Untangling the stranglehold through mathematical modelling of Streptococcus equi subspecies equi transmission.

Strangles, a disease caused by infection with Streptococccus equi subspecies equi (S. equi), is endemic worldwide and one of the most frequently diagnosed infectious diseases of horses. Recent work has improved our knowledge of key parameters of transmission dynamics, but important knowledge gaps remain. Our aim was to apply mathematical modelling of S. equi transmission dynamics to prioritise future research areas, and add precision to estimates of transmission parameters thereby improving understanding of S. equi epidemiology and quantifying the control effort required. A compartmental deterministic model was constructed. Parameter values were estimated from current literature wherever possible. We assessed the sensitivity of estimates for the basic reproduction number on the population scale to varying assumptions for the unknown or uncertain parameters of: (mean) duration of carriership (1∕γC), relative infectiousness of carriers (f), proportion of infections that result in carriership (p), and (mean) duration of immunity after natural infection (1∕γR). Available incidence and (sero-)prevalence data were compared to model outputs to improve point estimates and ranges for these currently unknown or uncertain transmission-related parameters. The required vaccination coverage of an ideal vaccine to prevent major outbreaks under a range of control scenarios was estimated, and compared available data on existing vaccines. The relative infectiousness of carriers (as compared to acutely ill horses) and the duration of carriership were identified as key knowledge gaps. Deterministic compartmental simulations, combined with seroprevalence data, suggest that 0.05

The Value of Warning Signs From the WHO 2009 Dengue Classification in Detecting Severe Dengue in Children.

BACKGROUND: World Health Organization proposed 7 warning signs to identify the risk of severe dengue in 2009. This study aimed to evaluate the value of these warning signs in detecting severe dengue in children. MATERIAL AND METHODS: A cross-sectional study was conducted utilizing data of children with clinical dengue infection obtained from medical records between January 2009 and December 2018 in Jakarta. Children with confirmed dengue were analyzed and stratified into 3 age groups: infants less than 1 year old, children 1-14 years and adolescents 15-18 years of age. Positive predictive value, negative predictive value (NPV), sensitivity and specificity of each warning sign present or absent on admission in detecting severe dengue were computed. RESULTS: Six hundred ninety-nine children with clinical dengue infection were enrolled, among whom 614 (87.8%) had confirmed dengue infection, either by antigen or antibody serological tests. Severe dengue occurred in 211/614 (34.4%) cases. In infants, important warning signs on admission to detect or exclude severe dengue were liver enlargement (NPV 80.8%) and clinical fluid accumulation (NPV 75%). In children and adolescents, warning sign with highest NPV (in children 76.6% and in adolescents 91.9%) was increase in hematocrit concurrent with a rapid decrease in platelet count. Other warning signs with high NPV values in children were abdominal pain (72%), vomiting (70%), clinical fluid accumulation (69.3%), and in adolescents' abdominal pain (80.7%), vomiting (75.7%), clinical fluid accumulation (82.7%). NPVs increase with more than 1 warning sign in all age groups. CONCLUSION: In infants, liver enlargement or clinical fluid accumulation are important warning signs for severe dengue, when both are absent, severe dengue is unlikely. In older children and adolescents, an increase in hematocrit with the concurrent rapid decrease in platelet count is most discriminative; followed by the absence of abdominal pain, vomiting or fluid accumulation are unlikely severe dengue.

Genetic analysis of infectious bronchitis virus (IBV) in vaccinated poultry populations over a period of 10 years.

