The curse of the Pharaoh revisited: evolutionary bi-stability in environmentally transmitted pathogens

It is increasingly evident that for a number of high-profile pathogens, transmission involves both direct and environmental pathways. Much of the distinguished evolutionary theory has, however, focused on each of transmission component separately. Herein, we use the framework of adaptive dynamics to study the evolutionary consequences of mixed transmission. We find that environmental transmission can select for increased virulence when direct transmission is low. Increasing the efficiency of direct transmission gives rise to an evolutionary bi-stability, with coexistence of different levels of virulence. We conclude that the overlooked contribution of environmental transmission may explain the curious appearance of high virulence in pathogens that are typically only moderately pathogenic, as observed for avian influenza viruses and cholera.     

Highly pathogenic avian influenza outbreak mitigated by seasonal low pathogenic strains: Insights from dynamic modeling

The spread of highly pathogenic avian influenza (HPAI) H5N1 remains a threat for both wild and domestic bird populations, while low pathogenic avian influenza (LPAI) strains have been reported to induce partial immunity to HPAI in poultry and some wild birds inoculated with both HPAI and LPAI strains. Here, based on the reported data and experiments, we develop a two-strain avian influenza model to examine the extent to which this partial immunity observed at the individual level can affect the outcome of the outbreaks among migratory birds in the wild at the population level during different seasons. We find a distinct mitigating effect of LPAI on the death toll induced by HPAI strain, and this effect is particularly important for populations previously exposed to and recovered from LPAI. We further investigate the effect of the dominant mode of transmission of an HPAI strain on the outcome of the epidemic. Four combinations of contact based direct transmission and indirect fecal-to-oral (or environmental) routes are examined. For a given infection peak of HPAI, indirect fecal-to-oral transmission of HPAI can lead to a higher death toll than that associated with direct transmission. The mitigating effect of LPAI can, in turn, be dependent on the route of infection of HPAI.     

The Role of Environmental Transmission in Recurrent Avian Influenza Epidemics

Avian influenza virus (AIV) persists in North American wild waterfowl, exhibiting major outbreaks every 2–4 years. Attempts to explain the patterns of periodicity and persistence using simple direct transmission models are unsuccessful. Motivated by empirical evidence, we examine the contribution of an overlooked AIV transmission mode: environmental transmission. It is known that infectious birds shed large concentrations of virions in the environment, where virions may persist for a long time. We thus propose that, in addition to direct fecal/oral transmission, birds may become infected by ingesting virions that have long persisted in the environment. We design a new host–pathogen model that combines within-season transmission dynamics, between-season migration and reproduction, and environmental variation. Analysis of the model yields three major results. First, environmental transmission provides a persistence mechanism within small communities where epidemics cannot be sustained by direct transmission only (i.e., communities smaller than the critical community size). Second, environmental transmission offers a parsimonious explanation of the 2–4 year periodicity of avian influenza epidemics. Third, very low levels of environmental transmission (i.e., few cases per year) are sufficient for avian influenza to persist in populations where it would otherwise vanish.     

A simple stochastic model with environmental transmission explains multi-year periodicity in outbreaks of avian flu

Avian influenza virus reveals persistent and recurrent outbreaks in North American wild waterfowl, and exhibits major outbreaks at 2-8 years intervals in duck populations. The standard susceptible-infected- recovered (SIR) framework, which includes seasonal migration and reproduction, but lacks environmental transmission, is unable to reproduce the multi-periodic patterns of avian influenza epidemics. In this paper, we argue that a fully stochastic theory based on environmental transmission provides a simple, plausible explanation for the phenomenon of multi-year periodic outbreaks of avian flu. Our theory predicts complex fluctuations with a dominant period of 2 to 8 years which essentially depends on the intensity of environmental transmission. A wavelet analysis of the observed data supports this prediction. Furthermore, using master equations and van Kampen system-size expansion techniques, we provide an analytical expression for the spectrum of stochastic fluctuations, revealing how the outbreak period varies with the environmental transmission.     

