A pilot to examine the logistical and feasibility issues in testing deceased tissue donors for vCJD using tonsil as the analyte

Transplanted tissues have transmitted transmissible spongiform encephalopathies and in the UK there have been more cases of variant Creutzfeldt-Jakob disease (vCJD) than elsewhere in the world. A pilot study was undertaken to look at the feasibility of testing for vCJD in deceased donors using tonsillar tissue. This pilot showed that obtaining consent for removal and testing tonsil tissue was feasible. Donor eligibility for inclusion in the pilot was limited to tissue donors from the National Health Service Blood and Transplant, Tissue Services and to donors shared with the Corneal Transplant Service Eye Banks. Obtaining tonsillar tissue in the immediate post–mortem period was limited by the presence of rigor mortis. Tonsillar tissue was suitable for routine analysis for the presence of prion associated with vCJD in deceased tissue donors. Production and processing of tissue was straightforward and a low assay background was obtained from most samples. Since palatine and lingual tonsil tissue can be obtained in pairs it was possible, in the majority of cases, to set aside an intact sample for confirmatory testing if required. In one instance a sample was reactive by Western blot. However, the pattern of reactivity was not typical for that obtained from vCJD patients. Unfortunately the sample was not of sufficient quality for the confirmatory test to provide a conclusive result.     

Evaluating surveillance strategies for the early detection of low pathogenicity avian influenza infections

In recent years, the early detection of low pathogenicity avian influenza (LPAI) viruses in poultry has become increasingly important, given their potential to mutate into highly pathogenic viruses. However, evaluations of LPAI surveillance have mainly focused on prevalence and not on the ability to act as an early warning system. We used a simulation model based on data from Italian LPAI epidemics in turkeys to evaluate different surveillance strategies in terms of their performance as early warning systems. The strategies differed in terms of sample size, sampling frequency, diagnostic tests, and whether or not active surveillance (i.e., routine laboratory testing of farms) was performed, and were also tested under different epidemiological scenarios. We compared surveillance strategies by simulating within-farm outbreaks. The output measures were the proportion of infected farms that are detected and the farm reproduction number (R(h)). The first one provides an indication of the sensitivity of the surveillance system to detect within-farm infections, whereas R(h) reflects the effectiveness of outbreak detection (i.e., if detection occurs soon enough to bring an epidemic under control). Increasing the sampling frequency was the most effective means of improving the timeliness of detection (i.e., it occurs earlier), whereas increasing the sample size increased the likelihood of detection. Surveillance was only effective in preventing an epidemic if actions were taken within two days of sampling. The strategies were not affected by the quality of the diagnostic test, although performing both serological and virological assays increased the sensitivity of active surveillance. Early detection of LPAI outbreaks in turkeys can be achieved by increasing the sampling frequency for active surveillance, though very frequent sampling may not be sustainable in the long term. We suggest that, when no LPAI virus is circulating yet and there is a low risk of virus introduction, a less frequent sampling approach might be admitted, provided that the surveillance is intensified as soon as the first outbreak is detected.     

Assessment of the risk posed by bovine spongiform encephalopathy in cattle in Great Britain and the impact of potential changes to current control measures

We extended an existing back-calculation model to analyse data on reported clinical cases of bovine spongiform encephalopathy (BSE), data from random testing of healthy animals slaughtered in abattoirs and testing data from animals reported as sick or dying on the farm. Extensive analysis of demographic data was also undertaken. We estimated past and current BSE infection prevalences in the cattle population and the degree of case under-ascertainment resulting from excess mortality in cattle near to disease onset. Ongoing levels of human exposure to BSE infectivity were also estimated, together with the effect on these of a range of possible exposure-reduction strategies that might replace the current rule banning tissue from cattle over 30 months (OTM) of age from the human food supply. While any policy change that allows a wider age range of animals into the human food supply will increase levels of human exposure to infectivity, the risk posed by such increases is small by comparison with historical exposure levels. Making the pessimistic assumption that there will be 5000 deaths during the variant Creutzfeldt-Jakob disease (vCJD) epidemic in total, our analysis indicates that replacement of the OTM rule with testing would result in 0.04 additional vCJD deaths over the next 60 years. However, there is substantial (more than 40-fold) uncertainty surrounding this estimate, the sources of which are discussed.     

