Informing the public health response to COVID-19: a systematic review of risk factors for disease, severity, and mortality.

BACKGROUND: Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) has challenged public health agencies globally. In order to effectively target government responses, it is critical to identify the individuals most at risk of coronavirus disease-19 (COVID-19), developing severe clinical signs, and mortality. We undertook a systematic review of the literature to present the current status of scientific knowledge in these areas and describe the need for unified global approaches, moving forwards, as well as lessons learnt for future pandemics. METHODS: Medline, Embase and Global Health were searched to the end of April 2020, as well as the Web of Science. Search terms were specific to the SARS-CoV-2 virus and COVID-19. Comparative studies of risk factors from any setting, population group and in any language were included. Titles, abstracts and full texts were screened by two reviewers and extracted in duplicate into a standardised form. Data were extracted on risk factors for COVID-19 disease, severe disease, or death and were narratively and descriptively synthesised. RESULTS: One thousand two hundred and thirty-eight papers were identified post-deduplication. Thirty-three met our inclusion criteria, of which 26 were from China. Six assessed the risk of contracting the disease, 20 the risk of having severe disease and ten the risk of dying. Age, gender and co-morbidities were commonly assessed as risk factors. The weight of evidence showed increasing age to be associated with severe disease and mortality, and general comorbidities with mortality. Only seven studies presented multivariable analyses and power was generally limited. A wide range of definitions were used for disease severity. CONCLUSIONS: The volume of literature generated in the short time since the appearance of SARS-CoV-2 has been considerable. Many studies have sought to document the risk factors for COVID-19 disease, disease severity and mortality; age was the only risk factor based on robust studies and with a consistent body of evidence. Mechanistic studies are required to understand why age is such an important risk factor. At the start of pandemics, large, standardised, studies that use multivariable analyses are urgently needed so that the populations most at risk can be rapidly protected. REGISTRATION: This review was registered on PROSPERO as CRD42020177714 .

Using genomics data to reconstruct transmission trees during disease outbreaks.

Genetic sequence data from pathogens present a novel means to investigate the spread of infectious disease between infected hosts or infected premises, complementing traditional contact-tracing approaches, and much recent work has gone into developing methods for this purpose. The objective is to recover the epidemic transmission tree, which identifies who infected whom. This paper reviews the various approaches that have been taken. The first step is to define a measure of difference between sequences, which must be done while taking into account such factors as recombination and convergent evolution. Three broad categories of method exist, of increasing complexity: those that assume no withinhost genetic diversity or mutation, those that assume no within-host diversity but allow mutation, and those that allow both. Until recently, the assumption was usually made that every host in the epidemic could be identified, but this is now being relaxed, and some methods are intended for sparsely sampled data, concentrating on the identification of pairs of sequences that are likely to be the result of direct transmission rather than inferring the complete transmission tree. Many of the procedures described here are available to researchers as free software.

L'accès aux données sur les séquences génétiques des agents pathogènes ouvre de nouvelles perspectives pour étudier la manière dont les maladies infectieuses se propagent entre différents hôtes ou établissements infectés, en complément des méthodes traditionnelles d'évaluation de l'exposition ; de grands efforts ont donc été déployés pour mettre au point des techniques permettant d'arriver à cette fin. Leur objectif est de reconstituer l'arborescence de la transmission d'une épidémie, ce qui permet d'identifier chaque individu ayant infecté d'autres individus. Les auteurs passent en revue les différentes méthodes appliquées. La première étape consiste à définir les modalités de mesure des différences entre séquences, ainsi que les facteurs à prendre en compte, par exemple les phénomènes de recombinaison ou d'évolution convergente. Les méthodes disponibles se répartissent en trois catégories principales, par ordre de complexité croissante : celles qui présupposent qu'il ne peut y avoir de diversité ni de mutation génétiques chez l'hôte ; celles qui présupposent qu'il peut y avoir une diversité génétique mais pas de mutation ; enfin celles qui présupposent qu'il peut y avoir les deux. Jusqu'à une période récente, le présupposé le plus courant était que tous les hôtes intervenant dans un foyer pouvaient être identifiés ; cette exigence s'est considérablement assouplie et de nouvelles méthodes ont été conçues pour travailler à partir d'un échantillon de données plus clairsemé, ce qui permet de se concentrer sur l'identification de paires de séquences révélatrices d'une transmission directe au lieu de déduire l'intégralité de l'arbre de transmission. La plupart des procédures décrites par les auteurs existent sous forme de logiciels libres accessibles aux chercheurs.