Modeling and Predicting Seasonal Influenza Transmission in Warm Regions Using Climatological Parameters

Background

Influenza transmission is often associated with climatic factors. As the epidemic pattern varies geographically, the roles of climatic factors may not be unique. Previous in vivo studies revealed the direct effect of winter-like humidity on air-borne influenza transmission that dominates in regions with temperate climate, while influenza in the tropics is more effectively transmitted through direct contact.

Methodology/Principal Findings

Using time series model, we analyzed the role of climatic factors on the epidemiology of influenza transmission in two regions characterized by warm climate: Hong Kong (China) and Maricopa County (Arizona, USA). These two regions have comparable temperature but distinctly different rainfall. Specifically we employed Autoregressive Integrated Moving Average (ARIMA) model along with climatic parameters as measured from ground stations and NASA satellites. Our studies showed that including the climatic variables as input series result in models with better performance than the univariate model where the influenza cases depend only on its past values and error signal. The best model for Hong Kong influenza was obtained when Land Surface Temperature (LST), rainfall and relative humidity were included as input series. Meanwhile for Maricopa County we found that including either maximum atmospheric pressure or mean air temperature gave the most improvement in the model performances.

Conclusions/Significance

Our results showed that including the environmental variables generally increases the prediction capability. Therefore, for countries without advanced influenza surveillance systems, environmental variables can be used for estimating influenza transmission at present and in the near future.     

A Multi-scale Analysis of Influenza A Virus Fitness Trade-offs due to Temperature-dependent Virus Persistence

Successful replication within an infected host and successful transmission between hosts are key to the continued spread of most pathogens. Competing selection pressures exerted at these different scales can lead to evolutionary trade-offs between the determinants of fitness within and between hosts. Here, we examine such a trade-off in the context of influenza A viruses and the differential pressures exerted by temperature-dependent virus persistence. For a panel of avian influenza A virus strains, we find evidence for a trade-off between the persistence at high versus low temperatures. Combining a within-host model of influenza infection dynamics with a between-host transmission model, we study how such a trade-off affects virus fitness on the host population level. We show that conclusions regarding overall fitness are affected by the type of link assumed between the within- and between-host levels and the main route of transmission (direct or environmental). The relative importance of virulence and immune response mediated virus clearance are also found to influence the fitness impacts of virus persistence at low versus high temperatures. Based on our results, we predict that if transmission occurs mainly directly and scales linearly with virus load, and virulence or immune responses are negligible, the evolutionary pressure for influenza viruses to evolve toward good persistence at high within-host temperatures dominates. For all other scenarios, influenza viruses with good environmental persistence at low temperatures seem to be favored.     

Pathogen adaptation to seasonal forcing and climate change

Many diverse infectious diseases exhibit seasonal dynamics. Seasonality in disease incidence has been attributed to seasonal changes in pathogen transmission rates, resulting from fluctuations in extrinsic climate factors. Multi-strain infectious diseases with strain-specific seasonal signatures, such as cholera, indicate that a range of seasonal patterns in transmission rates is possible in identical environments. We therefore consider pathogens capable of evolving their 'seasonal phenotype', a trait that determines the sensitivity of their transmission rates to environmental variability. We introduce a theoretical framework, based on adaptive dynamics, for predicting the evolution of disease dynamics in seasonal environments. Changes in the seasonality of environmental factors are one important avenue for the effects of climate change on disease. This model also provides a framework for examining these effects on pathogen evolution and associated disease dynamics. An application of this approach gives an explanation for the recent cholera strain replacement in Bangladesh, based on changes in monsoon rainfall patterns.     

