Asymptomatic Bordetella pertussis infections in young African infants and their mothers identified within a longitudinal cohort.

Despite long-standing vaccination programs, pertussis incidence has increased in numerous countries; transmission by asymptomatic individuals is a suspected driver of this resurgence. However, unequivocal evidence documenting asymptomatic infections in adults and children is lacking due, in part, to the cross-sectional nature of most pertussis surveillance studies. In addition, modern pertussis surveillance relies on quantitative PCR (qPCR) using fixed diagnostic thresholds to identify cases. To address this gap, we present a longitudinal analysis of 17,442 nasopharyngeal samples collected from a cohort of 1,320 Zambian mother/infant pairs. Using full-range cycle threshold (CT) values from IS481 qPCR assays, we document widespread asymptomatic infections among mothers and also, surprisingly, among young infants. From an initial group of eight symptomatic infants who tested positive by qPCR, we identify frequent contemporaneous subclinical infections in mothers. Within the full cohort, we observe strong temporal correlation between low- and high-intensity qPCR signals. We compute a single time-averaged score for each individual summarizing the evidence for pertussis infection (EFI), and show that EFI strongly clusters within mother/infant pairs, and is strongly associated with clinical symptomatology and antibiotic use. Overall, the burden of pertussis here is substantially underestimated when restricting diagnostic criteria to IS481 CT≤35. Rather, we find that full-range CT values provide valuable insights into pertussis epidemiology in this population, and illuminate the infection arc within individuals. These findings have significant implications for quantifying asymptomatic pertussis prevalence and its contribution to overall transmission. Our results also expose limitations of threshold-based interpretations of qPCR assays in infectious disease surveillance.

Increased number of regulatory T cells in esophageal tissue of patients with eosinophilic esophagitis in comparison to gastro esophageal reflux disease and control groups

Background: Eosinophilic esophagitis (EoE) is a primarily polygenic allergic disorder. Although most patients have IgE sensitization, it seems that non-IgE mediated responses mainly contribute to the pathogenesis of EoE. Regulatory T cells (Tregs) may have an important role in allergies. There are limited data on the association of Tregs and EoE. In this study, we enumerated and compared T lymphocytes and Tregs in esophageal tissue of patients with EoE, gastroesophageal reflux disease (GERD) and normal controls. Methods: Ten patients with EoE, ten patients with GERD and eight normal controls were included. Immunohistochemistry staining was used to enumerate T lymphocytes and Tregs. CD3+ cells were considered as T cells and FOXP3+, CD3+ cells were considered as Tregs. T cells and Tregs were counted in 10 high power fields (HPF) (×400) for each patient and the average of 10 HPFs was recorded. Results: The mean±SEM of Tregs in esophageal tissue of patients with EoE (10.90 ± 2.14cells/HPF) was significantly higher than the GERD (2.77 ± 0.66 cells/HPF) and control groups (0.37 ± 0.08 cells/HPF) (P < 0.001). Additionally, the mean ± SEM of T lymphocytes in esophageal tissue of patients with EoE (24.39 ± 3.86 cells/HPF) were increased in comparison to the GERD (10.07 ± 2.65 cells/HPF) and control groups (3.17 ± 0.93 cells/HPF) (P < 0.001). Conclusion: There is an increase in the number of esophageal T lymphocytes and regulatory T cells in patients with EoE compared to the GERD and control groups

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Age-structure and transient dynamics in epidemiological systems.

Mathematical models of childhood diseases date back to the early twentieth century. In several cases, models that make the simplifying assumption of homogeneous time-dependent transmission rates give good agreement with data in the absence of secular trends in population demography or transmission. The prime example is afforded by the dynamics of measles in industrialized countries in the pre-vaccine era. Accurate description of the transient dynamics following the introduction of routine vaccination has proved more challenging, however. This is true even in the case of measles which has a well-understood natural history and an effective vaccine that confers long-lasting protection against infection. Here, to shed light on the causes of this problem, we demonstrate that, while the dynamics of homogeneous and age-structured models can be qualitatively similar in the absence of vaccination, they diverge subsequent to vaccine roll-out. In particular, we show that immunization induces changes in transmission rates, which in turn reshapes the age distribution of infection prevalence, which effectively modulates the amplitude of seasonality in such systems. To examine this phenomenon empirically, we fit transmission models to measles notification data from London that span the introduction of the vaccine. We find that a simple age-structured model provides a much better fit to the data than does a homogeneous model, especially in the transition period from the pre-vaccine to the vaccine era. Thus, we propose that age structure and heterogeneities in contact rates are critical features needed to accurately capture transient dynamics in the presence of secular trends.

