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.     

Estimation of the Exposure of the UK Population to the Bovine Spongiform Encephalopathy Agent through Dietary Intake During the Period 1980 to 1996

Although the incidence of variant Creutzfeldt-Jakob disease (vCJD) has declined to 1 since 2012 in the UK, uncertainty remains regarding possible future cases and the size of the subclinical population that may cause secondary transmission of the disease through blood transfusion. Estimating the number of individuals who were exposed to the bovine spongiform encephalopathy (BSE) infectious agent and may be susceptible to vCJD will help to clarify related public health concerns and plan strategies. In this paper, we explore this estimate by describing the probability of potential exposure due to dietary intake throughout the BSE epidemic period from 1980 to 1996 as a stochastic Poisson process. We estimate the age- and gender-specific exposure intensities in food categories of beef and beef-containing dishes, burgers and kebabs, pies, and sausages, separating the two periods of 1980–1989 and 1990–1996 due to the specified bovine offal legislation of 1989. The estimated total number of (living) exposed individuals during each period is 5,089,027 (95% confidence interval [CI] 4,514,963–6,410,317), which was obtained by multiplying the population size of different birth cohorts by the probability of exposure via dietary intake and the probability of survival until the end of 2013. The estimated number is approximately doubled, assuming a contamination rate of . Among those individuals estimated, 31,855 (95% CI 26,849–42,541) are susceptible to infection. We also examined the threshold hypothesis by fitting an extreme-value distribution to the estimated infectious dose of the exposed individuals and obtained a threshold estimate of 13.7 bID₅₀ (95% CI 6.6–26.2 bID₅₀) (Weibull). The results provide useful information on potential carriers of prion disease who may pose a threat of infection via blood transfusion and thus provide insight into the likelihood of new incidents of vCJD occurring in the future.     

Implications of BSE infection screening data for the scale of the British BSE epidemic and current European infection levels

The incidence of confirmed clinical cases of bovine spongiform encephalopathy (BSE) in Great Britain continues to decline, but the recent discovery of cases in previously unaffected countries (including Israel, Japan, Poland, Slovenia and Spain) has heightened concerns that BSE transmission was more intense and widespread than previously thought. We use back-calculation methods to undertake an integrated analysis of data on infection prevalence in apparently healthy cattle and the incidence of confirmed clinical disease. The results indicate substantial underascertainment of clinical cases over the course of the British epidemic, and consequently that two- to fourfold more animals were infected than previously estimated. Upper bounds on the predicted size of the new variant Creutzfeldt-Jakob Disease (vCJD) epidemic are unaffected, as the prediction methods employed fit to observed vCJD mortality data, and are not sensitive to estimates of the absolute magnitude of past human exposure to BSE-infected cattle, only to relative changes in exposure through time. We also estimate the per-head incidence of infection in cattle born between 1993 and 1997 in other European Union countries, using data on the testing of apparently healthy cattle slaughtered for consumption. Infection incidence for cattle born after mid-1996 was highest in Greece, Italy and Belgium, with Spain and The Netherlands having intermediate levels, and estimates for Great Britain, Germany and France being comparably low.     

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.     

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.     

Prominent and persistent extraneural infection in human PrP transgenic mice infected with variant CJD

Background

The evolution of the variant Creutzfeldt-Jakob disease (vCJD) epidemic is hazardous to predict due to uncertainty in ascertaining the prevalence of infection and because the disease might remain asymptomatic or produce an alternate, sporadic-like phenotype.

Methodology/Principal Findings

Transgenic mice were produced that overexpress human prion protein with methionine at codon 129, the only allele found so far in vCJD-affected patients. These mice were infected with prions derived from variant and sporadic CJD (sCJD) cases by intracerebral or intraperitoneal route, and transmission efficiency and strain phenotype were analyzed in brain and spleen. We showed that i) the main features of vCJD infection in humans, including a prominent involvement of the lymphoid tissues compared to that in sCJD infection were faithfully reproduced in such mice; ii) transmission of vCJD agent by intracerebral route could lead to the propagation of either vCJD or sCJD-like prion in the brain, whereas vCJD prion was invariably propagated in the spleen, iii) after peripheral exposure, inefficient neuroinvasion was observed, resulting in an asymptomatic infection with life-long persistence of vCJD prion in the spleen at stable and elevated levels.

Conclusion/Significance

Our findings emphasize the possibility that human-to-human transmission of vCJD might produce alternative neuropathogical phenotypes and that lymphoid tissue examination of CJD cases classified as sporadic might reveal an infection by vCJD-type prions. They also provide evidence for the strong propensity of this agent to establish long-lasting, subclinical vCJD infection of lymphoreticular tissues, thus amplifying the risk for iatrogenic transmission.     

