Neuroimaging in encephalitis: analysis of imaging findings and interobserver agreement.

AIM: To assess the role of imaging in the early management of encephalitis and the agreement on findings in a well-defined cohort of suspected encephalitis cases enrolled in the Prospective Aetiological Study of Encephalitis conducted by the Health Protection Agency (now incorporated into Public Health England). MATERIALS AND METHODS: Eighty-five CT examinations from 68 patients and 101 MRI examinations from 80 patients with suspected encephalitis were independently rated by three neuroradiologists blinded to patient and clinical details. The level of agreement on the interpretation of images was measured using the kappa statistic. The sensitivity, specificity, and negative and positive predictive values of CT and MRI for herpes simplex virus (HSV) encephalitis and acute disseminated encephalomyelitis (ADEM) were estimated. RESULTS: The kappa value for interobserver agreement on rating the scans as normal or abnormal was good (0.65) for CT and moderate (0.59) for MRI. Agreement for HSV encephalitis was very good for CT (0.87) and MRI (0.82), but only fair for ADEM (0.32 CT; 0.31 MRI). Similarly, the overall sensitivity of imaging for HSV encephalitis was ∼80% for both CT and MRI, whereas for ADEM it was 0% for CT and 20% for MRI. MRI specificity for HSV encephalitis between 3-10 days after symptom onset was 100%. CONCLUSION: There is a subjective component to scan interpretation that can have important implications for the clinical management of encephalitis cases. Neuroradiologists were good at diagnosing HSV encephalitis; however, agreement was worse for ADEM and other alternative aetiologies. Findings highlight the importance of a comprehensive and multidisciplinary approach to diagnosing the cause of encephalitis that takes into account individual clinical, microbiological, and radiological features of each patient.

Epidemiology of serogroup C and Y invasive meningococcal disease (IMD) in Ontario, 2000-2013: Vaccine program impact assessment.

OBJECTIVES: A publicly-funded meningococcal serogroup C conjugate vaccine (MCCV) program was introduced in Ontario, in 2004/2005 for 1-year-old children as well as adolescents (approximately 12 years old). In 2009, quadrivalent meningococcal conjugate vaccine (MCV4) replaced MCCV for grade seven students. Our objective was to determine meningococcal vaccine program impact on reported cases of serogroup C and Y invasive meningococcal disease (IMD) at the population level in Ontario, Canada. METHODS: Data were obtained from the Ontario reportable diseases system, the integrated Public Health Information System (iPHIS), and Public Health Ontario Laboratories (PHOL) for 2000-2013. Descriptive epidemiologic analyses, including age-specific rates for age groups based on program eligibility, were conducted. Changes over the 14-year observation period and comparison of pre- and post-program periods for MCCV and MCV4 were assessed. Analyses were conducted using SAS 9.3. RESULTS: There were 161 serogroup C IMD cases and its annual incidence decreased significantly over time (17.2% reduction per year [95% CI: 13.4 to 20.7]). The incidence of serogroup C IMD decreased significantly in children aged 1-17 years in the post-program period, based on age-specific incidence rate ratios (IRRs) and their 95% confidence intervals (CIs). Adolescents 12-16 years had the lowest serogroup C IRR (0.07 [95% CI: 0.01 to 0.55]); the rate decreased more than 14-fold between the pre- and post-periods. There were 187 serogroup Y IMD cases and there was a non-significant 1.6% reduction per year [95% CI: -1.9 to 5.1]) over the surveillance period. Likewise, there was a non-significant decrease in serogroup Y IMD among persons 12-16 years (MCV4 eligible) in the post-program period. CONCLUSIONS: Reductions in serogroup C IMD among program eligible and ineligible age groups suggest both direct and indirect MCCV vaccine program impact. Continued surveillance of IMD in Ontario is important to further assess MCV4 program impact.

Strengths and limitations of assessing influenza vaccine effectiveness using routinely collected, passive surveillance data in Ontario, Canada, 2007 to 2012: balancing efficiency versus quality.

Prompt evaluation of annual influenza vaccine effectiveness (IVE) is important. IVE is estimated in Ontario using a test-negative design (TND) within a national sentinel surveillance network (SPSN). To explore alternative approaches, we applied the screening method (SM) during five seasons spanning 2007 to 2012 to passive surveillance data to determine whether routinely collected data could provide unbiased IVE estimates. Age-adjusted SM-IVE estimates, excluding 2008/09 pandemic cases and cases with missing immunisation status, were compared with TND-IVE estimates in SPSN participants, adjusted for age, comorbidity, week of illness onset and interval to specimen collection. In four seasons, including the 2009 pandemic, the SM underestimated IVE (22­39% seasonal; 72% pandemic) by 20 to 35% relative to the TND-IVE (58­63% seasonal; 93% pandemic), except for the 2010/11 season when both estimates were low (33% and 30%, respectively). Half of the cases in the routine surveillance data lacked immunisation information; imputing all to be unimmunised better aligned SM-IVE with TND-IVE, instead overestimating in four seasons by 4 to 29%. While the SM approach applied to routine data may offer the advantage of timeliness, ease and efficiency, methodological issues related to completeness of vaccine information and/or case ascertainment may constitute trade-offs in reliability.

Canadian vaccine research networks: Vaccine safety resources for Canada.

