Modeling rapidly disseminating infectious disease during mass gatherings

published_or_final_versio

Detecting Signals of Seasonal Influenza Severity Through Age Dynamics

BACKGROUND: Measures of population-level influenza severity are important for public health planning, but estimates are often based on case-fatality and case-hospitalization risks, which require multiple data sources, are prone to surveillance biases, and are typically unavailable in the early stages of an outbreak. To address the limitations of traditional indicators, we propose a novel severity index based on influenza age dynamics estimated from routine physician diagnosis data that can be used retrospectively and for early warning. METHODS: We developed a quantitative \u27ground truth\u27 severity benchmark that synthesizes multiple traditional severity indicators from publicly available influenza surveillance data in the United States. Observing that the age distribution of cases may signal severity early in an epidemic, we constructed novel retrospective and early warning severity indexes based on the relative risk of influenza-like illness (ILI) among working-age adults to that among school-aged children using weekly outpatient medical claims. We compared our relative risk-based indexes to the composite benchmark and estimated seasonal severity for flu seasons from 2001-02 to 2008-09 at the national and state levels. RESULTS: The severity classifications made by the benchmark were not uniquely captured by any single contributing metric, including pneumonia and influenza mortality; the influenza epidemics of 2003-04 and 2007-08 were correctly identified as the most severe of the study period. The retrospective index was well correlated with the severity benchmark and correctly identified the two most severe seasons. The early warning index performance varied, but it projected 2007-08 as relatively severe 10 weeks prior to the epidemic peak. Influenza severity varied significantly among states within seasons, and four states were identified as possible early warning sentinels for national severity. CONCLUSIONS: Differences in age patterns of ILI may be used to characterize seasonal influenza severity in the United States in real-time and in a spatially resolved way. Future research on antigenic changes among circulating viruses, pre-existing immunity, and changing contact patterns may better elucidate the mechanisms underlying these indexes. Researchers and practitioners should consider the use of composite or ILI-based severity metrics in addition to traditional severity measures to inform epidemiological understanding and situational awareness in future seasonal outbreaks

Characterizing Ebola Transmission Patterns based on Internet News Reports.

BACKGROUND:  Detailed information on patient exposure, contact patterns, and discharge status, is rarely available in real time from traditional surveillance systems in the context of an emerging infectious disease outbreak. Here we validate the systematic collection of Internet news reports to characterize epidemiological patterns of Ebola virus disease (EVD) infections during the West African 2014-2015 outbreak. METHODS:  Based on 58 news reports, we analyzed a total of 79 EVD clusters (286 cases) of size ranging from 1 to 33 cases between January 2014 and February 2015 in Guinea, Sierra Leone and Liberia. RESULTS AND CONCLUSIONS:  The great majority of reported exposures stemmed from contact with family members (57.3%) followed by hospitals (18.2%) and funerals (12.7%). Our data indicated that funeral exposure was significantly more frequent in Sierra Leone (27.3%) followed by Guinea (18.2%) and Liberia (1.8%) (Chi-square test;

Epidemic dynamics of respiratory syncytial virus in current and future climates.

A key question for infectious disease dynamics is the impact of the climate on future burden. Here, we evaluate the climate drivers of respiratory syncytial virus (RSV), an important determinant of disease in young children. We combine a dataset of county-level observations from the US with state-level observations from Mexico, spanning much of the global range of climatological conditions. Using a combination of nonlinear epidemic models with statistical techniques, we find consistent patterns of climate drivers at a continental scale explaining latitudinal differences in the dynamics and timing of local epidemics. Strikingly, estimated effects of precipitation and humidity on transmission mirror prior results for influenza. We couple our model with projections for future climate, to show that temperature-driven increases to humidity may lead to a northward shift in the dynamic patterns observed and that the likelihood of severe outbreaks of RSV hinges on projections for extreme rainfall

Multiple reassortment events in the evolutionary history of H1N1 influenza A virus since 1918