The epidemiology of variant Creutzfeldt-Jakob disease in Europe

Variant Creutzfeldt-Jakob disease is one of a family of neurodegenerative diseases, first diagnosed in 1996. Scientific evidence strongly supports the hypothesis that it is acquired through consumption of bovine spongiform encephalopathy-infected meat. The majority of cases have been diagnosed in the UK in young individuals, with an excess of cases in the north and a significant cluster of cases in Leicestershire. Many uncertainties in its biology and epidemiology, in particular the length of the incubation period, make predictions of any future epidemic difficult. Studies are currently under way to obtain more precise estimates of the prevalence of asymptomatic infection through testing tonsil and appendix tissues for the abnormal prion protein.     

Epidemiological determinants of the pattern and magnitude of the vCJD epidemic in Great Britain.

Understanding the epidemiology and aetiology of new-variant Creutzfeldt-Jakob (vCJD) disease in humans has become increasingly important given the scientific evidence linking it to bovine spongiform encephalopathy (BSE) in cattle and hence the wide exposure of the population of Great Britain (GB) to potentially infectious tissue. The recent analysis undertaken to determine the risk to the population from dorsal route ganglia illustrated the danger in presenting point estimates rather than ranges of scenarios in the face of uncertainty. We present a mathematical template that relates the past pattern of the BSE epidemic in cattle to the future course of any vCJD epidemic in humans, and use extensive scenario analysis to explore the wide range of possible outcomes given the uncertainty in epidemiological determinants. We demonstrate that the average number of humans infected by one infectious bovine and the incubation period distribution are the two epidemiological factors that have the greatest impact on epidemic size and duration. Using the time-series of the BSE epidemic and the cases seen to date, we show that the minimum length of the incubation period is approximately nine years, and that at least 20% of the cases diagnosed to date were exposed prior to 1986. We also demonstrate that the current age distribution of vCJD cases can only arise if younger people were either exposed to a greater extent, more susceptible to infection, or have shorter incubation periods. Extensive scenario analyses show that given the information currently available, the very high degree of uncertainty in the future size of the epidemic will remain for the next 3-5 years. Furthermore, we demonstrate that this uncertainty is unlikely to be reduced by mass screening for late-stage infection.     

Impacts and concerns for vCJD in blood transfusion: current status

The impact of vCJD upon blood transfusion practice hinges on its lymphoreticular involvement. B lymphocytes play a key supporting role for the capture and replication of infectivity by follicular dendritic cells of the lymphoid tissue in animal models of transmissible spongiform encephalopathies (TSE) and tonsils, spleen and appendix in man can harbour vCJD infectivity, a situation not seen with the other human TSEs. Leucodepletion of blood donations in the UK was implemented to reduce possible vCJD transmission and preliminary data suggests that white cell associated infectivity will be effectively removed although plasma infectivity will not. Blood screening assays are under development but none yet are ready for application. The conformation dependant immunoassay, based on differences in secondary and tertiary structure between normal and TSE-associated abnormal prion protein, has a sensitivity now approaching the best bioassay. Even so further development is needed to detect the fg/ml levels likely in the event that vCJD blood does contain abnormal prion, which is as yet unproven. Surrogate assays, such as for erythroid associated factor, may provide additional means of identifying donors harbouring vCJD. Validation of clearance of TSEs from pooled plasma products consistently demonstrates effective removal of the agents in downscaled systems and studies comparing vCJD, BSE and scrapie agents yield similar results. Many approaches to therapy are under investigation, in cell culture and animal models, targeted to normal or abnormal prion metabolism, including chemical and immunological interventions. Efficacy of quinacrine/chlorpromazine and pentosan polysulphate in a clinical setting, and agents yet to be used, will be more accurately known following recent agreement of clinical drug evaluation protocols.     