Increased number of regulatory T cells in esophageal tissue of patients with eosinophilic esophagitis in comparison to gastro esophageal reflux disease and control groups.

BACKGROUND: Eosinophilic esophagitis (EoE) is a primarily polygenic allergic disorder. Although most patients have IgE sensitization, it seems that non-IgE mediated responses mainly contribute to the pathogenesis of EoE. Regulatory T cells (Tregs) may have an important role in allergies. There are limited data on the association of Tregs and EoE. In this study, we enumerated and compared T lymphocytes and Tregs in esophageal tissue of patients with EoE, gastroesophageal reflux disease (GERD) and normal controls. METHODS: Ten patients with EoE, ten patients with GERD and eight normal controls were included. Immunohistochemistry staining was used to enumerate T lymphocytes and Tregs. CD3+ cells were considered as T cells and FOXP3+, CD3+ cells were considered as Tregs. T cells and Tregs were counted in 10 high power fields (HPF) (×400) for each patient and the average of 10 HPFs was recorded. RESULTS: The mean±SEM of Tregs in esophageal tissue of patients with EoE (10.90±2.14cells/HPF) was significantly higher than the GERD (2.77±0.66cells/HPF) and control groups (0.37±0.08cells/HPF) (P<0.001). Additionally, the mean±SEM of T lymphocytes in esophageal tissue of patients with EoE (24.39±3.86cells/HPF) were increased in comparison to the GERD (10.07±2.65cells/HPF) and control groups (3.17±0.93cells/HPF) (P<0.001). CONCLUSION: There is an increase in the number of esophageal T lymphocytes and regulatory T cells in patients with EoE compared to the GERD and control groups.

Commentary: resolving pertussis resurgence and vaccine immunity using mathematical transmission models.

The epidemiology of pertussis-a vaccine-preventable respiratory infection typically caused by the bacterium Bordetella pertussis-remains puzzling. Indeed, the disease seems nowhere close to eradication and has even re-emerged in certain countries-such as the US-that have maintained high vaccination coverage. Because the dynamics of pertussis are shaped by past vaccination and natural infection rates, with the relevant timescale spanning decades, the interpretation of such unexpected trends is not straightforward. In this commentary, we propose that mathematical transmission models play an essential role in helping to interpret the data and in closing knowledge gaps in pertussis epidemiology. We submit that recent advances in statistical inference methods now allow us to estimate key parameters, such as the nature and duration of vaccinal immunity, which have to date been difficult to quantify. We illustrate these points with the results of a recent study based on data from Massachusetts (Domenech de Cellès, Magpantay, King, and Rohani, Sci. Transl. Med. 2018;10: eaaj1748. doi:10.1126/scitranslmed.aaj1748), in which we used such methods to elucidate the mechanisms underlying the ongoing resurgence of pertussis. In addition, we list a number of safety checks that can be used to critically assess mathematical models. Finally, we discuss the remaining uncertainties surrounding pertussis vaccines, in particular the acellular vaccines used for teenage booster immunizations.

Using age-stratified incidence data to examine the transmission consequences of pertussis vaccination.

Pertussis is a highly infectious respiratory disease that has been on the rise in many countries worldwide over the past several years. The drivers of this increase in pertussis incidence remain hotly debated, with a central and long-standing hypothesis that questions the ability of vaccines to eliminate pertussis transmission rather than simply modulate the severity of disease. In this paper, we present age-structured case notification data from all provinces of Thailand between 1981 and 2014, a period during which vaccine uptake rose substantially, permitting an evaluation of the transmission impacts of vaccination. Our analyses demonstrate decreases in incidence across all ages with increased vaccine uptake - an observation that is at odds with pertussis case notification data in a number of other countries. To explore whether these observations are consistent with a rise in herd immunity and a reduction in bacterial transmission, we analyze an age-structured model that incorporates contrasting hypotheses concerning the immunological and transmission consequences of vaccines. Our results lead us to conclude that the most parsimonious explanation for the combined reduction in incidence and the shift to older age groups in the Thailand data is vaccine-induced herd immunity.