The H1N1 subtype of influenza A virus has caused substantial morbidity and mortality in humans, first documented in the global pandemic of 1918 and continuing to the present day. Despite this disease burden, the evolutionary history of the A/H1N1 virus is not well understood, particularly whether there is a virological basis for several notable epidemics of unusual severity in the 1940s and 1950s. Using a data set of 71 representative complete genome sequences sampled between 1918 and 2006, we show that segmental reassortment has played an important role in the genomic evolution of A/H1N1 since 1918. Specifically, we demonstrate that an A/H1N1 isolate from the 1947 epidemic acquired novel PB2 and HA genes through intra-subtype reassortment, which may explain the abrupt antigenic evolution of this virus. Similarly, the 1951 influenza epidemic may also have been associated with reassortant A/H1N1 viruses. Intra-subtype reassortment therefore appears to be a more important process in the evolution and epidemiology of H1N1 influenza A virus than previously realized

Direct and indirect effects of rotavirus vaccination: Comparing predictions from transmission dynamic models

Early observations from countries that have introduced rotavirus vaccination suggest that there may be indirect protection for unvaccinated individuals, but it is unclear whether these benefits will extend to the long term. Transmission dynamic models have attempted to quantify the indirect protection that might be expected from rotavirus vaccination in developed countries, but results have varied. To better understand the magnitude and sources of variability in model projections, we undertook a comparative analysis of transmission dynamic models for rotavirus. We fit five models to reported rotavirus gastroenteritis (RVGE) data from England and Wales, and evaluated outcomes for short- and long-term vaccination effects. All of our models reproduced the important features of rotavirus epidemics in England and Wales. Models predicted that during the initial year after vaccine introduction, incidence of severe RVGE would be reduced 1.8-2.9 times more than expected from the direct effects of the vaccine alone (28-50% at 90% coverage), but over a 5-year period following vaccine introduction severe RVGE would be reduced only by 1.1-1.7 times more than expected from the direct effects (54-90% at 90% coverage). Projections for the long-term reduction of severe RVGE ranged from a 55% reduction at full coverage to elimination with at least 80% coverage. Our models predicted short-term reductions in the incidence of RVGE that exceeded estimates of the direct effects, consistent with observations from the United States and other countries. Some of the models predicted that the short-term indirect benefits may be offset by a partial shifting of the burden of RVGE to older unvaccinated individuals. Nonetheless, even when such a shift occurs, the overall reduction in severe RVGE is considerable. Discrepancies among model predictions reflect uncertainties about age variation in the risk and reporting of RVGE, and the duration of natural and vaccine-induced immunity, highlighting important questions for future research

Long intervals of stasis punctuated by bursts of positive selection in the seasonal evolution of influenza A virus

BACKGROUND: The interpandemic evolution of the influenza A virus hemagglutinin (HA) protein is commonly considered a paragon of rapid evolutionary change under positive selection in which amino acid replacements are fixed by virtue of their effect on antigenicity, enabling the virus to evade immune surveillance. RESULTS: We performed phylogenetic analyses of the recently obtained large and relatively unbiased samples of the HA sequences from 1995–2005 isolates of the H3N2 and H1N1 subtypes of influenza A virus. Unexpectedly, it was found that the evolution of H3N2 HA includes long intervals of generally neutral sequence evolution without apparent substantial antigenic change ("stasis" periods) that are characterized by an excess of synonymous over nonsynonymous substitutions per site, lack of association of amino acid replacements with epitope regions, and slow extinction of coexisting virus lineages. These long periods of stasis are punctuated by shorter intervals of rapid evolution under positive selection during which new dominant lineages quickly displace previously coexisting ones. The preponderance of positive selection during intervals of rapid evolution is supported by the dramatic excess of amino acid replacements in the epitope regions of HA compared to replacements in the rest of the HA molecule. In contrast, the stasis intervals showed a much more uniform distribution of replacements over the HA molecule, with a statistically significant difference in the rate of synonymous over nonsynonymous substitution in the epitope regions between the two modes of evolution. A number of parallel amino acid replacements – the same amino acid substitution occurring independently in different lineages – were also detected in H3N2 HA. These parallel mutations were, largely, associated with periods of rapid fitness change, indicating that there are major limitations on evolutionary pathways during antigenic change. The finding that stasis is the prevailing modality of H3N2 evolution suggests that antigenic changes that lead to an increase in fitness typically result from epistatic interactions between several amino acid substitutions in the HA and, perhaps, other viral proteins. The strains that become dominant due to increased fitness emerge from low frequency strains thanks to the last amino acid replacement that completes the set of replacements required to produce a significant antigenic change; no subset of substitutions results in a biologically significant antigenic change and corresponding fitness increase. In contrast to H3N2, no clear intervals of evolution under positive selection were detected for the H1N1 HA during the same time span. Thus, the ascendancy of H1N1 in some seasons is, most likely, caused by the drop in the relative fitness of the previously prevailing H3N2 lineages as the fraction of susceptible hosts decreases during the stasis intervals. CONCLUSION: We show that the common view of the evolution of influenza virus as a rapid, positive selection-driven process is, at best, incomplete. Rather, the interpandemic evolution of influenza appears to consist of extended intervals of stasis, which are characterized by neutral sequence evolution, punctuated by shorter intervals of rapid fitness increase when evolutionary change is driven by positive selection. These observations have implications for influenza surveillance and vaccine formulation; in particular, the possibility exists that parallel amino acid replacements could serve as a predictor of new dominant strains. REVIEWERS: Ron Fouchier (nominated by Andrey Rzhetsky), David Krakauer, Christopher Le