Trade-offs between and within scales: environmental persistence and within-host fitness of avian influenza viruses

Trade-offs between different components of a pathogen''s replication and transmission cycle are thought to be common. A number of studies have identified trade-offs that emerge across scales, reflecting the tension between strategies that optimize within-host proliferation and large-scale population spread. Most of these studies are theoretical in nature, with direct experimental tests of such cross-scale trade-offs still rare. Here, we report an analysis of avian influenza A viruses across scales, focusing on the phenotype of temperature-dependent viral persistence. Taking advantage of a unique dataset that reports both environmental virus decay rates and strain-specific viral kinetics from duck challenge experiments, we show that the temperature-dependent environmental decay rate of a strain does not impact within-host virus load. Hence, for this phenotype, the scales of within-host infection dynamics and between-host environmental persistence do not seem to interact: viral fitness may be optimized on each scale without cross-scale trade-offs. Instead, we confirm the existence of a temperature-dependent persistence trade-off on a single scale, with some strains favouring environmental persistence in water at low temperatures while others reduce sensitivity to increasing temperatures. We show that this temperature-dependent trade-off is a robust phenomenon and does not depend on the details of data analysis. Our findings suggest that viruses might employ different environmental persistence strategies, which facilitates the coexistence of diverse strains in ecological niches. We conclude that a better understanding of the transmission and evolutionary dynamics of influenza A viruses probably requires empirical information regarding both within-host dynamics and environmental traits, integrated within a combined ecological and within-host framework.     

Quantifying the Routes of Transmission for Pandemic Influenza

Motivated by the desire to assess nonpharmaceutical interventions for pandemic influenza, we seek in this study to quantify the routes of transmission for this disease. We construct a mathematical model of aerosol (i.e., droplet-nuclei) and contact transmission of influenza within a household containing one infected. An analysis of this model in conjunction with influenza and rhinovirus data suggests that aerosol transmission is far more dominant than contact transmission for influenza. We also consider a separate model of a close expiratory event, and find that a close cough is unlikely (≈1% probability) to generate traditional droplet transmission (i.e., direct deposition on the mucous membranes), although a close, unprotected and horizontally-directed sneeze is potent enough to cause droplet transmission. There are insufficient data on the frequency of close expiratory events to assess the relative importance of aerosol transmission and droplet transmission, and it is prudent to leave open the possibility that droplet transmission is important until proven otherwise. However, the rarity of close, unprotected and horizontally-directed sneezes—coupled with the evidence of significant aerosol and contact transmission for rhinovirus and our comparison of hazard rates for rhinovirus and influenza—leads us to suspect that aerosol transmission is the dominant mode of transmission for influenza.     

Aerosol influenza transmission risk contours: A study of humid tropics versus winter temperate zone

Background

In recent years, much attention has been given to the spread of influenza around the world. With the continuing human outbreak of H5N1 beginning in 2003 and the H1N1 pandemic in 2009, focus on influenza and other respiratory viruses has been increased. It has been accepted for decades that international travel via jet aircraft is a major vector for global spread of influenza, and epidemiological differences between tropical and temperate regions observed. Thus we wanted to study how indoor environmental conditions (enclosed locations) in the tropics and winter temperate zones contribute to the aerosol spread of influenza by travelers. To this end, a survey consisting of 632 readings of temperature (T) versus relative humidity (RH) in 389 different enclosed locations air travelers are likely to visit in 8 tropical nations were compared to 102 such readings in 2 Australian cities, including ground transport, hotels, shops, offices and other publicly accessible locations, along with 586 time course readings from aircraft.

Results

An influenza transmission risk contour map was developed for T versus RH. Empirical equations were created for estimating: 1. risk relative to temperature and RH, and 2. time parameterized influenza transmission risk. Using the transmission risk contours and equations, transmission risk for each country's locations was compared with influenza reports from the countries. Higher risk enclosed locations in the tropics included new automobile transport, luxury buses, luxury hotels, and bank branches. Most temperate locations were high risk.

Conclusion

Environmental control is recommended for public health mitigation focused on higher risk enclosed locations. Public health can make use of the methods developed to track potential vulnerability to aerosol influenza. The methods presented can also be used in influenza modeling. Accounting for differential aerosol transmission using T and RH can potentially explain anomalies of influenza epidemiology in addition to seasonality in temperate climates.     