Assessment of the prevalence of vCJD through testing tonsils and appendices for abnormal prion protein

The objective of this study was to determine the age group or groups which will provide the most information on the potential size of the vCJD epidemic in Great Britain via the sampling of tonsil and appendix material to detect the presence of abnormal prion protein (PrP(Sc)). A subsidiary aim was to determine the degree to which such an anonymous age-stratified testing programme will reduce current uncertainties in the size of the epidemic in future years. A cohort- and time-stratified model was used to generate epidemic scenarios consistent with the observed vCJD case incidence. These scenarios, together with data on the age distribution of tonsillectomies and appendectomies, were used to evaluate the optimal age group and calendar time for undertaking testing and to calculate the range of epidemic sizes consistent with different outcomes. The analyses suggested that the optimal five-year age group to test is 25-29 years, although a random sample of appendix tissue from all age groups is nearly as informative. A random sample of tonsil tissue from all age groups is less informative, but the information content is improved if sampling is restricted to tissues removed from those over ten years of age. Based on the assumption that the test is able to detect infection in the last 75% of the incubation period, zero detected infections in an initial random sample of 1000 tissues would suggest that the epidemic will be less than 870,000 cases. If infections are detected, then the model prediction suggests that both relatively small epidemics (800+ cases if one is detected or 8300+ if two are detected) and larger epidemics (21,000+ cases if three or more are detected) are possible. It was concluded that testing will be most informative if undertaken using appendix tissues or tonsil tissues removed from those over ten years of age. Large epidemics can only be excluded if a small number of infections are detected and the test is able to detect infection early in the incubation period.     

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.     

Astrocytoma risk related to job exposure to electric and magnetic fields

To investigate the association between occupational exposure to low-frequency electric and magnetic (EM) fields and risk of brain tumors, a study was performed in Los Angeles County on 272 male adults with primary intracranial gliomas or meningiomas and 272 neighborhood controls. Complete occupational histories were collected. Risk associated with employment for more than 10 years in jobs that are presumed to entail exposure to EM fields was computed for various histological groupings. A nonsignificantly elevated risk of 1.7 was found for gliomas (all types pooled: 95% confidence interval 0.7-4.4), and a nonsignificantly reduced risk of 0.3 (95% confidence interval 0.03-3.2) was found for meningiomas. For astrocytomas, which form a subtype of the gliomas, a significantly elevated risk of 10.3 (95% confidence interval 1.3-80.8) was found; a significant upward trend (P = .01) of tumor incidence with increasing length of employment was observed. Most astrocytoma patients who worked in occupations involving exposure to EM fields were electricians or electrical engineers.     

Prevalence of hypospadias in the same geographic region as ascertained by three different registries

Hypospadias birth prevalence may be increasing with maternal exposure to endocrine disrupters. Yet hypospadias registers are hindered by data quality concerns. We compare the birth prevalence per thousand male births (BP) and ascertainment of hypospadias in the South East of England between 1st January 1997 to 31st September 1998 in a population-based hypospadias case register (surgeons' register) 731 cases, BP 3.8, (95% confidence interval 3.7-3.9), the National Congenital Anomaly System (NCAS) 645 cases (88% of surgeons' register), BP 3.4, (95% confidence interval 3.29-3.5) and Hospital Episode Statistics (HES) 221 cases (30% of the surgeons register), BP 1.15 (95% confidence interval 1.1-1.2). There were 191,438 male births (National Statistics). We found considerable differences in birth prevalence estimates and ascertainment according to data source. Compared with the Surgeons' register, the HES under-ascertainment of 10% was possibly explained by procedural weaknesses. NCAS's 70% under-ascertainment is explained by exclusion of so-called mild hypospadias (since 1990). This exclusion does not appear warranted since mild and severe hypospadias probably share aetiology and all require surgery. NCAR's utility could be improved if it returned to including "minor" hypospadias. Meanwhile routine data such as HES are potentially suitable for surveillance of this condition.     

Incidence of leukaemia in young people in the vicinity of Hinkley Point nuclear power station, 1959-86.

The incidence of leukaemia and non-Hodgkin''s lymphoma in young people (aged under 25) living in a predefined area around the nuclear power station at Hinkley Point, Somerset, was examined for the period 1959-86 by using cancer registry data. During the period since Hinley Point began operations--that is, 1964-86--there were 19 cases in the area compared with 10.4 expected from national rates, giving a standardised registration ratio of 1.82 (95% confidence interval 1.10 to 2.85). The incidence in the rest of Somerset was also high, however (standardised registration ratio 1.18; 95% confidence interval 0.98 to 1.41), and the high rate around Hinkley Point may simply have been reflecting the high local incidence (ratio of the two standardised registration ratio''s 1.54; 95% confidence interval 0.90 to 2.52). Analysis of predetermined five year periods showed that the excess cases in the Hinkley Point area were concentrated in the 10 years 1964-73 after commissioning of the station, at a time when rates in the rest of Somerset were close to the national average. In particular the nine cases occurring in the five years 1969-73 were about four times the number expected from national rates (standardised registration ratio 3.96; 95% confidence interval 1.81 to 7.52). Rates in the Hinkley Point area after 1973 were fairly low, especially as compared with the rest of Somerset. In the five years 1959-63 (that is, before Hinkley Point was commissioned) rates throughout Somerset (including the Hinkley Point area) were higher than the national rate. These findings should be interpreted with caution, and further studies are required to test the plausibility of theories relating to radiation and viruses.     