Phylogenetic Analysis Reveals the Global Migration of Seasonal Influenza A Viruses

The winter seasonality of influenza A virus in temperate climates is one of the most widely recognized, yet least understood, epidemiological patterns in infectious disease. Central to understanding what drives the seasonal emergence of this important human pathogen is determining what becomes of the virus during the non-epidemic summer months. Herein, we take a step towards elucidating the seasonal emergence of influenza virus by determining the evolutionary relationship between populations of influenza A virus sampled from opposite hemispheres. We conducted a phylogenetic analysis of 487 complete genomes of human influenza A/H3N2 viruses collected between 1999 and 2005 from Australia and New Zealand in the southern hemisphere, and a representative sub-sample of viral genome sequences from 413 isolates collected in New York state, United States, representing the northern hemisphere. We show that even in areas as relatively geographically isolated as New Zealand's South Island and Western Australia, global viral migration contributes significantly to the seasonal emergence of influenza A epidemics, and that this migration has no clear directional pattern. These observations run counter to suggestions that local epidemics are triggered by the climate-driven reactivation of influenza viruses that remain latent within hosts between seasons or transmit at low efficiency between seasons. However, a complete understanding of the seasonal movements of influenza A virus will require greatly expanded global surveillance, particularly of tropical regions where the virus circulates year-round, and during non-epidemic periods in temperate climate areas

The Cost of Simplifying Air Travel When Modeling Disease Spread

BACKGROUND: Air travel plays a key role in the spread of many pathogens. Modeling the long distance spread of infectious disease in these cases requires an air travel model. Highly detailed air transportation models can be over determined and computationally problematic. We compared the predictions of a simplified air transport model with those of a model of all routes and assessed the impact of differences on models of infectious disease. METHODOLOGY/PRINCIPAL FINDINGS: Using U.S. ticket data from 2007, we compared a simplified "pipe" model, in which individuals flow in and out of the air transport system based on the number of arrivals and departures from a given airport, to a fully saturated model where all routes are modeled individually. We also compared the pipe model to a "gravity" model where the probability of travel is scaled by physical distance; the gravity model did not differ significantly from the pipe model. The pipe model roughly approximated actual air travel, but tended to overestimate the number of trips between small airports and underestimate travel between major east and west coast airports. For most routes, the maximum number of false (or missed) introductions of disease is small (<1 per day) but for a few routes this rate is greatly underestimated by the pipe model. CONCLUSIONS/SIGNIFICANCE: If our interest is in large scale regional and national effects of disease, the simplified pipe model may be adequate. If we are interested in specific effects of interventions on particular air routes or the time for the disease to reach a particular location, a more complex point-to-point model will be more accurate. For many problems a hybrid model that independently models some frequently traveled routes may be the best choice. Regardless of the model used, the effect of simplifications and sensitivity to errors in parameter estimation should be analyzed