Infectious bronchitis virus (IBV) is an avian pathogen from the Coronavirus family causing major health issues in poultry flocks worldwide. Because of its negative impact on health, performance, and bird welfare, commercial poultry are routinely vaccinated by administering live attenuated virus. However, field strains are capable of rapid adaptation and may evade vaccine-induced immunity. We set out to describe dynamics within and between lineages and assess potential escape from vaccine-induced immunity. We investigated a large nucleotide sequence database of over 1700 partial sequences of the S1 spike protein gene collected from clinical samples of Dutch chickens submitted to the laboratory of Royal GD between 2011 and 2020. Relative frequencies of the two major lineages GI-13 (793B) and GI-19 (QX) did not change in the investigated period, but we found a succession of distinct GI-19 sublineages. Analysis of dN/dS ratio over all sequences demonstrated episodic diversifying selection acting on multiple sites, some of which overlap predicted N-glycosylation motifs. We assessed several measures that would indicate divergence from vaccine strains, both in the overall database and in the two major lineages. However, the frequency of vaccine-homologous lineages did not decrease, no increase in genetic variation with time was detected, and the sequences did not grow more divergent from vaccine sequences in the examined time window. Concluding, our results show sublineage turnover within the GI-19 lineage and we demonstrate episodic diversifying selection acting on the partial sequence, but we cannot confirm nor rule out escape from vaccine-induced immunity.RESEARCH HIGHLIGHTSSuccession of GI-19 IBV variants in broiler populations.IBV lineages overrepresented in either broiler, or layer production chickens.Ongoing episodic selection at the IBV S1 spike protein gene sequence.Several positively selected codons coincident with N-glycosylation motifs.

Exploring the influence of competition on arbovirus invasion risk in communities.

Arbovirus outbreaks in communities are affected by how vectors, hosts and non-competent species interact. In this study, we investigate how ecological interactions between species and epidemiological processes influence the invasion potential of a vector-borne disease. We use an eco-epidemiological model to explore the basic reproduction number R0 for a range of interaction strengths in key processes, using West Nile virus infection to parameterize the model. We focus our analysis on intra and interspecific competition between vectors and between hosts, as well as competition with non-competent species. We show that such ecological competition has non-linear effects on R0 and can greatly impact invasion risk. The presence of multiple competing vector species results in lower values for R0 while host competition leads to the highest values of risk of disease invasion. These effects can be understood in terms of how the competitive pressures influence the vector-to-host ratio, which has a positive relationship with R0. We also show numerical examples of how vector feeding preferences become more relevant in high competition conditions between hosts. Under certain conditions, non-competent hosts, which can lead to a dilution effect for the pathogen, can have an amplification effect if they compete strongly with the competent hosts, hence facilitating pathogen invasion in the community.

Infection dynamics in ecosystems: on the interaction between red and grey squirrels, pox virus, pine martens and trees.

Ecological and epidemiological processes and interactions influence each other, positively and negatively, directly and indirectly. The invasion potential of pathogens is influenced by the ecosystem context of their host species' populations. This extends to the capacity of (multiple) host species to maintain their (common) pathogen and the way pathogen dynamics are influenced by changes in ecosystem composition. This paper exemplifies these interactions and consequences in a study of red and grey squirrel dynamics in the UK. Differences and changes in background habitat and trophic levels above and below the squirrel species lead to different dynamic behaviour in many subtle ways. The range of outcomes of the different interactions shows that one has to be careful when drawing conclusions about the mechanisms and processes involved in explaining observed phenomena concerning pathogens in their natural environment. The dynamic behaviour also shows that planning interventions, for example for conservation purposes, benefits from understanding the complexity of interactions beyond the particular pathogen and its threatened host species.

Characterizing reservoirs of infection and the maintenance of pathogens in ecosystems.

We use a previously published compartmental model of the dynamics of pathogens in ecosystems to define and explore the concepts of maintenance host, maintenance community and reservoir of infection in a full ecological context of interacting host and non-host species. We show that, contrary to their current use in the literature, these concepts can only be characterized relative to the ecosystem in which the host species are embedded, and are not 'life-history traits' of (groups of) species. We give a number of examples to demonstrate that the same (group of) host species can lose or gain maintenance or reservoir capability as a result of a changing ecosystem context, even when these changes primarily affect non-hosts. One therefore has to be careful in designating host species as either maintenance or reservoir in absolute terms.