Association between occupational exposure to mineral oil and rheumatoid arthritis: results from the Swedish EIRA case-control study

The aim of the present study was to investigate the association between exposure to mineral oil and the risk of developing rheumatoid arthritis (RA), and in addition to perform a separate analysis on the major subphenotypes for the disease; namely, rheumatoid factor (RF)-positive RA, RF-negative RA, anticitrulline-positive RA and anticitrulline-negative RA, respectively. A population-based case-control study of incident cases of RA was performed among the population aged 18-70 years in a defined area of Sweden during May 1996-December 2003. A case was defined as an individual from the study base who for the first time received a diagnosis of RA according to the American College of Rheumatology criteria of 1987. Controls were randomly selected from the study base with consideration taken for age, gender and residential area. Cases (n = 1,419) and controls (n = 1,674) answered an extensive questionnaire regarding lifestyle factors and occupational exposures, including different types of mineral oils. Sera from cases and controls were investigated for RF and anticitrulline antibodies. Among men, exposure to any mineral oil was associated with a 30% increased relative risk of developing RA (relative risk = 1.3, 95% confidence interval = 1.0-1.7). When cases were subdivided into RF-positive RA and RF-negative RA, an increased risk was only observed for RF-positive RA (relative risk = 1.4, 95% confidence interval 1.0-2.0). When RA cases were subdivided according to the presence of anticitrulline antibodies, an increased risk associated with exposure to any mineral oil was observed only for anticitrulline-positive RA (relative risk = 1.6, 95% confidence interval = 1.1-2.2). Analysis of the interaction between oil exposure and the presence of HLA-DR shared epitope genes regarding the incidence of RA indicated that the increased risk associated with exposure to mineral oil was not related to the presence of shared epitope genotypes. In conclusion, our study shows that exposure to mineral oil is associated with an increased risk to develop RF-positive RA and anticitrulline-positive RA, respectively. The findings are of particular interest since the same mineral oils can induce polyarthritis in rats.     

BSE in France: epidemiological analysis and predictions

Attention throughout Europe continues to focus on bovine spongiform encephalopathy (BSE) with increasing evidence linking it to the new variant of Creutzfeldt-Jakob disease (vCJD) in humans. The age- and cohort-specific incidence of BSE in French cattle was modelled as a function of the survival distribution, the cohort-specific incidence of BSE infection, the underreporting rate of BSE cases, and the age-specific probability, conditional on survival, that an infected animal would experience clinical onset. The results reveal that thousands of French cattle were infected with BSE over the course of the epidemic. However, case incidence is predicted to decline in future years.     

Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration

Using a large sample of cases and controls from a single center, we show that a T-->C substitution in exon 9 (Y402H) of the complement factor H gene is strongly associated with susceptibility to age-related macular degeneration, the most common cause of blindness in the elderly. Frequency of the C allele was 0.61 in cases, versus 0.34 in age-matched controls (P<1x10(-24)). Genotype frequencies also differ markedly between cases and controls (chi2=112.68 [2 degrees of freedom]; P<1x10(-24)). A multiplicative model fits the data well, and we estimate the population frequency of the high-risk C allele to be 0.39 (95% confidence interval 0.36-0.42) and the genotype relative risk to be 2.44 (95% confidence interval 2.08-2.83) for TC heterozygotes and 5.93 (95% confidence interval 4.33-8.02) for CC homozygotes.     

All clinically-relevant blood components transmit prion disease following a single blood transfusion: a sheep model of vCJD

Variant CJD (vCJD) is an incurable, infectious human disease, likely arising from the consumption of BSE-contaminated meat products. Whilst the epidemic appears to be waning, there is much concern that vCJD infection may be perpetuated in humans by the transfusion of contaminated blood products. Since 2004, several cases of transfusion-associated vCJD transmission have been reported and linked to blood collected from pre-clinically affected donors. Using an animal model in which the disease manifested resembles that of humans affected with vCJD, we examined which blood components used in human medicine are likely to pose the greatest risk of transmitting vCJD via transfusion. We collected two full units of blood from BSE-infected donor animals during the pre-clinical phase of infection. Using methods employed by transfusion services we prepared red cell concentrates, plasma and platelets units (including leucoreduced equivalents). Following transfusion, we showed that all components contain sufficient levels of infectivity to cause disease following only a single transfusion and also that leucoreduction did not prevent disease transmission. These data suggest that all blood components are vectors for prion disease transmission, and highlight the importance of multiple control measures to minimise the risk of human to human transmission of vCJD by blood transfusion.     