Los datos de la secuencia genética de patógenos ofrecen un medio novedoso para investigar la propagación de enfermedades infecciosas entre individuos o establecimientos infectados, medio que viene a complementar la fórmula tradicional consistente en rastrear los contactos. De ahí que últimamente se haya dedicado un ingente trabajo a definir métodos útiles para ese fin. El objetivo radica en desentrañar el árbol de transmisión epidémica, que permite determinar quién infectó a quién. Los autores pasan revista a los diferentes planteamientos adoptados. El primer paso consiste en definir una medida de la diferencia entre secuencias, para lo cual hay que tener en cuenta factores como la recombinación o la convergencia evolutiva. Existen tres grandes clases de métodos, que presentan un grado creciente de complejidad: aquellos que presuponen que no hay diversidad genética ni mutaciones dentro del individuo infectado; aquellos que presuponen que no hay diversidad, pero admiten la posibilidad de mutaciones; y aquellos que postulan que ambas cosas pueden producirse. Hasta hace poco, en general se partía de la premisa de que era posible identificar a todos los individuos infectados en una epidemia. Ahora, sin embargo, se está flexibilizando este postulado, y existen métodos que se aplican específicamente a datos obtenidos con muestreos dispersos, con los cuales se trata de determinar pares de secuencias que probablemente sean resultado de la transmisión directa, y no tanto de inferir el árbol de transmisión completo. Muchos de los procedimientos aquí descritos están a disposición de los investigadores en forma de programas informáticos gratuitos.

Variation and covariation in strongyle infection in East African shorthorn zebu calves.

Parasite burden varies widely between individuals within a population, and can covary with multiple aspects of individual phenotype. Here we investigate the sources of variation in faecal strongyle eggs counts, and its association with body weight and a suite of haematological measures, in a cohort of indigenous zebu calves in Western Kenya, using relatedness matrices reconstructed from single nucleotide polymorphism (SNP) genotypes. Strongyle egg count was heritable (h(2) = 23.9%, s.e. = 11.8%) and we also found heritability of white blood cell counts (WBC) (h(2) = 27.6%, s.e. = 10.6%). All the traits investigated showed negative phenotypic covariances with strongyle egg count throughout the first year: high worm counts were associated with low values of WBC, red blood cell count, total serum protein and absolute eosinophil count. Furthermore, calf body weight at 1 week old was a significant predictor of strongyle EPG at 16-51 weeks, with smaller calves having a higher strongyle egg count later in life. Our results indicate a genetic basis to strongyle EPG in this population, and also reveal consistently strong negative associations between strongyle infection and other important aspects of the multivariate phenotype.

Efficient national surveillance for health-care-associated infections.

BACKGROUND: Detecting novel healthcare-associated infections (HCAI) as early as possible is an important public health priority. However, there is currently no evidence base to guide the design of efficient and reliable surveillance systems. Here we address this issue in the context of a novel pathogen spreading primarily between hospitals through the movement of patients. METHODS: Using a mathematical modelling approach we compare the current surveillance system for a HCAI that spreads primarily between hospitals due to patient movements as it is implemented in Scotland with a gold standard to determine if the current system is maximally efficient or whether it would be beneficial to alter the number and choice of hospitals in which to concentrate surveillance effort. RESULTS: We validated our model by demonstrating that it accurately predicts the risk of meticillin-resistant Staphylococcus aureus bacteraemia cases in Scotland. Using the 29 (out of 182) sentinel hospitals that currently contribute most of the national surveillance effort results in an average detection time of 117 days. A reduction in detection time to 87 days is possible by optimal selection of 29 hospitals. Alternatively, the same detection time (117 days) can be achieved using just 22 optimally selected hospitals. Increasing the number of sentinel hospitals to 38 (teaching and general hospitals) reduces detection time by 43 days; however decreasing the number to seven sentinel hospitals (teaching hospitals) increases detection time substantially to 268 days. CONCLUSIONS: Our results show that the current surveillance system as it is used in Scotland is not optimal in detecting novel pathogens when compared to a gold standard. However, efficiency gains are possible by better choice of sentinel hospitals, or by increasing the number of hospitals involved in surveillance. Similar studies could be used elsewhere to inform the design and implementation of efficient national, hospital-based surveillance systems that achieve rapid detection of novel HCAIs for minimal effort.

Time-Scaled Evolutionary Analysis of the Transmission and Antibiotic Resistance Dynamics of Staphylococcus aureus Clonal Complex 398.