On the evolutionary dynamics of pathogens with direct and environmental transmission

A number of ecologically and economically important pathogens exhibit a complex transmission dynamics that involves distinct transmission modes. In this paper, we study the evolutionary dynamics of pathogens for which transmission includes direct host-to-host as well as indirect environmental transmission. Different routes of infection spread require specific adaptations of the parasite, which may result in conflicting selection pressures. Using the framework of Adaptive dynamics, we investigate how these conflicting selection pressures are resolved in the course of evolution and determine the conditions for evolutionary diversification of pathogen strains. We show that evolutionary branching and subsequent evolution of specialist strains occurs in wide parameter regions but evolutionary bistability and evolution of generalist pathogens are possible as well. Our analysis reveals that the relative contributions of direct and environmental transmission, as well as the underlying ecological dynamics, play a crucial role in shaping the course of pathogen evolution. Our findings may explain the coexistence of high and low virulence strains observed in several pathogenic organisms using different transmission modes (e.g., influenza viruses) and highlight the importance of considering ecological dynamics in virulence management.     

The influence of meteorology on the spread of influenza: survival analysis of an equine influenza (A/H3N8) outbreak

The influences of relative humidity and ambient temperature on the transmission of influenza A viruses have recently been established under controlled laboratory conditions. The interplay of meteorological factors during an actual influenza epidemic is less clear, and research into the contribution of wind to epidemic spread is scarce. By applying geostatistics and survival analysis to data from a large outbreak of equine influenza (A/H3N8), we quantified the association between hazard of infection and air temperature, relative humidity, rainfall, and wind velocity, whilst controlling for premises-level covariates. The pattern of disease spread in space and time was described using extraction mapping and instantaneous hazard curves. Meteorological conditions at each premises location were estimated by kriging daily meteorological data and analysed as time-lagged time-varying predictors using generalised Cox regression. Meteorological covariates time-lagged by three days were strongly associated with hazard of influenza infection, corresponding closely with the incubation period of equine influenza. Hazard of equine influenza infection was higher when relative humidity was <60% and lowest on days when daily maximum air temperature was 20-25°C. Wind speeds >30 km hour(-1) from the direction of nearby infected premises were associated with increased hazard of infection. Through combining detailed influenza outbreak and meteorological data, we provide empirical evidence for the underlying environmental mechanisms that influenced the local spread of an outbreak of influenza A. Our analysis supports, and extends, the findings of studies into influenza A transmission conducted under laboratory conditions. The relationships described are of direct importance for managing disease risk during influenza outbreaks in horses, and more generally, advance our understanding of the transmission of influenza A viruses under field conditions.     

Cholera Transmission in Ouest Department of Haiti: Dynamic Modeling and the Future of the Epidemic

In the current study, a comprehensive, data driven, mathematical model for cholera transmission in Haiti is presented. Along with the inclusion of short cycle human-to-human transmission and long cycle human-to-environment and environment-to-human transmission, this novel dynamic model incorporates both the reported cholera incidence and remote sensing data from the Ouest Department of Haiti between 2010 to 2014. The model has separate compartments for infectious individuals that include different levels of infectivity to reflect the distribution of symptomatic and asymptomatic cases in the population. The environmental compartment, which serves as a source of exposure to toxigenic V. cholerae, is also modeled separately based on the biology of causative bacterium, the shedding of V. cholerae O1 by humans into the environment, as well as the effects of precipitation and water temperature on the concentration and survival of V. cholerae in aquatic reservoirs. Although the number of reported cholera cases has declined compared to the initial outbreak in 2010, the increase in the number of susceptible population members and the presence of toxigenic V. cholerae in the environment estimated by the model indicate that without further improvements to drinking water and sanitation infrastructures, intermittent cholera outbreaks are likely to continue in Haiti.     