Pertussis immunity and epidemiology: mode and duration of vaccine-induced immunity.

The resurgence of pertussis in some countries that maintain high vaccination coverage has drawn attention to gaps in our understanding of the epidemiological effects of pertussis vaccines. In particular, major questions surround the nature, degree and durability of vaccine protection. To address these questions, we used mechanistic transmission models to examine regional time series incidence data from Italy in the period immediately following the introduction of acellular pertussis (aP) vaccine. Our results concur with recent animal-challenge experiments wherein infections in aP-vaccinated individuals proved as transmissible as those in naive individuals but much less symptomatic. On the other hand, the data provide evidence for vaccine-driven reduction in susceptibility, which we quantify via a synthetic measure of vaccine impact. As to the precise nature of vaccine failure, the data do not allow us to distinguish between leakiness and waning of vaccine immunity, or some combination of these. Across the range of well-supported models, the nature and duration of vaccine protection, the age profile of incidence and the range of projected epidemiological futures differ substantially, underscoring the importance of the remaining unknowns. We identify key data gaps: sources of data that can supply the information needed to eliminate these remaining uncertainties.

Dynamics of Pertussis Transmission in the United States.

Past patterns of infectious disease transmission set the stage on which modern epidemiologic dynamics are played out. Here, we present a comprehensive account of pertussis (whooping cough) transmission in the United States during the early vaccine era. We analyzed recently digitized weekly incidence records from Morbidity and Mortality Weekly Reports from 1938 to 1955, when the whole-cell pertussis vaccine was rolled out, and related them to contemporary patterns of transmission and resurgence documented in monthly incidence data from the National Notifiable Diseases Surveillance System. We found that, during the early vaccine era, pertussis epidemics in US states could be categorized as 1) annual, 2) initially annual and later multiennial, or 3) multiennial. States with predominantly annual cycles tended to have higher per capita birth rates, more household crowding, more children per family, and lower rates of school attendance than the states with multiennial cycles. Additionally, states that exhibited annual epidemics during 1938-1955 have had the highest recent (2001-2010) incidence, while those states that transitioned from annual cycles to multiennial cycles have had relatively low recent incidence. Our study provides an extensive picture of pertussis epidemiology in the United States dating back to the onset of vaccination, a back-story that could aid epidemiologists in understanding contemporary transmission patterns.

Using quantitative disease dynamics as a tool for guiding response to avian influenza in poultry in the United States of America.

Wild birds are the primary source of genetic diversity for influenza A viruses that eventually emerge in poultry and humans. Much progress has been made in the descriptive ecology of avian influenza viruses (AIVs), but contributions are less evident from quantitative studies (e.g., those including disease dynamic models). Transmission between host species, individuals and flocks has not been measured with sufficient accuracy to allow robust quantitative evaluation of alternate control protocols. We focused on the United States of America (USA) as a case study for determining the state of our quantitative knowledge of potential AIV emergence processes from wild hosts to poultry. We identified priorities for quantitative research that would build on existing tools for responding to AIV in poultry and concluded that the following knowledge gaps can be addressed with current empirical data: (1) quantification of the spatio-temporal relationships between AIV prevalence in wild hosts and poultry populations, (2) understanding how the structure of different poultry sectors impacts within-flock transmission, (3) determining mechanisms and rates of between-farm spread, and (4) validating current policy-decision tools with data. The modeling studies we recommend will improve our mechanistic understanding of potential AIV transmission patterns in USA poultry, leading to improved measures of accuracy and reduced uncertainty when evaluating alternative control strategies.

EPIDEMIOLOGICAL CONSEQUENCES OF IMPERFECT VACCINES FOR IMMUNIZING INFECTIONS.