The effect of superspreading on epidemic outbreak size distributions

Recently, evidence has been presented to suggest that there are significant heterogeneities in the transmission of communicable diseases. Here, a stochastic simulation model of an epidemic process that allows for these heterogeneities is used to demonstrate the potentially considerable effect that heterogeneity of transmission will have on epidemic outbreak size distributions. Our simulation results agree well with approximations gained from the theory of branching processes. Outbreak size distributions have previously been used to infer basic epidemiological parameters. We show that if superspreading does occur then such distributions must be interpreted with care. The simulation results are discussed in relation to measles epidemics in isolated populations and in predominantly urban scenarios. The effect of three different disease control policies on outbreak size distributions are shown for varying levels of heterogeneity and disease control effort.     

A Bayesian Inference Framework to Reconstruct Transmission Trees Using Epidemiological and Genetic Data

The accurate identification of the route of transmission taken by an infectious agent through a host population is critical to understanding its epidemiology and informing measures for its control. However, reconstruction of transmission routes during an epidemic is often an underdetermined problem: data about the location and timings of infections can be incomplete, inaccurate, and compatible with a large number of different transmission scenarios. For fast-evolving pathogens like RNA viruses, inference can be strengthened by using genetic data, nowadays easily and affordably generated. However, significant statistical challenges remain to be overcome in the full integration of these different data types if transmission trees are to be reliably estimated. We present here a framework leading to a bayesian inference scheme that combines genetic and epidemiological data, able to reconstruct most likely transmission patterns and infection dates. After testing our approach with simulated data, we apply the method to two UK epidemics of Foot-and-Mouth Disease Virus (FMDV): the 2007 outbreak, and a subset of the large 2001 epidemic. In the first case, we are able to confirm the role of a specific premise as the link between the two phases of the epidemics, while transmissions more densely clustered in space and time remain harder to resolve. When we consider data collected from the 2001 epidemic during a time of national emergency, our inference scheme robustly infers transmission chains, and uncovers the presence of undetected premises, thus providing a useful tool for epidemiological studies in real time. The generation of genetic data is becoming routine in epidemiological investigations, but the development of analytical tools maximizing the value of these data remains a priority. Our method, while applied here in the context of FMDV, is general and with slight modification can be used in any situation where both spatiotemporal and genetic data are available.     

Mixed respiratory viral infections during influenza A epidemics

Mixed respiratory viral infections occurring in the course of 8 influenza A epidemics in the Estonian SSR between 1969 and 1978 were investigated. A total of 1638 patients were followed up. The IF method, serological test CFR and HIR and isolation of the virus on tissue cultures and chick embryos were used. Mixed infections were found in 0-77.7% of laboratory-confirmed cases, depending on the epidemic. A combination of influenza A + parainfluenza was observed most frequently during the influenza epidemics in 1971-1977 and a combination of influenza A + influenza B during the 1977-1978 epidemic.     

Ig isotypes produced by EBV-transformed B cells as a function of age and tissue distribution

EBV can transform human B cells giving rise to lymphoblastoid cell lines that produce and secrete Ig. Herein B cells from various tissues of newborns and adults were transformed by EBV and their Ig products were analyzed with isotype-specific mAb. Although IgG- and IgA-bearing B cells were present in the newborn, EBV transformed IgM-producing cells almost exclusively in both newborn blood and breast milk. IgM-secreting cells were derived from IgM+ B cells and IgM- pre-B cells present in neonatal blood, but only from IgM+ cells in adult blood. Whereas in adults most EBV-transformed cells produced IgM, producers of IgG and of IgA were present in frequencies that varied according to the tissue source. Precursors of IgG-producing cells were relatively abundant in blood, spleen, and tonsil, and relatively infrequent in bone marrow and appendix. EBV-inducible IgA producers were relatively concentrated in the appendix and to a lesser extent in tonsils and blood. Differences in the subclass composition of EBV-transformed populations of IgG- and IgA-producers were also observed for the various adult lymphoid tissues. IgG1-producing cells predominated in most tissues, and precursors of IgG2 were largely confined to the circulation. Whereas IgA1-producing cells were predominant in all tissues, a marked enrichment in IgA2-producers was observed in the appendix. These results indicate a remarkable heterogeneity in the isotype distribution pattern of EBV-transformable B cells that is determined both by developmental age and tissue localization. We propose that EBV selectively transforms primed B cells, the isotype commitment of which varies according to tissue origin and age.     