Childhood exposure to ionizing radiation to the head and risk of schizophrenia

While the association between exposure to ionizing radiation and cancer is well established, its association with schizophrenia is unclear. The aim of our study was to assess risk of schizophrenia after childhood exposure to ionizing radiation to the head (mean dose: 1.5 Gy). The study population included an exposed group of 10,834 individuals irradiated during childhood for treatment of tinea capitis in the 1950s and two unexposed comparison groups of 5392 siblings and 10,834 subjects derived from the National Population Registry individually matched to the exposed group by age, sex (when possible), country of birth, and year of immigration to Israel. These groups were followed for a median 46 years for diagnosis of schizophrenia updated to December 2002. The Cox proportional hazards model stratified by matched sets was used to compare the risk of schizophrenia between the groups. Based on 1,217,531 person-years of follow-up, 451 cases were identified. No statistically significant association was found between radiation exposure and schizophrenia for the total group (hazard ratio per 1 Gy to the brain: 1.05, 95% confidence interval: 0.93-1.18) or within subgroups of sex, dose categories or latent period. When comparing a subgroup of subjects irradiated under 5 years of age with the matched unexposed group, the estimated hazard ratio reached 1.18 (95% confidence interval: 0.96-1.44; P = 0.1). The results of our analysis do not support an association between exposure to ionizing radiation and risk of schizophrenia. More research on possible effects of early exposure to ionizing radiation on schizophrenia specifically and brain tissue in general is needed.     

Incomplete Protection against Dengue Virus Type 2 Re-infection in Peru

Background

Nearly half of the world’s population is at risk for dengue, yet no licensed vaccine or anti-viral drug is currently available. Dengue is caused by any of four dengue virus serotypes (DENV-1 through DENV-4), and infection by a DENV serotype is assumed to provide life-long protection against re-infection by that serotype. We investigated the validity of this fundamental assumption during a large dengue epidemic caused by DENV-2 in Iquitos, Peru, in 2010–2011, 15 years after the first outbreak of DENV-2 in the region.

Methodology/Principal Findings

We estimated the age-dependent prevalence of serotype-specific DENV antibodies from longitudinal cohort studies conducted between 1993 and 2010. During the 2010–2011 epidemic, active dengue cases were identified through active community- and clinic-based febrile surveillance studies, and acute inapparent DENV infections were identified through contact tracing studies. Based on the age-specific prevalence of DENV-2 neutralizing antibodies, the age distribution of DENV-2 cases was markedly older than expected. Homologous protection was estimated at 35.1% (95% confidence interval: 0%–65.2%). At the individual level, pre-existing DENV-2 antibodies were associated with an incomplete reduction in the frequency of symptoms. Among dengue cases, 43% (26/66) exhibited elevated DENV-2 neutralizing antibody titers for years prior to infection, compared with 76% (13/17) of inapparent infections (age-adjusted odds ratio: 4.2; 95% confidence interval: 1.1–17.7).

Conclusions/Significance

Our data indicate that protection from homologous DENV re-infection may be incomplete in some circumstances, which provides context for the limited vaccine efficacy against DENV-2 in recent trials. Further studies are warranted to confirm this phenomenon and to evaluate the potential role of incomplete homologous protection in DENV transmission dynamics.     

Real-time investigation of measles epidemics with estimate of vaccine efficacy

As part of measles elimination effort, evaluation of the vaccination program and real-time assessment of the epidemic dynamics constitute two important tasks to improve and strengthen the control. The present study aimed to develop an epidemiological modeling method which can be applied to estimating the vaccine efficacy at an individual level while conducting the timely investigation of the epidemic. The multivariate renewal process model was employed to describe the temporal evolution of infection by vaccination history, jointly estimating the time-dependent reproduction number and the vaccine efficacy. Analyzing the enhanced surveillance data of measles in Aichi prefecture, Japan from 2007-08, the vaccine efficacy was estimated at 96.7% (95% confidence interval: 95.8, 97.4). Using an age structured model, the vaccine efficacy among those aged from 5-19 years was shown to be smaller than that among those from 0-4 years. The age-dependent vaccine efficacy estimate informs the age-groups to be targeted for revaccination. Because the estimation method can rest on readily available epidemiological data, the proposed model has a potential to be integrated with routine surveillance.