The control of some childhood diseases has proven to be difficult even in countries that maintain high vaccination coverage. This may be due to the use of imperfect vaccines and there has been much discussion on the different modes by which vaccines might fail. To understand the epidemiological implications of some of these different modes, we performed a systematic analysis of a model based on the standard SIR equations with a vaccinated component that permits vaccine failure in degree ("leakiness"), take ("all-or-nothingness") and duration (waning of vaccine-derived immunity). The model was first considered as a system of ordinary differential equations, then extended to a system of partial differential equations to accommodate age structure. We derived analytic expressions for the steady states of the system and the final age distributions in the case of homogenous contact rates. The stability of these equilibria are determined by a threshold parameter Rp , a function of the vaccine failure parameters and the coverage p. The value of p for which Rp = 1 yields the critical vaccination ratio, a measure of herd immunity. Using this concept we can compare vaccines that confer the same level of herd immunity to the population but may fail at the individual level in different ways. For any fixed Rp > 1, the leaky model results in the highest prevalence of infection, while the all-or-nothing and waning models have the same steady state prevalence. The actual composition of a vaccine cannot be determined on the basis of steady state levels alone, however the distinctions can be made by looking at transient dynamics (such as after the onset of vaccination), the mean age of infection, the age distributions at steady state of the infected class, and the effect of age-specific contact rates.

Dissecting a wildlife disease hotspot: the impact of multiple host species, environmental transmission and seasonality in migration, breeding and mortality.

Avian influenza viruses (AIVs) have been implicated in all human influenza pandemics in recent history. Despite this, surprisingly little is known about the mechanisms underlying the maintenance and spread of these viruses in their natural bird reservoirs. Surveillance has identified an AIV 'hotspot' in shorebirds at Delaware Bay, in which prevalence is estimated to exceed other monitored sites by an order of magnitude. To better understand the factors that create an AIV hotspot, we developed and parametrized a mechanistic transmission model to study the simultaneous epizootiological impacts of multi-species transmission, seasonal breeding, host migration and mixed transmission routes. We scrutinized our model to examine the potential for an AIV hotspot to serve as a 'gateway' for the spread of novel viruses into North America. Our findings identify the conditions under which a novel influenza virus, if introduced into the system, could successfully invade and proliferate.

The population ecology of infectious diseases: pertussis in Thailand as a case study.

Many of the fundamental concepts in studying infectious diseases are rooted in population ecology. We describe the importance of population ecology in exploring central issues in infectious disease research including identifying the drivers and dynamics of host-pathogen interactions and pathogen persistence, and evaluating the success of public health policies. The use of ecological concepts in infectious disease research is demonstrated with simple theoretical examples in addition to an analysis of case notification data of pertussis, a childhood respiratory disease, in Thailand as a case study. We stress that further integration of these fields will have significant impacts in infectious diseases research.

Impact of vaccination and birth rate on the epidemiology of pertussis: a comparative study in 64 countries.

Bordetella pertussis infection remains an important public health problem worldwide despite decades of routine vaccination. A key indicator of the impact of vaccination programmes is the inter-epidemic period, which is expected to increase with vaccine uptake if there is significant herd immunity. Based on empirical data from 64 countries across the five continents over the past 30-70 years, we document the observed relationship between the average inter-epidemic period, birth rate and vaccine coverage. We then use a mathematical model to explore the range of scenarios for duration of immunity and transmission resulting from repeat infections that are consistent with empirical evidence. Estimates of pertussis periodicity ranged between 2 and 4.6 years, with a strong association with susceptible recruitment rate, defined as birth rate × (1 - vaccine coverage). Periodicity increased by 1.27 years on average after the introduction of national vaccination programmes (95% CI: 1.13, 1.41 years), indicative of increased herd immunity. Mathematical models suggest that the observed patterns of pertussis periodicity are equally consistent with loss of immunity that is not as rapid as currently thought, or with negligible transmission generated by repeat infections. We conclude that both vaccine coverage and birth rate drive pertussis periodicity globally and that vaccination induces strong herd immunity effects. A better understanding of the role of repeat infections in pertussis transmission is critical to refine existing control strategies.

Decreasing stochasticity through enhanced seasonality in measles epidemics.

Seasonal changes in the environment are known to be important drivers of population dynamics, giving rise to sustained population cycles. However, it is often difficult to measure the strength and shape of seasonal forces affecting populations. In recent years, statistical time-series methods have been applied to the incidence records of childhood infectious diseases in an attempt to estimate seasonal variation in transmission rates, as driven by the pattern of school terms. In turn, school-term forcing was used to show how susceptible influx rates affect the interepidemic period. In this paper, we document the response of measles dynamics to distinct shifts in the parameter regime using previously unexplored records of measles mortality from the early decades of the twentieth century. We describe temporal patterns of measles epidemics using spectral analysis techniques, and point out a marked decrease in birth rates over time. Changes in host demography alone do not, however, suffice to explain epidemiological transitions. By fitting the time-series susceptible-infected-recovered model to measles mortality data, we obtain estimates of seasonal transmission in different eras, and find that seasonality increased over time. This analysis supports theoretical work linking complex population dynamics and the balance between stochastic and deterministic forces as determined by the strength of seasonality.