Clinical Course and Management of Dengue in Children Admitted to Hospital: A 5 Years Prospective Cohort Study in Jakarta, Indonesia.

BACKGROUND: Dengue incidence is rising globally which was estimated 100 million per year, whereas in Indonesia was estimated 7.5 million per year. Dengue clinical course varies from mild dengue fever (DF) to dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Patients, clinicians and care facilities would benefit if reliable predictors can determine at admission which cases with clinically suspected dengue will progress to DHF or DSS. METHODS: From 2009 through 2013, a cohort of 494 children admitted with clinically suspected dengue at a tertiary care hospital in Jakarta, Indonesia, was followed until discharge. We evaluated the clinical course and disease outcome of admitted patients and estimated the burden of dengue cases hospitalized over time. RESULTS: Of all 494 children, 185 (37%) were classified at admission as DF, 158 (32%) as DHF and 151 (31%) as DSS. Of DF patients, 52 (28%) progressed to DHF or DSS, 10 (5%) had other viral diseases. Of DHF patients, 9(6%) progressed to DSS. Of 33 routinely collected parameters at admission, duration of fever ≤4 days was the only significant predictor of disease progression (P = 0.01). Five cases (3%) admitted with DSS died. Between 2009 and 2013, annual dengue admissions declined, while distribution of disease severity remained stable. CONCLUSIONS: Almost a third of children admitted to tertiary care with clinically suspected DF progress to DHF or DSS. Among routinely collected parameters at admission, only fever duration was significantly associated with clinical progression, emphasizing unpredictability of dengue disease course from parameters currently routinely collected.

Clinical Course and Management of Dengue in Children Admitted to Hospital; A 5 Years Prospective Cohort Study in Jakarta, Indonesia.

BACKGROUND: Dengue incidence is rising globally which was estimated 100 million per year, whereas in Indonesia was estimated 7.5 million per year. Dengue clinical course varies from mild dengue fever (DF) to dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Patients, clinicians and care facilities would benefit if reliable predictors can determine at admission which cases with clinically suspected dengue will progress to DHF or DSS. METHODS: From 2009 through 2013, a cohort of 496 children admitted with clinically suspected dengue at a tertiary care hospital in Jakarta, Indonesia in, was followed until discharge. We evaluated the clinical course and disease outcome of admitted patients, and estimated the burden of dengue cases hospitalized over time. RESULTS: Of all 496 children, 185 (37%) were classified at admission as DF, 158 (32%) as DHF and 153 (31%) as DSS. Of DF patients, 52 (28%) progressed to DHF or DSS, 10 (5%) had other viral diseases. Of DHF patients, 9(6%) progressed to DSS. No patients died. Of 33 routinely collected parameters at admission, duration of fever ≤ 4 days was the only significant predictor of disease progression (p= 0.01). Between 2009 and 2013, annual dengue admissions declined, while the distribution of disease severity remained stable. CONCLUSIONS: Almost a third of children admitted to tertiary care with clinically suspected DF progress to DHF or DSS. Among routinely collected parameters at admission, only fever duration was significantly associated with clinical progression, emphasizing the unpredictability of dengue disease course from parameters currently routinely collected.

Quantifying the dilution effect for models in ecological epidemiology.

The dilution effect, where an increase in biodiversity results in a reduction in the prevalence of an infectious disease, has been the subject of speculation and controversy. Conversely, an amplification effect occurs when increased biodiversity is related to an increase in prevalence. We explore the conditions under which these effects arise, using multi species compartmental models that integrate ecological and epidemiological interactions. We introduce three potential metrics for quantifying dilution and amplification, one based on infection prevalence in a focal host species, one based on the size of the infected subpopulation of that species and one based on the basic reproduction number. We introduce our approach in the simplest epidemiological setting with two species, and show that the existence and strength of a dilution effect is influenced strongly by the choices made to describe the system and the metric used to gauge the effect. We show that our method can be generalized to any number of species and to more complicated ecological and epidemiological dynamics. Our method allows a rigorous analysis of ecological systems where dilution effects have been postulated, and contributes to future progress in understanding the phenomenon of dilution in the context of infectious disease dynamics and infection risk.