Staphylococcus aureus clonal complex 398 (CC398) is associated with disease in humans and livestock, and its origins and transmission have generated considerable interest. We performed a time-scaled phylogenetic analysis of CC398, including sequenced isolates from the United Kingdom (Scotland), along with publicly available genomes. Using state-of-the-art methods for mapping traits onto phylogenies, we quantified transitions between host species to identify sink and source populations for CC398 and employed a novel approach to investigate the gain and loss of antibiotic resistance in CC398 over time. We identified distinct human- and livestock-associated CC398 clades and observed multiple transmissions of CC398 from livestock to humans and between countries, lending quantitative support to previous reports. Of note, we identified a subclade within the livestock-associated clade comprised of isolates from hospital environments and newborn babies, suggesting that livestock-associated CC398 is capable of onward transmission in hospitals. In addition, our analysis revealed significant differences in the dynamics of resistance to methicillin and tetracycline related to contrasting historical patterns of antibiotic usage between the livestock industry and human medicine. We also identified significant differences in patterns of gain and loss of different tetracycline resistance determinants, which we ascribe to epistatic interactions between the resistance genes and/or differences in the modes of inheritance of the resistance determinants.

Genome-wide analysis reveals the ancient and recent admixture history of East African Shorthorn Zebu from Western Kenya.

The Kenyan East African zebu cattle are valuable and widely used genetic resources. Previous studies using microsatellite loci revealed the complex history of these populations with the presence of taurine and zebu genetic backgrounds. Here, we estimate at genome-wide level the genetic composition and population structure of the East African Shorthorn Zebu (EASZ) of western Kenya. A total of 548 EASZ from 20 sub-locations were genotyped using the Illumina BovineSNP50 v. 1 beadchip. STRUCTURE analysis reveals admixture with Asian zebu, African and European taurine cattle. The EASZ were separated into three categories: substantial (⩾12.5%), moderate (1.56%

A longitudinal assessment of the serological response to Theileria parva and other tick-borne parasites from birth to one year in a cohort of indigenous calves in western Kenya.

Tick-borne diseases are a major impediment to improved productivity of livestock in sub-Saharan Africa. Improved control of these diseases would be assisted by detailed epidemiological data. Here we used longitudinal, serological data to determine the patterns of exposure to Theileria parva, Theileria mutans, Babesia bigemina and Anaplasma marginale from 548 indigenous calves in western Kenya. The percentage of calves seropositive for the first three parasites declined from initial high levels due to maternal antibody until week 16, after which the percentage increased until the end of the study. In contrast, the percentage of calves seropositive for T. mutans increased from week 6 and reached a maximal level at week 16. Overall 423 (77%) calves seroconverted to T. parva, 451 (82%) to T. mutans, 195 (36%) to B. bigemina and 275 (50%) to A. marginale. Theileria parva antibody levels were sustained following infection, in contrast to those of the other three haemoparasites. Three times as many calves seroconverted to T. mutans before seroconverting to T. parva. No T. parva antibody response was detected in 25 calves that died of T. parva infection, suggesting that most deaths due to T. parva are the result of acute disease from primary exposure.

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.

Low-coverage vaccination strategies for the conservation of endangered species.

The conventional objective of vaccination programmes is to eliminate infection by reducing the reproduction number of an infectious agent to less than one, which generally requires vaccination of the majority of individuals. In populations of endangered wildlife, the intervention required to deliver such coverage can be undesirable and impractical; however, endangered populations are increasingly threatened by outbreaks of infectious disease for which effective vaccines exist. As an alternative, wildlife epidemiologists could adopt a vaccination strategy that protects a population from the consequences of only the largest outbreaks of disease. Here we provide a successful example of this strategy in the Ethiopian wolf, the world's rarest canid, which persists in small subpopulations threatened by repeated outbreaks of rabies introduced by domestic dogs. On the basis of data from past outbreaks, we propose an approach that controls the spread of disease through habitat corridors between subpopulations and that requires only low vaccination coverage. This approach reduces the extent of rabies outbreaks and should significantly enhance the long-term persistence of the population. Our study shows that vaccination used to enhance metapopulation persistence through elimination of the largest outbreaks of disease requires lower coverage than the conventional objective of reducing the reproduction number of an infectious agent to less than one.

Epidemiology of and risk factors for mortality due to carbapenemase-producing organisms (CPO) in healthcare facilities.