Absolute Humidity and the Seasonal Onset of Influenza in the Continental United States

Much of the observed wintertime increase of mortality in temperate regions is attributed to seasonal influenza. A recent reanalysis of laboratory experiments indicates that absolute humidity strongly modulates the airborne survival and transmission of the influenza virus. Here, we extend these findings to the human population level, showing that the onset of increased wintertime influenza-related mortality in the United States is associated with anomalously low absolute humidity levels during the prior weeks. We then use an epidemiological model, in which observed absolute humidity conditions temper influenza transmission rates, to successfully simulate the seasonal cycle of observed influenza-related mortality. The model results indicate that direct modulation of influenza transmissibility by absolute humidity alone is sufficient to produce this observed seasonality. These findings provide epidemiological support for the hypothesis that absolute humidity drives seasonal variations of influenza transmission in temperate regions.     

A generalized cholera model and epidemic-endemic analysis

The transmission of cholera involves both human-to-human and environment-to-human pathways that complicate its dynamics. In this paper, we present a new and unified deterministic model that incorporates a general incidence rate and a general formulation of the pathogen concentration to analyse the dynamics of cholera. Particularly, this work unifies many existing cholera models proposed by different authors. We conduct equilibrium analysis to carefully study the complex epidemic and endemic behaviour of the disease. Our results show that despite the incorporation of the environmental component, there exists a forward transcritical bifurcation at R (0)=1 for the combined human-environment epidemiological model under biologically reasonable conditions.     

Impact of School Cycles and Environmental Forcing on the Timing of Pandemic Influenza Activity in Mexican States,May-December 2009

While a relationship between environmental forcing and influenza transmission has been established in inter-pandemic seasons, the drivers of pandemic influenza remain debated. In particular, school effects may predominate in pandemic seasons marked by an atypical concentration of cases among children. For the 2009 A/H1N1 pandemic, Mexico is a particularly interesting case study due to its broad geographic extent encompassing temperate and tropical regions, well-documented regional variation in the occurrence of pandemic outbreaks, and coincidence of several school breaks during the pandemic period. Here we fit a series of transmission models to daily laboratory-confirmed influenza data in 32 Mexican states using MCMC approaches, considering a meta-population framework or the absence of spatial coupling between states. We use these models to explore the effect of environmental, school–related and travel factors on the generation of spatially-heterogeneous pandemic waves. We find that the spatial structure of the pandemic is best understood by the interplay between regional differences in specific humidity (explaining the occurrence of pandemic activity towards the end of the school term in late May-June 2009 in more humid southeastern states), school vacations (preventing influenza transmission during July-August in all states), and regional differences in residual susceptibility (resulting in large outbreaks in early fall 2009 in central and northern Mexico that had yet to experience fully-developed outbreaks). Our results are in line with the concept that very high levels of specific humidity, as present during summer in southeastern Mexico, favor influenza transmission, and that school cycles are a strong determinant of pandemic wave timing.     

Dynamics of infection with multiple transmission mechanisms in unmanaged/managed animal populations

Deterministic and stochastic models motivated by Salmonella transmission in unmanaged/managed populations are studied. The SIRS models incorporate three routes of transmission (direct, vertical and indirect via free-living infectious units in the environment). With deterministic models we are able to understand the effects of different routes of transmission and other epidemiological factors on infection dynamics. In particular, vertical transmission has little influence on this dynamics, whereas the higher the indirect (direct) transmission rate the greater the tendency to persistent oscillation (stable endemic states). We show that the sustained cycles are also prone to demographic effect, i.e., persistent oscillation becomes impossible in the managed case (in the sense of balanced recruitment and death rates) by comparing with results in unmanaged populations (exponential population dynamics). Further, approximations of quasi-stationary distributions are derived for stochastic versions of the proposed models based on a diffusion approximation to the infection process. The effect of transmission parameters on the ratio of mean to standard deviation of the approximating distribution, used to judge the validity of the approximations and the expected time until fade out of infection, is further discussed. We conclude that strengthening any route of transmission may or may not reduce the expected time to fade out of infection, depending on the population dynamics.     