Validation of the Modes of Transmission Model as a Tool to Prioritize HIV Prevention Targets: A Comparative Modelling Analysis

Background

The static Modes of Transmission (MOT) model predicts the annual fraction of new HIV infections acquired across subgroups (MOT metric), and is used to focus HIV prevention. Using synthetic epidemics via a dynamical model, we assessed the validity of the MOT metric for identifying epidemic drivers (behaviours or subgroups that are sufficient and necessary for HIV to establish and persist), and the potential consequence of MOT-guided policies.

Methods and Findings

To generate benchmark MOT metrics for comparison, we simulated three synthetic epidemics (concentrated, mixed, and generalized) with different epidemic drivers using a dynamical model of heterosexual HIV transmission. MOT metrics from generic and complex MOT models were compared against the benchmark, and to the contribution of epidemic drivers to overall HIV transmission (cumulative population attributable fraction over t years, PAF_t). The complex MOT metric was similar to the benchmark, but the generic MOT underestimated the fraction of infections in epidemic drivers. The benchmark MOT metric identified epidemic drivers early in the epidemics. Over time, the MOT metric did not identify epidemic drivers. This was not due to simplified MOT models or biased parameters but occurred because the MOT metric (irrespective of the model used to generate it) underestimates the contribution of epidemic drivers to HIV transmission over time (PAF_5–30). MOT-directed policies that fail to reach epidemic drivers could undermine long-term impact on HIV incidence, and achieve a similar impact as random allocation of additional resources.

Conclusions

Irrespective of how it is obtained, the MOT metric is not a valid stand-alone tool to identify epidemic drivers, and has limited additional value in guiding the prioritization of HIV prevention targets. Policy-makers should use the MOT model judiciously, in combination with other approaches, to identify epidemic drivers.     

Cyclical Patterns of Hand,Foot and Mouth Disease Caused by Enterovirus A71 in Malaysia

Enterovirus A71 (EV-A71) is an important emerging pathogen causing large epidemics of hand, foot and mouth disease (HFMD) in children. In Malaysia, since the first EV-A71 epidemic in 1997, recurrent cyclical epidemics have occurred every 2–3 years for reasons that remain unclear. We hypothesize that this cyclical pattern is due to changes in population immunity in children (measured as seroprevalence). Neutralizing antibody titers against EV-A71 were measured in 2,141 residual serum samples collected from children ≤12 years old between 1995 and 2012 to determine the seroprevalence of EV-A71. Reported national HFMD incidence was highest in children <2 years, and decreased with age; in support of this, EV-A71 seroprevalence was significantly associated with age, indicating greater susceptibility in younger children. EV-A71 epidemics are also characterized by peaks of increased genetic diversity, often with genotype changes. Cross-sectional time series analysis was used to model the association between EV-A71 epidemic periods and EV-A71 seroprevalence adjusting for age and climatic variables (temperature, rainfall, rain days and ultraviolet radiance). A 10% increase in absolute monthly EV-A71 seroprevalence was associated with a 45% higher odds of an epidemic (adjusted odds ratio, aOR1.45; 95% CI 1.24–1.69; P<0.001). Every 10% decrease in seroprevalence between preceding and current months was associated with a 16% higher odds of an epidemic (aOR = 1.16; CI 1.01–1.34 P<0.034). In summary, the 2–3 year cyclical pattern of EV-A71 epidemics in Malaysia is mainly due to the fall of population immunity accompanying the accumulation of susceptible children between epidemics. This study will impact the future planning, timing and target populations for vaccine programs.     