BACKGROUND: Carbapenemase-producing organisms (CPO) have been largely responsible for the extensive spread of carbapenem resistance, and their prevalence is increasing in many parts of the world. AIM: To evaluate clinical and molecular epidemiology and mortality associated with CPO among patients. METHODS: All CPO from clinical and long-term healthcare surveillance cultures across Scotland in 2003-2017 were reviewed retrospectively. Polymerase chain reaction was used to detect genes coding for carbapenemases. A generalized linear mixed model was used to identify risk factors for mortality. FINDINGS: In total, 290 individuals with CPO were identified. The overall incidence increased over time (P<0.001) from 0.02 to 1.38 per 100,000 population between 2003 and 2017. A total of 243 distinct CPO isolates were obtained from 269 isolations in 214 individuals with available metadata. The majority of the isolates were Enterobacterales (206/243, 84.8%), and Klebsiella pneumoniae (65/206, 31.6%) and Enterobacter cloacae (52/206, 25.2%) were the most common species. VIM (75/243, 30.9%) and NDM (56/243, 23.0%) were the most common carbapenemases. The crude 30-day mortality rate was 11.8% (25/211), while the case fatality rate was 5.7% (12/211). Age >60 years [adjusted odds ratio (aOR) 3.36, 95% confidence interval (CI) 1.06-10.63; P=0.033], presence of non-fermenters (aOR 4.88, 95% CI 1.64-14.47; P=0.005), and systemic infection or organ failure (aOR 4.21, 95% CI 1.38-12.81; P=0.032) were independently associated with 30-day mortality. CONCLUSION: The incidence of CPO in Scotland is low but increasing. Awareness is required that inpatients aged >60 years, patients with systemic infection or organ failure, and patients presenting with non-fermenters are at higher risk of death from CPO.

Reflections on IDEAL: What we have learnt from a unique calf cohort study.

The year 2020 marks a decade since the final visit was made in the 'Infectious Diseases of East African Livestock' (IDEAL) project. However, data generation from samples obtained during this ambitious longitudinal study still continues. As the project launches its extensive open-access database and biobank to the scientific community, we reflect on the challenges overcome, the knowledge gained, and the advantages of such a project. We discuss the legacy of the IDEAL project and how it continues to generate evidence since being adopted by the Centre for Tropical Livestock Genetics and Health (CTLGH). We also examine the impact of the IDEAL project, from the authors perspective, for each of the stakeholders (the animal, the farmer, the consumer, the policy maker, the funding body, and the researcher and their institution) involved in the project and provide recommendations for future researchers who are interested in running longitudinal field studies.

Deterministic processes structure bacterial genetic communities across an urban landscape.

Land-use change is predicted to act as a driver of zoonotic disease emergence through human exposure to novel microbial diversity, but evidence for the effects of environmental change on microbial communities in vertebrates is lacking. We sample wild birds at 99 wildlife-livestock-human interfaces across Nairobi, Kenya, and use whole genome sequencing to characterise bacterial genes known to be carried on mobile genetic elements (MGEs) within avian-borne Escherichia coli (n = 241). By modelling the diversity of bacterial genes encoding virulence and antimicrobial resistance (AMR) against ecological and anthropogenic forms of urban environmental change, we demonstrate that communities of avian-borne bacterial genes are shaped by the assemblage of co-existing avian, livestock and human communities, and the habitat within which they exist. In showing that non-random processes structure bacterial genetic communities in urban wildlife, these findings suggest that it should be possible to forecast the effects of urban land-use change on microbial diversity.

The predicted impact of immunosuppression upon population age-intensity profiles for schistosomiasis.

The slow development of acquired immunity is thought to be responsible for the characteristic convex age-intensity curve seen in human schistosome infection, which peaks earlier in more heavily infected populations (this is described as a peak shift). Schistosomes are able to suppress protective host responses, and it is hypothesized that this suppression is responsible for the delayed development of protective responses. A deterministic mathematical model is used to describe levels of infection and immunity in an endemic population, incorporating protective immune responses which either reduce adult worm burden or reduce superinfection. Suppression, related to current worm burden, is also included and acts against one or both protective responses. If suppression acts against the entire protective response, it is able to delay the development of protective immunity, and the peak shift is predicted to be reversed at higher infection intensities, with removal of the peaks altogether at the highest levels of infection and/or suppression. If only the anti-adult worm protective immune response is vulnerable to suppression, while the anti-reinfection response remains intact, then suppression does not remove the peak in the age-intensity curve. These findings are discussed in the light of existing field and experimental data.

Modelling the impact of curtailing antibiotic usage in food animals on antibiotic resistance in humans.