How mathematical epidemiology became a field of biology: a commentary on Anderson and May (1981) 'The population dynamics of microparasites and their invertebrate hosts'.

We discuss the context, content and importance of the paper 'The population dynamics of microparasites and their invertebrate hosts', by R. M. Anderson and R. M. May, published in the Philosophical Transactions of the Royal Society as a stand-alone issue in 1981. We do this from the broader perspective of the study of infectious disease dynamics, rather than the specific perspective of the dynamics of insect pathogens. We argue that their 1981 paper fits seamlessly in the systematic study of infectious disease dynamics that was initiated by the authors in 1978, combining effective use of simple mathematical models, firmly rooted in biology, with observable or empirically measurable ingredients and quantities, and promoting extensive capacity building. This systematic approach, taking ecology and biology rather than applied mathematics as the motivation for advance, proved essential for the maturation of the field, and culminated in their landmark textbook of 1991. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society.

Principal climatic and edaphic determinants of Culicoides biting midge abundance during the 2007-2008 bluetongue epidemic in the Netherlands, based on OVI light trap data.

Palaearctic Culicoides midges (Diptera: Ceratopogonidae) represent a vital link in the northward advance of certain arboviral pathogens of livestock such as that caused by bluetongue virus. The effects of relevant ecological factors on weekly Culicoides vector abundances during the bluetongue virus serotype 8 epidemics in the Netherlands in 2007 and 2008 were quantified within a hurdle modelling framework. The relative role of meteorological parameters showed a broadly consistent association across species, with larger catches linked to temperature-related variables and lower wind speed. Moreover, vector abundance was found to be influenced by edaphic factors, likely related to species-specific breeding habitat preferences that differed markedly amongst some species. This is the first study on Culicoides vector species in the Netherlands identified during an entomological surveillance programme, in which an attempt is made to pinpoint the factors that influence midge abundance levels. In addition to providing key inputs into risk-mitigating tools for midge-borne pathogens and disease transmission models, the adoption of methods that explicitly address certain features of abundance datasets (frequent zero-count observations and over-dispersion) helped enhance the robustness of the ecological analysis.

Mapping the distribution of the main host for plague in a complex landscape in Kazakhstan: An object-based approach using SPOT-5 XS, Landsat 7 ETM+, SRTM and multiple Random Forests.

Plague is a zoonotic infectious disease present in great gerbil populations in Kazakhstan. Infectious disease dynamics are influenced by the spatial distribution of the carriers (hosts) of the disease. The great gerbil, the main host in our study area, lives in burrows, which can be recognized on high resolution satellite imagery. In this study, using earth observation data at various spatial scales, we map the spatial distribution of burrows in a semi-desert landscape. The study area consists of various landscape types. To evaluate whether identification of burrows by classification is possible in these landscape types, the study area was subdivided into eight landscape units, on the basis of Landsat 7 ETM+ derived Tasselled Cap Greenness and Brightness, and SRTM derived standard deviation in elevation. In the field, 904 burrows were mapped. Using two segmented 2.5 m resolution SPOT-5 XS satellite scenes, reference object sets were created. Random Forests were built for both SPOT scenes and used to classify the images. Additionally, a stratified classification was carried out, by building separate Random Forests per landscape unit. Burrows were successfully classified in all landscape units. In the 'steppe on floodplain' areas, classification worked best: producer's and user's accuracy in those areas reached 88% and 100%, respectively. In the 'floodplain' areas with a more heterogeneous vegetation cover, classification worked least well; there, accuracies were 86 and 58% respectively. Stratified classification improved the results in all landscape units where comparison was possible (four), increasing kappa coefficients by 13, 10, 9 and 1%, respectively. In this study, an innovative stratification method using high- and medium resolution imagery was applied in order to map host distribution on a large spatial scale. The burrow maps we developed will help to detect changes in the distribution of great gerbil populations and, moreover, serve as a unique empirical data set which can be used as input for epidemiological plague models. This is an important step in understanding the dynamics of plague.