Untangling the Interplay between Epidemic Spread and Transmission Network Dynamics

The epidemic spread of infectious diseases is ubiquitous and often has a considerable impact on public health and economic wealth. The large variability in the spatio-temporal patterns of epidemics prohibits simple interventions and requires a detailed analysis of each epidemic with respect to its infectious agent and the corresponding routes of transmission. To facilitate this analysis, we introduce a mathematical framework which links epidemic patterns to the topology and dynamics of the underlying transmission network. The evolution, both in disease prevalence and transmission network topology, is derived from a closed set of partial differential equations for infections without allowing for recovery. The predictions are in excellent agreement with complementarily conducted agent-based simulations. The capacity of this new method is demonstrated in several case studies on HIV epidemics in synthetic populations: it allows us to monitor the evolution of contact behavior among healthy and infected individuals and the contributions of different disease stages to the spreading of the epidemic. This gives both direction to and a test bed for targeted intervention strategies for epidemic control. In conclusion, this mathematical framework provides a capable toolbox for the analysis of epidemics from first principles. This allows for fast, in silico modeling--and manipulation--of epidemics and is especially powerful if complemented with adequate empirical data for parameterization.     

The chemical bases of the various AIDS epidemics: Recreational drugs,anti-viral chemotherapy and malnutrition

In 1981 a new epidemic of about two-dozen heterogeneous diseases began to strike non-randomly growing numbers of male homosexuals and mostly male intravenous drug users in the US and Europe. Assuming immunodeficiency as the common denominator the US Centers for Disease Control (CDC) termed the epidemic, AIDS, for acquired immunodeficiency syndrome. From 1981-1984 leading researchers including those from the CDC proposed that recreational drug use was the cause of AIDS, because of exact correlations and of drug-specific diseases. However, in 1984 US government researchers proposed that a virus, now termed human immunodeficiency virus (HIV), is the cause of the non-random epidemics of the US and Europe but also of a new, sexually random epidemic in Africa. The virus-AIDS hypothesis was instantly accepted, but it is burdened with numerous paradoxes, none of which could be resolved by 2003: Why is there no HIV in most AIDS patients, only antibodies against it? Why would HIV take 10 years from infection to AIDS? Why is AIDS not self-limiting via antiviral immunity? Why is there no vaccine against AIDS? Why is AIDS in the US and Europe not random like other viral epidemics? Why did AIDS not rise and then decline exponentially owing to antiviral immunity like all other viral epidemics? Why is AIDS not contagious? Why would only HIV carriers get AIDS who use either recreational or anti-HIV drugs or are subject to malnutrition? Why is the mortality of HIV-antibody-positives treated with anti-HIV drugs 7–9%, but that of all (mostly untreated) HIV-positives globally is only 1–4%? Here we propose that AIDS is a collection of chemical epidemics, caused by recreational drugs, anti-HIV drugs, and malnutrition. According to this hypothesis AIDS is not contagious, not immunogenic, not treatable by vaccines or antiviral drugs, and HIV is just a passenger virus. The hypothesis explains why AIDS epidemics strike non-randomly if caused by drugs and randomly if caused by malnutrition, why they manifest in drug- and malnutrition-specific diseases, and why they are not self-limiting via anti-viral immunity. The hypothesis predicts AIDS prevention by adequate nutrition and abstaining from drugs, and even cures by treating AIDS diseases with proven medications.     

Health newscasts for increasing influenza vaccination coverage: an inductive reasoning game approach

Both pandemic and seasonal influenza are receiving more attention from mass media than ever before. Topics such as epidemic severity and vaccination are changing the way in which we perceive the utility of disease prevention. Voluntary influenza vaccination has been recently modeled using inductive reasoning games. It has thus been found that severe epidemics may occur because individuals do not vaccinate and, instead, attempt to benefit from the immunity of their peers. Such epidemics could be prevented by voluntary vaccination if incentives were offered. However, a key assumption has been that individuals make vaccination decisions based on whether there was an epidemic each influenza season; no other epidemiological information is available to them. In this work, we relax this assumption and investigate the consequences of making more informed vaccination decisions while no incentives are offered. We obtain three major results. First, individuals will not cooperate enough to constantly prevent influenza epidemics through voluntary vaccination no matter how much they learned about influenza epidemiology. Second, broadcasting epidemiological information richer than whether an epidemic occurred may stabilize the vaccination coverage and suppress severe influenza epidemics. Third, the stable vaccination coverage follows the trend of the perceived benefit of vaccination. However, increasing the amount of epidemiological information released to the public may either increase or decrease the perceived benefit of vaccination. We discuss three scenarios where individuals know, in addition to whether there was an epidemic, (i) the incidence, (ii) the vaccination coverage and (iii) both the incidence and the vaccination coverage, every influenza season. We show that broadcasting both the incidence and the vaccination coverage could yield either better or worse vaccination coverage than broadcasting each piece of information on its own.     