Consumption of antibiotics in food animals is increasing worldwide and is approaching, if not already surpassing, the volume consumed by humans. It is often suggested that reducing the volume of antibiotics consumed by food animals could have public health benefits. Although this notion is widely regarded as intuitively obvious there is a lack of robust, quantitative evidence to either support or contradict the suggestion. As a first step towards addressing this knowledge gap, we develop a simple mathematical model for exploring the generic relationship between antibiotic consumption by food animals and levels of resistant bacterial infections in humans. We investigate the impact of restricting antibiotic consumption by animals and identify which model parameters most strongly determine that impact. Our results suggest that, for a wide range of scenarios, curtailing the volume of antibiotics consumed by food animals has, as a stand-alone measure, little impact on the level of resistance in humans. We also find that reducing the rate of transmission of resistance from animals to humans may be more effective than an equivalent reduction in the consumption of antibiotics in food animals. Moreover, the response to any intervention is strongly determined by the rate of transmission from humans to animals, an aspect which is rarely considered.

Molecular characterisation of bovine faecal Escherichia coli shows persistence of defined ampicillin resistant strains and the presence of class 1 integrons on an organic beef farm.

Antimicrobial use is heavily restricted on organic farms; however, few studies have been conducted to investigate the impact this has on the epidemiology of resistance in pathogenic and commensal bacteria. We investigated the persistence of antimicrobial resistant Escherichia coli within an organic beef herd over a period of 28 months. Faecal samples collected monthly from three calf cohorts and annually from adult cattle and environmental samples, were screened for the presence of ampicillin, apramycin and nalidixic acid resistant E. coli. The prevalence of ampicillin resistance ranged from 27.3 to 40.7% in the annual herd and environmental samplings (n=22-55) and was greater in the calf cohorts, with a peak cohort prevalence of >47% in all 3 years (n=16-18). Apramycin and nalidixic acid resistant E. coli were rare. Pulsed-field gel electrophoresis (PFGE) identified 10 main genotype groups within the herd, with evidence of strain transmission between different livestock groups, animal species and years. Multiple resistance was found in >44% of isolates tested, with ampicillin, neomycin, sulphamethoxazole and tetracycline carriage the commonest phenotype identified. PCR detected the presence of class 1 integrons in <5% of resistant isolates, 6/7 of which were of cattle origin. These data demonstrate that ampicillin resistant E. coli was common on the farm despite restricted antimicrobial use, although strain diversity was low. Persistence of defined genotype groups was observed between years, together with the transmission of resistant strains between different animal species on the farm.

Seroprevalence of respiratory viral pathogens of indigenous calves in Western Kenya.

Most studies of infectious diseases in East African cattle have concentrated on gastro-intestinal parasites and vector-borne diseases. As a result, relatively little is known about viral diseases, except for those that are clinically symptomatic or which affect international trade such as foot and mouth disease, bluetongue and epizootic haemorrhagic disease. Here, we investigate the seroprevalence, distribution and relationship between the viruses involved in respiratory disease, infectious bovine rhinotracheitis virus (IBR), bovine parainfluenza virus Type 3 (PIV3) and bovine viral diarrhoea virus (BVDV) in East African Shorthorn Zebu calves. These viruses contribute to the bovine respiratory disease complex (BRD) which is responsible for major economic losses in cattle from intensive farming systems as a result of pneumonia. We found that calves experience similar risks of infection for IBR, PIV3, and BVDV with a seroprevalence of 20.9%, 20.1% and 19.8% respectively. We confirm that positive associations exist between IBR, PIV3 and BVDV; being seropositive for any one of these three viruses means that an individual is more likely to be seropositive for the other two viruses than expected by chance.

Neighbourhood control policies and the spread of infectious diseases.

We present a model of a control programme for a disease outbreak in a population of livestock holdings. Control is achieved by culling infectious holdings when they are discovered and by the pre-emptive culling of livestock on holdings deemed to be at enhanced risk of infection. Because the pre-emptive control programme cannot directly identify exposed holdings, its implementation will result in the removal of both infected and uninfected holdings. This leads to a fundamental trade-off: increased levels of control produce a greater reduction in transmission by removing more exposed holdings, but increase the number of uninfected holdings culled. We derive an expression for the total number of holdings culled during the course of an outbreak and demonstrate that there is an optimal control policy, which minimizes this loss. Using a metapopulation model to incorporate local clustering of infection, we examine a neighbourhood control programme in a locally spreading outbreak. We find that there is an optimal level of control, which increases with increasing basic reproduction ratio, R(0); moreover, implementation of control may be optimal even when R(0) < 1. The total loss to the population is relatively insensitive to the level of control as it increases beyond the optimal level, suggesting that over-control is a safer policy than under-control.