Characterizing the next-generation matrix and basic reproduction number in ecological epidemiology.

We address the interaction of ecological processes, such as consumer-resource relationships and competition, and the epidemiology of infectious diseases spreading in ecosystems. Modelling such interactions seems essential to understand the dynamics of infectious agents in communities consisting of interacting host and non-host species. We show how the usual epidemiological next-generation matrix approach to characterize invasion into multi-host communities can be extended to calculate R0, and how this relates to the ecological community matrix. We then present two simple examples to illustrate this approach. The first of these is a model of the rinderpest, wildebeest, grass interaction, where our inferred dynamics qualitatively matches the observed phenomena that occurred after the eradication of rinderpest from the Serengeti ecosystem in the 1980s. The second example is a prey-predator system, where both species are hosts of the same pathogen. It is shown that regions for the parameter values exist where the two host species are only able to coexist when the pathogen is present to mediate the ecological interaction.

Extending the type reproduction number to infectious disease control targeting contacts between types.

A new quantity called the target reproduction number is defined to measure control strategies for infectious diseases with multiple host types such as waterborne, vector-borne and zoonotic diseases. The target reproduction number includes as a special case and extends the type reproduction number to allow disease control targeting contacts between types. Relationships among the basic, type and target reproduction numbers are established. Examples of infectious disease models from the literature are given to illustrate the use of the target reproduction number.

Assessing the impact of feline immunodeficiency virus and bovine tuberculosis co-infection in African lions.

Bovine tuberculosis (BTB), caused by Mycobacterium bovis, is a disease that was introduced relatively recently into the Kruger National Park (KNP) lion population. Feline immunodeficiency virus (FIV(ple)) is thought to have been endemic in lions for a much longer time. In humans, co-infection between Mycobacterium tuberculosis and human immunodeficiency virus increases disease burden. If BTB were to reach high levels of prevalence in lions, and if similar worsening effects would exist between FIV(ple) and BTB as for their human equivalents, this could pose a lion conservation problem. We collected data on lions in KNP from 1993 to 2008 for spatio-temporal analysis of both FIV(ple) and BTB, and to assess whether a similar relationship between the two diseases exists in lions. We found that BTB prevalence in the south was higher than in the north (72 versus 19% over the total study period) and increased over time in the northern part of the KNP (0-41%). No significant spatio-temporal differences were seen for FIV(ple) in the study period, in agreement with the presumed endemic state of the infection. Both infections affected haematology and blood chemistry values, FIV(ple) in a more pronounced way than BTB. The effect of co-infection on these values, however, was always less than additive. Though a large proportion (31%) of the lions was co-infected with FIV(ple) and M. bovis, there was no evidence for a synergistic relation as in their human counterparts. Whether this results from different immunopathogeneses remains to be determined.

Local persistence and extinction of plague in a metapopulation of great gerbil burrows, Kazakhstan.

Speculation on how the bacterium Yersinia pestis re-emerges after years of absence in the Prebalkhash region in Kazakhstan has been ongoing for half a century, but the mechanism is still unclear. One of the theories is that plague persists in its reservoir host (the great gerbil) in so-called hotspots, i.e. small regions in which the conditions remain favourable for plague to persist during times where the conditions in the Prebalkhash region as a whole have become unfavourable for plague persistence. In this paper we use a metapopulation model that describes the dynamics of the great gerbil. With this model we study the minimum size of an individual hotspot and the combined size of multiple hotspots in the Prebalkhash region that would be required for Y. pestis to persist through an inter-epizootic period. We show that the combined area of hotspots required for plague persistence is so large that it would be unlikely to have been missed by existing plague surveillance. This suggests that persistence of plague in that region cannot solely be explained by the existence of hotspots, and therefore other hypotheses, such as survival in multiple host species, and persistence in fleas or in the soil should be considered as well.