The effect of intrinsic stochasticity on transmitted HIV drug resistance patterns

Estimates of transmitted HIV drug-resistance prevalence vary widely among and within epidemiological surveys. Interpretation of trends from available survey data is therefore difficult. Because the emergence of drug-resistance involves small populations of infected drug-resistant individuals, the role of stochasticity (chance events) is likely to be important. The question addressed here is: how much variability in transmitted HIV drug-resistance prevalence patterns arises due to intrinsic stochasticity alone, i.e., if all starting conditions in the different epidemics surveyed were identical? This ‘thought experiment’ gives insight into the minimum expected variabilities within and among epidemics. A simple stochastic mathematical model was implemented. Our results show that stochasticity alone can generate a significant degree of variability and that this depends on the size and variation of the pool of new infections when drug treatment is first introduced. The variability in transmitted drug-resistance prevalence within an epidemic (i.e., the temporal variability) is large when the annual pool of all new infections is small (fewer than 200, typical of the HIV epidemics in Central European and Scandinavian countries) but diminishes rapidly as that pool grows. Epidemiological surveys involving hundreds of new infections annually are therefore needed to allow meaningful interpretation of temporal trends in transmitted drug-resistance prevalence within individual epidemics. The stochastic variability among epidemics shows a similar dependence on the pool of new infections if treatment is introduced after endemic equilibrium is established, but can persist even when there are more than 10,000 new infections annually if drug therapy is introduced earlier. Stochastic models may therefore have an important role to play in interpreting differences in transmitted drug-resistance prevalence trends among epidemiological surveys.     

Factors determining the pattern of the variant Creutzfeldt-Jakob disease (vCJD) epidemic in the UK

Following the emergence of a new variant of Creutzfeldt-Jakob disease (vCJD) 6 years ago, and the gradual rise in clinical cases, there has been increased speculation regarding the overall magnitude of this epidemic in Great Britain. In this paper, we explore the epidemiological factors and uncertainties determining the scale of this epidemic in light of the most recent data on reported vCJD mortality. Our results demonstrate that, while the magnitude of the uncertainty has decreased dramatically since 1996, it is still not possible to predict with any degree of accuracy the final magnitude of this epidemic, with the 95% confidence interval for future cases being from 10 to 7000 deaths. However, short-term projections show that it is unlikely that a dramatic increase in case numbers will be observed in the next 2-5 years (95% confidence interval for 2 years: 10-80 cases, for 5 years: 10-200 cases). The results confirm significant age-dependent susceptibility/exposure to infection, with the likelihood profile demonstrating that those aged between 10 and 20 years are at highest risk of infection. We also demonstrate how projections based on onset data may be substantially biased, and explore the sensitivity of results to assumptions concerning the exposure to bovine spongiform encephalopathy (BSE) and the incubation-period distribution.     

Update on human prion disease

The recognition that variant Creutzfeldt–Jakob disease (vCJD) is caused by the same prion strain as bovine spongiform encephalopathy in cattle has dramatically highlighted the need for a precise understanding of the molecular biology of human prion diseases. Detailed clinical, pathological and molecular data from a large number of human prion disease patients indicate that phenotypic diversity in human prion disease relates in part to the propagation of disease-related PrP isoforms with distinct physicochemical properties. Incubation periods of prion infection in humans can exceed 50 years and therefore it will be some years before the extent of any human vCJD epidemic can be predicted with confidence.