Modelling the effect of a booster vaccination on disease epidemiology.

Despite the effectiveness of vaccines in dramatically decreasing the number of new infectious cases and severity of illnesses, imperfect vaccines may not completely prevent infection. This is because the immunity afforded by these vaccines is not complete and may wane with time, leading to resurgence and epidemic outbreaks notwithstanding high levels of primary vaccination. To prevent an endemic spread of disease, and achieve eradication, several countries have introduced booster vaccination programs. The question of whether this strategy could eventually provide the conditions for global eradication is addressed here by developing a seasonally-forced mathematical model. The analysis of the model provides the threshold condition for disease control in terms of four major parameters: coverage of the primary vaccine; efficacy of the vaccine; waning rate; and the rate of booster administration. The results show that if the vaccine provides only temporary immunity, then the infection typically cannot be eradicated by a single vaccination episode. Furthermore, having a booster program does not necessarily guarantee the control of a disease, though the level of epidemicity may be reduced. In addition, these findings strongly suggest that the high coverage of primary vaccination remains crucial to the success of a booster strategy. Simulations using estimated parameters for measles illustrate model predictions.

Ecological interference between fatal diseases.

An important issue in population biology is the dynamic interaction between pathogens. Interest has focused mainly on the indirect interaction of pathogen strains, mediated by cross immunity. However, a mechanism has recently been proposed for 'ecological interference' between pathogens through the removal of individuals from the susceptible pool after an acute infection. To explore this possibility, we have analysed and modelled historical measles and whooping cough records. Here we show that ecological interference is particularly strong when fatal infections permanently remove susceptibles. Disease interference has substantial dynamical consequences, making multi-annual outbreaks of different infections characteristically out of phase. So, when disease prevalence is high and is associated with significant mortality, it might be impossible to understand epidemic patterns by studying pathogens in isolation. This new ecological null model has important consequences for understanding the multi-strain dynamics of pathogens such as dengue and echoviruses.

Coherence and conservation.

A principal aim of current conservation policy is to reduce the impact of habitat fragmentation. Conservation corridors may achieve this goal by facilitating movement among isolated patches, but there is a risk that increased connectivity could synchronize local population fluctuations (causing coherent oscillations) and thereby increase the danger of global extinction. We identify general conditions under which populations can or cannot undergo coherent oscillations, and we relate these conditions to local and global extinction probabilities. We suggest a simple method to explore the potential success of conservation corridors and, more generally, any manipulations of dispersal patterns that aim to protect threatened species or control pests.

Impact of immunisation on pertussis transmission in England and Wales.

Pertussis immunisation reduces disease frequency, but is not thought to prevent transmission. We show that vaccination has substantially reduced transmission in England and Wales.

A simple model for complex dynamical transitions in epidemics.

Dramatic changes in patterns of epidemics have been observed throughout this century. For childhood infectious diseases such as measles, the major transitions are between regular cycles and irregular, possibly chaotic epidemics, and from regionally synchronized oscillations to complex, spatially incoherent epidemics. A simple model can explain both kinds of transitions as the consequences of changes in birth and vaccination rates. Measles is a natural ecological system that exhibits different dynamical transitions at different times and places, yet all of these transitions can be predicted as bifurcations of a single nonlinear model.

Opposite patterns of synchrony in sympatric disease metapopulations.

Measles epidemics in UK cities, which were regular and highly synchronous before vaccination, are known to have become irregular and spatially uncorrelated in the vaccine era. Whooping cough shows the reverse pattern, namely a shift from spatial incoherence and irregularity before vaccination to regular, synchronous epidemics afterward. Models show that these patterns can arise from disease-specific responses to dynamical noise. This analysis has implications for vaccination strategies and illustrates the power of comparative dynamical studies of sympatric metapopulations.