Household Transmission of Vibrio cholerae in Bangladesh

Background

Vibrio cholerae infections cluster in households. This study''s objective was to quantify the relative contribution of direct, within-household exposure (for example, via contamination of household food, water, or surfaces) to endemic cholera transmission. Quantifying the relative contribution of direct exposure is important for planning effective prevention and control measures.

Methodology/Principal Findings

Symptom histories and multiple blood and fecal specimens were prospectively collected from household members of hospital-ascertained cholera cases in Bangladesh from 2001–2006. We estimated the probabilities of cholera transmission through 1) direct exposure within the household and 2) contact with community-based sources of infection. The natural history of cholera infection and covariate effects on transmission were considered. Significant direct transmission (p-value<0.0001) occurred among 1414 members of 364 households. Fecal shedding of O1 El Tor Ogawa was associated with a 4.9% (95% confidence interval: 0.9%–22.8%) risk of infection among household contacts through direct exposure during an 11-day infectious period (mean length). The estimated 11-day risk of O1 El Tor Ogawa infection through exposure to community-based sources was 2.5% (0.8%–8.0%). The corresponding estimated risks for O1 El Tor Inaba and O139 infection were 3.7% (0.7%–16.6%) and 8.2% (2.1%–27.1%) through direct exposure, and 3.4% (1.7%–6.7%) and 2.0% (0.5%–7.3%) through community-based exposure. Children under 5 years-old were at elevated risk of infection. Limitations of the study may have led to an underestimation of the true risk of cholera infection. For instance, available covariate data may have incompletely characterized levels of pre-existing immunity to cholera infection. Transmission via direct exposure occurring outside of the household was not considered.

Conclusions

Direct exposure contributes substantially to endemic transmission of symptomatic cholera in an urban setting. We provide the first estimate of the transmissibility of endemic cholera within prospectively-followed members of households. The role of direct transmission must be considered when planning cholera control activities.     

Scientific barriers to developing vaccines against avian influenza viruses

The increasing number of reports of direct transmission of avian influenza viruses to humans underscores the need for control strategies to prevent an influenza pandemic. Vaccination is the key strategy to prevent severe illness and death from pandemic influenza. Despite long-term experience with vaccines against human influenza viruses, researchers face several additional challenges in developing human vaccines against avian influenza viruses. In this Review, we discuss the features of avian influenza viruses, the gaps in our understanding of infections caused by these viruses in humans and of the immune response to them that distinguishes them from human influenza viruses, and the current status of vaccine development.     

Environmental Conditions Affect Exhalation of H3N2 Seasonal and Variant Influenza Viruses and Respiratory Droplet Transmission in Ferrets

The seasonality of influenza virus infections in temperate climates and the role of environmental conditions like temperature and humidity in the transmission of influenza virus through the air are not well understood. Using ferrets housed at four different environmental conditions, we evaluated the respiratory droplet transmission of two influenza viruses (a seasonal H3N2 virus and an H3N2 variant virus, the etiologic virus of a swine to human summertime infection) and concurrently characterized the aerosol shedding profiles of infected animals. Comparisons were made among the different temperature and humidity conditions and between the two viruses to determine if the H3N2 variant virus exhibited enhanced capabilities that may have contributed to the infections occurring in the summer. We report here that although increased levels of H3N2 variant virus were found in ferret nasal wash and exhaled aerosol samples compared to the seasonal H3N2 virus, enhanced respiratory droplet transmission was not observed under any of the environmental settings. However, overall environmental conditions were shown to modulate the frequency of influenza virus transmission through the air. Transmission occurred most frequently at 23°C/30%RH, while the levels of infectious virus in aerosols exhaled by infected ferrets agree with these results. Improving our understanding of how environmental conditions affect influenza virus infectivity and transmission may reveal ways to better protect the public against influenza virus infections.