infectious livestock diseases remain a major threat to attaining food security and are a source of economic and livelihood losses for people dependent on livestock for their livelihood. Knowledge of the vital infectious diseases that account for the majority of deaths is crucial in determining disease control strategies and in the allocation of limited funds available for disease control. Here we have estimated the mortality rates in zebu cattle raised in a smallholder mixed farming system during their first year of life, identified the periods of increased risk of death and the risk factors for calf mortality, and through analysis of post-mortem data, determined the aetiologies of calf mortality in this population. A longitudinal cohort study of 548 zebu cattle was conducted between 2007 and 2010. Each calf was followed during its first year of life or until lost from the study. Calves were randomly selected from 20 sub-locations and recruited within a week of birth from different farms over a 45 km radius area centered on Busia in the Western part of Kenya. The data comprised of 481.1 calf years of observation. Clinical examinations, sample collection and analysis were carried out at 5 week intervals, from birth until one year old. Cox proportional hazard models with frailty terms were used for the statistical analysis of risk factors. A standardized post-mortem examination was conducted on all animals that died during the study and appropriate samples collected. RESULTS: The all-cause mortality rate was estimated at 16.1 (13.0-19.2; 95% CI) per 100 calf years at risk. The Cox models identified high infection intensity with Theileria spp., the most lethal of which causes East Coast Fever disease, infection with Trypanosome spp., and helminth infections as measured by Strongyle spp. eggs per gram of faeces as the three important infections statistically associated with infectious disease mortality in these calves. Analysis of post-mortem data identified East Coast Fever as the main cause of death accounting for 40% of all deaths, haemonchosis 12% and heartwater disease 7%. CONCLUSION: The findings demonstrate the impact of endemic parasitic diseases in indigenous animals expected to be well adapted against disease pressures. Additionally, agreement between results of Cox models using data from simple diagnostic procedures and results from post-mortem analysis underline the potential use such diagnostic data to reduce calf mortality. The control strategies for the identified infectious diseases have been discussed.The Wellcome Trust (grant No. 079,445)http://www.biomedcentral.com/1746-6148/9/175am2013ab201

Parasite co-infections and their impact on survival of indigenous cattle

In natural populations, individuals may be infected with multiple distinct pathogens at a time. These pathogens may act independently or interact with each other and the host through various mechanisms, with resultant varying outcomes on host health and survival. To study effects of pathogens and their interactions on host survival, we followed 548 zebu cattle during their first year of life, determining their infection and clinical status every 5 weeks. Using a combination of clinical signs observed before death, laboratory diagnostic test results, gross-lesions on post-mortem examination, histo-pathology results and survival analysis statistical techniques, cause-specific aetiology for each death case were determined, and effect of co-infections in observed mortality patterns. East Coast fever (ECF) caused by protozoan parasite Theileria parva and haemonchosis were the most important diseases associated with calf mortality, together accounting for over half (52%) of all deaths due to infectious diseases. Co-infection with Trypanosoma species increased the hazard for ECF death by 6 times (1.4–25; 95% CI). In addition, the hazard for ECF death was increased in the presence of Strongyle eggs, and this was burden dependent. An increase by 1000 Strongyle eggs per gram of faeces count was associated with a 1.5 times (1.4–1.6; 95% CI) increase in the hazard for ECF mortality. Deaths due to haemonchosis were burden dependent, with a 70% increase in hazard for death for every increase in strongyle eggs per gram count of 1000. These findings have important implications for disease control strategies, suggesting a need to consider co-infections in epidemiological studies as opposed to singlepathogen focus, and benefits of an integrated approach to helminths and East Coast fever disease control.The Wellcome Trust (grant No. 079445)http://www.plosone.orgam201

Hematological profile of East African short-horn zebu calves from birth to 51 weeks of age

This paper is the first attempt to accurately describe the hematological parameters for any African breed of cattle, by capturing the changes in these parameters over the first 12 months of an animal’s life using a population-based sample of calves reared under field conditions and natural disease challenge. Using a longitudinal study design, a stratified clustered random sample of newborn calves was recruited into the IDEAL study and monitored at 5-weekly intervals until 51 weeks of age. The blood cell analysis performed at each visit included: packed cell volume; red cell count; red cell distribution width; mean corpuscular volume; mean corpuscular hemoglobin concentration; hemoglobin concentration; white cell count; absolute lymphocyte, eosinophil, monocyte, and neutrophil counts; platelet count; mean platelet volume; and total serum protein. The most significant age-related change in the red cell parameters was a rise in red cell count and hemoglobin concentration during the neonatal period. This is in contrast to what is reported for other ruminants, including European cattle breeds where the neonatal period is marked by a fall in the red cell parameters. There is a need to establish breed-specific reference ranges for blood parameters for indigenous cattle breeds. The possible role of the postnatal rise in the red cell parameters in the adaptability to environmental constraints and innate disease resistance warrants further research into the dynamics of blood cell parameters of these breeds.Wellcome Trust (project no.079445).http://link.springer.com/journal/580hb2013ab201

Randomized controlled field trial to assess the immunogenicity and safety of rift valley fever clone 13 vaccine in livestock