The construction and analysis of epidemic trees with reference to the 2001 UK foot-and-mouth outbreak.

The case-reproduction ratio for the spread of an infectious disease is a critically important concept for understanding dynamics of epidemics and for evaluating impact of control measures on spread of infection. Reliable estimation of this ratio is a problem central to epidemiology and is most often accomplished by fitting dynamic models to data and estimating combinations of parameters that equate to the case-reproduction ratio. Here, we develop a novel parameter-free method that permits direct estimation of the history of transmission events recoverable from detailed observation of a particular epidemic. From these reconstructed 'epidemic trees', case-reproduction ratios can be estimated directly. We develop a bootstrap algorithm that generates percentile intervals for these estimates that shows the procedure to be both precise and robust to possible uncertainties in the historical reconstruction. Identifying and 'pruning' branches from these trees whose occurrence might have been prevented by implementation of more stringent control measures permits estimation of the possible efficacy of these alternative measures. Examination of the cladistic structure of these trees as a function of the distance of each case from its infection source reveals useful insights about the relationship between long-distance transmission events and epidemic size. We demonstrate the utility of these methods by applying them to data from the 2001 foot-and-mouth disease outbreak in the UK.

Contrasting cellular responses in Schistosoma haematobium infected and exposed individuals from areas of high and low transmission in Zimbabwe.

The study compared cytokine profiles of individuals from two areas with different transmission patterns for Schistosoma haematobium. One area was a high transmission (HT) while the other was a low transmission (LT) area for S. haematobium. Observations on cellular immune responses were made on stimulated peripheral blood mononuclear cells (PBMC), which were collected pre-treatment, then at 12 and 18 months post treatment. Stimulation was with schistosome worm and egg antigens and a mitogen, phaetohaemaglutinin (PHA). Observations were made on PBMC proliferation and the profiles of cytokine produced over a 5-day incubation period. The two distinct areas showed significant differences on both levels of proliferation and cytokine production for all the measured classes (IL-4, IL-5, IL-10 and IFN-gamma). PBMC from individuals from the LT area had high levels of proliferation but low cytokine production to both antigen stimulants while PBMC from individuals from the HT area showed low levels of proliferation but high cytokine production levels. Prior to treatment, individuals not excreting schistosome ova in the HT area had higher levels of proliferation to the stimulants, than the infected individuals. However, after treatment re-infected individuals showed high levels of proliferation. Before treatment, both infected and uninfected groups showed low and similar ratios, respectively, of IL-4:IFN-gamma, IL-5:IFN-gamma and IL-10:IFN-gamma, while IFN-gamma was high in the infected individuals. After treatment the non re-infected had higher levels of IL-4, IL-5 and IL-10, with the infected having high levels of IFN-gamma. Th1-like response dominated during infection with the Th2-like responses dominating post treatment and in uninfected individuals. The results indicated that the cytokine balance determines, in part, susceptibility or resistance to S. haematobium infection.

Spatial and temporal risk factors for the early detection of Trypanosoma brucei rhodesiense sleeping sickness patients in Tororo and Busia districts, Uganda.

We have carried out a study of risk factors for early detection of Trypanosoma brucei rhodesiense sleeping sickness. Records of sleeping sickness patients from 1987 to 2001 from Tororo and Busia districts in Uganda were reviewed for their village of origin and clinical stage (early or late). All villages that reported sleeping sickness and fixed post-diagnostic sleeping sickness health units in Tororo and Busia districts were geo-referenced. The spatial distribution of early and late stage patient detection by health units was analysed using Geographical Information Systems (GIS). Of 1316 sleeping sickness patients admitted at the Livestock Health Research Institute and Busolwe hospitals and Lumino health centre from Tororo and Busia districts, 471 (35.8%) were early stage, 825 (62.7%) were late stage, while 20 (1.5%) were not staged. Five hundred and eighty-five (44.5%) came from within a 10 km radius of the reporting health units. After multivariate analysis, the proportion of early stage patients detected was found to be significantly associated with patients originating from within a 10 km radius of the health unit (P < 0.01), with adults (>19 years) (P < 0.01), and with annual parish incidence (P < 0.01). Application of GIS and the early to late stages ratio are an informative and powerful means of determining efficiency of surveillance of sleeping sickness.