Cardiovascular performance of adult breeding sows fails to obey allometric scaling laws.

In view of the remarkable decrease of the relative heart weight (HW) and the relative blood volume in growing pigs, we investigated whether HW, cardiac output (CO), and stroke volume (SV) of modern growing pigs are proportional to BW, as predicted by allometric scaling laws: HW (or CO or SV) = a·BW(b), in which a and b are constants, and constant b is a multiple of 0.25 (quarter-power scaling law). Specifically, we tested the hypothesis that both HW and CO scale with BW to the power of 0.75 (HW or CO = a·BW(0.75)) and SV scales with BW to the power of 1.00 (SV = a·BW(1.0)). For this purpose, 2 groups of pigs (group 1, consisting of 157 pigs of 50 ± 1 kg; group 2, consisting of 45 pigs of 268 ± 18 kg) were surgically instrumented with a flow probe or a thermodilution dilution catheter, under open-chest anesthetized conditions to measure CO and SV, after which HW was determined. The 95% confidence intervals of power-coefficient b for HW were 0.74 to 0.80, encompassing the predicted value of 0.75, suggesting that HW increased proportionally with BW, as predicted by the allometric scaling laws. In contrast, the 95% confidence intervals of power-coefficient b for CO and SV as measured with flow probes were 0.40 to 0.56 and 0.39 to 0.61, respectively, and values obtained with the thermodilution technique were 0.34 to 0.53 and 0.40 to 0.62, respectively. Thus, the 95% confidence limits failed to encompass the predicted values of b for CO and SV of 0.75 and 1.0, respectively. In conclusion, although adult breeding sows display normal heart growth, cardiac performance appears to be disproportionately low for BW. This raises concern regarding the health status of adult breeding sows.

Effect of Eimeria acervulina infection history on the immune response and transmission in broilers.

Heterogeneity in exposure to Eimeria spp. of chickens in a flock will result in differences between individual birds in oocyst output and acquired immunity, which subsequently affects transmission of the parasite in the population. The aim of this study was to quantify effects of previous infection of broilers with Eimeria acervulina on immune responses, oocyst output and transmission. A transmission experiment was carried out with pair-wise housed broilers, that differed in infection history. This "infection history" was achieved by establishment of a primary infection by inoculation of birds with 50,000 sporulated E. acervulina oocysts at day 6 of age ("primed"); the other birds did not receive a primary infection ("naïve"). The actual transmission experiment started at day 24 of age: one bird (I) was inoculated with 50,000 sporulated oocysts and was housed together with a non-inoculated contact bird (C). Oocyst excretion and parameters describing transmission, i.e. the number of infected C birds and time passed before start of excretion of C birds, were determined from day 28 to day 50 for six pairs of four different combinations of I and C birds (I-C): naïve-naïve, naïve-primed, primed-naïve and primed-primed. Immune parameters, CD4(+), CD8(+), αßTCR(+) and γδTCR(+) T cells and macrophages in duodenum, were determined in an additional 25 non-primed, non-inoculated control birds, and in the naïve-naïve and naïve-primed groups, each group consisting of 25 pairs. Although the numbers of CD4(+) T cells and γδTCR(+) T cells increased after primary infection, none of the immunological cell types provided an indication of differences in infectivity, susceptibility or transmission between birds. Oocyst output was significantly reduced in primed I and C birds. Transmission was reduced most in the primed-primed group, but nonetheless transmission occurred in all groups. This study also showed that acquired immunity significantly reduced oocyst output after inoculation and contact-infection, but not sufficiently to prevent transmission to contact-exposed birds.