BACKGROUND:Although livestock vaccination is effective in preventing Rift Valley fever (RVF) epidemics, there are concerns about safety and effectiveness of the only commercially available RVF Smithburn vaccine. We conducted a randomized controlled field trial to evaluate the immunogenicity and safety of the new RVF Clone 13 vaccine, recently registered in South Africa. METHODS:In a blinded randomized controlled field trial, 404 animals (85 cattle, 168 sheep, and 151 goats) in three farms in Kenya were divided into three groups. Group A included males and non-pregnant females that were randomized and assigned to two groups; one vaccinated with RVF Clone 13 and the other given placebo. Groups B included animals in 1st half of pregnancy, and group C animals in 2nd half of pregnancy, which were also randomized and either vaccinated and given placebo. Animals were monitored for one year and virus antibodies titers assessed on days 14, 28, 56, 183 and 365. RESULTS:In vaccinated goats (N = 72), 72% developed anti-RVF virus IgM antibodies and 97% neutralizing IgG antibodies. In vaccinated sheep (N = 77), 84% developed IgM and 91% neutralizing IgG antibodies. Vaccinated cattle (N = 42) did not develop IgM antibodies but 67% developed neutralizing IgG antibodies. At day 14 post-vaccination, the odds of being seropositive for IgG in the vaccine group was 3.6 (95% CI, 1.5 - 9.2) in cattle, 90.0 (95% CI, 25.1 - 579.2) in goats, and 40.0 (95% CI, 16.5 - 110.5) in sheep. Abortion was observed in one vaccinated goat but histopathologic analysis did not indicate RVF virus infection. There was no evidence of teratogenicity in vaccinated or placebo animals. CONCLUSIONS:The results suggest RVF Clone 13 vaccine is safe to use and has high (>90%) immunogenicity in sheep and goats but moderate (> 65%) immunogenicity in cattle

Design and descriptive epidemiology of the Infectious Diseases of East African Livestock (IDEAL) project, a longitudinal calf cohort study in western Kenya

BACKGROUND: There is a widely recognised lack of baseline epidemiological data on the dynamics and impacts of infectious cattle diseases in east Africa. The Infectious Diseases of East African Livestock (IDEAL) project is an epidemiological study of cattle health in western Kenya with the aim of providing baseline epidemiological data, investigating the impact of different infections on key responses such as growth, mortality and morbidity, the additive and/or multiplicative effects of co-infections, and the influence of management and genetic factors. A longitudinal cohort study of newborn calves was conducted in western Kenya between 2007-2009. Calves were randomly selected from all those reported in a 2 stage clustered sampling strategy. Calves were recruited between 3 and 7 days old. A team of veterinarians and animal health assistants carried out 5-weekly, clinical and postmortem visits. Blood and tissue samples were collected in association with all visits and screened using a range of laboratory based diagnostic methods for over 100 different pathogens or infectious exposures. RESULTS: The study followed the 548 calves over the first 51 weeks of life or until death and when they were reported clinically ill. The cohort experienced a high all cause mortality rate of 16% with at least 13% of these due to infectious diseases. Only 307 (6%) of routine visits were classified as clinical episodes, with a further 216 reported by farmers. 54% of calves reached one year without a reported clinical episode. Mortality was mainly to east coast fever, haemonchosis, and heartwater. Over 50 pathogens were detected in this population with exposure to a further 6 viruses and bacteria. CONCLUSION: The IDEAL study has demonstrated that it is possible to mount population based longitudinal animal studies. The results quantify for the first time in an animal population the high diversity of pathogens a population may have to deal with and the levels of co-infections with key pathogens such as Theileria parva. This study highlights the need to develop new systems based approaches to study pathogens in their natural settings to understand the impacts of co-infections on clinical outcomes and to develop new evidence based interventions that are relevant

Accelerating Progress Towards the 2030 Neglected Tropical Diseases Targets: How Can Quantitative Modeling Support Programmatic Decisions?

Over the past decade, considerable progress has been made in the control, elimination, and eradication of neglected tropical diseases (NTDs). Despite these advances, most NTD programs have recently experienced important setbacks; for example, NTD interventions were some of the most frequently and severely impacted by service disruptions due to the coronavirus disease 2019 (COVID-19) pandemic. Mathematical modeling can help inform selection of interventions to meet the targets set out in the NTD road map 2021-2030, and such studies should prioritize questions that are relevant for decision-makers, especially those designing, implementing, and evaluating national and subnational programs. In September 2022, the World Health Organization hosted a stakeholder meeting to identify such priority modeling questions across a range of NTDs and to consider how modeling could inform local decision making. Here, we summarize the outputs of the meeting, highlight common themes in the questions being asked, and discuss how quantitative modeling can support programmatic decisions that may accelerate progress towards the 2030 targets

One Health education in Kakuma refugee camp (Kenya): From a MOOC to projects on real world challenges

Today, the world counts millions of refugees but only a fraction of them have access to higher education. Despite the multiple public health problems in refugee camps and the need to build local capacities to prevent and combat them, University level courses in public health are largely unavailable for refugees. This paper describes the development, implementation and evaluation of an innovative two-module blended-learning programme on One Health in Kakuma refugee camp (Kenya). This programme combines: (I) Interdisciplinary and multi-expert MOOC on “Global Health at the Human-Animal-Ecosystem interface”; (II) peer-to-peer learning involving students from University of Geneva Master of science in Global Health and research collaborations around specific and locally-relevant problems; (III) online mentoring and lecturing by experts from the Institute of Global Health of the University of Geneva in Kakuma. A total of 67 refugees applied to Module 1; 15 started the Module 1 in October 2017, of these 14 completed it and 6 passed the exams, finally five students started the Module 2 in October 2018 which they all passed in February 2019. Five student-led collaborative projects were developed focusing on the conception of a community-based monitoring system for prevalent diseases in the camp. With such a pedagogic approach, the programme provides an overview on Global Health challenges at the human-animal-ecosystem interface and the importance of the One Health approach, and introduces students to scientific research through interdisciplinary and international collaborations and innovation. The high number of applicants and positive feedback from students in Kakuma show the interest in One Health education in the camp. This learning experience ultimately aims at building local knowledge and capacity fostering “One Health” champions to reinforce local and national health system. This framework for One Health education could be potentially scaled up to other camps in Africa and the world