The Public Health Agency of Canada / Canadian Institutes of Health Research Influenza Research Network (PCIRN), established in 2009 to undertake evaluative research to inform public health decision making in Canada, is now being replaced by the Canadian Immunization Research Network (CIRN), which will retain the mandate of PCIRN but expand it to all vaccines including influenza vaccine. CIRN is organized as a network of networks focusing on undertaking research in the areas of vaccine safety, adverse events following immunization (AEFIs), vaccine hesitancy, vaccine effectiveness, and vaccine coverage. CIRN's networks include: a clinical trial network; a laboratory network; a modelling and economics network; a network of social science and humanities researchers; a vaccine safety surveillance network; a hospital-based surveillance network; a clinic network to evaluate serious AEFIs; and a network that links vaccine research capacity in provincial health agencies and departments. PCIRN has contributed to Canada's vaccine safety surveillance system and has facilitated the translation of safety research into policy. Vaccine safety surveillance and research will remain a focus of the newly formed Canadian Immunization Research Network.

Human Rabies Post-Exposure Prophylaxis and Animal Rabies in Ontario, Canada, 2001-2012.

In Ontario, Canada, the implementation of an annual rabies control programme in wildlife that began in 1989 resulted in a marked, steady decrease in the number of animal rabies cases. The number of animal rabies cases decreased from 1870 in 1989 to 183 in 2000 (Nunan et al., 2002 Emerg Infect Dis 8, 214). In our study period, the number of animal rabies cases continued to decrease from 210 in 2001 to 28 in 2012. The marked decrease in animal rabies cases since 1989 has resulted in a decrease in the risk of human infection. A concomitant decrease in the number of rabies post-exposure prophylaxis (RPEP) administered was anticipated but failed to occur. The mean rate of RPEP, 13.9 RPEP administered per 100,000 persons, from 2001-2012 was approximately the same as the rate in the 1990 s. Two possible reasons that the rate of RPEP administration has not decreased include strict adherence to RPEP recommendations and administration of RPEP when it is not recommended. A reduction in the number of RPEP administered, consistent with the decrease in the animal rabies cases, would provide some financial savings for the government. Ideally, an increased use of the risk assessment approach in keeping with recent guidelines, rather than adhering to previous prescriptive recommendations for RPEP administration, coupled with a continuing low incidence of animal rabies cases will result in decreased, and yet appropriate, use of RPEP. Consideration should be given to identify how guidelines could be revised to more effectively target high-risk exposures and reduce the administration of RPEP for instances in which the risk of rabies virus exposure is exceedingly low.

The ethics of sharing preliminary research findings during public health emergencies: a case study from the 2009 influenza pandemic.

During the 2009 A(H1N1) influenza pandemic, a suite of studies conducted in Canada showed an unexpected finding, that patients with medically attended laboratory-confirmed pandemic influenza were more likely to have received seasonal influenza vaccination than test-negative control patients. Different bodies, including scientific journals and government scientific advisory committees, reviewed the evidence simultaneously to determine its scientific validity and implications. Decision-making was complicated when the findings made their way into the media. The normal trajectory of non-urgent research includes peer-review publication after which decision-makers can process the information taking into account other evidence and logistic considerations. In the situation that arose, however, the congruence of an unexpected finding and the simultaneous review of the evidence both within and outside the traditional peer-review sphere raised several interesting issues about how to deal with emerging evidence during a public health emergency. These events are used in this article to aid discussion of the complex interrelationship between researchers, public health decision-makers and scientific journals, the trade-offs between sharing information early and maintaining the peer-review quality assurance process, and to emphasise the need for critical reflection on the practical and ethical norms that govern the way in which research is evaluated, published and communicated in public health emergencies.

A cocoon immunisation strategy against pertussis for infants: does it make sense for Ontario?

Pertussis deaths occur primarily among infants who have not been fully immunised. In Ontario, Canada, an adult booster dose was recently added to the publicly funded immunisation programme. We applied number-needed-to-treat analyses to estimate the number of adults that would need to be vaccinated (NNV) to prevent pertussis disease, hospitalisation and death among infants if a cocoon strategy were implemented. NNV=1/(P(M) X R) + 1/(P(F) X R), where P(M),P(F) (proportion of infants infected by mothers, fathers) were sourced from several studies. Rates of disease, hospitalisation or death (R) were derived from Ontario's reportable disease data and Discharge Abstract Database. After adjusting for under-reporting, the NNV to prevent one case, hospitalisation or death from pertussis was between 500-6,400, 12,000-63,000 and 1.1-12.8 million, respectively. Without adjustment, NNV increased to 5,000-60,000, 55,000-297,000 and 2.5-30.2 million, respectively. Rarer outcomes were associated with higher NNV. These analyses demonstrate the relative inefficiency of a cocoon strategy in Ontario, which has a well-established universal immunisation programme with relatively high coverage and low disease incidence. Other jurisdictions considering a cocoon programme should consider their local epidemiology.

Risk factors for sporadic domestically acquired Salmonella serovar Enteritidis infections: a case-control study in Ontario, Canada, 2011.

In Ontario, Canada, the number of Salmonella Enteritidis (SE) cases increased over the years 2005-2010. A population-based case-control study was undertaken from January to August 2011 for the purpose of identifying risk factors for acquiring illness due to SE within Ontario. A total of 199 cases and 241 controls were enrolled. After adjustment for confounders, consuming any poultry meat [adjusted odds ratio (aOR) 2·24, 95% confidence interval (CI) 1·31-3·83], processed chicken (aOR 3·32, 95% CI 1·26-8·76) and not washing hands following handling of raw eggs (OR 2·82, 95% CI 1·48-5·37) were significantly associated with SE infection. The population attributable fraction was 46% for any poultry meat consumption and 10% for processed chicken. Poultry meat continues to be identified as a risk factor for SE illness. Control of SE at source, as well as proper food handling practices, are required to reduce the number of SE cases.

The challenges of sustaining measles elimination in Canada.

Recent importations of measles into Canada have not generally led to large outbreaks, indicating that measles is well controlled in Canada. Isolated large outbreaks that have occurred remind us of the need to remain vigilant. Measles presents particular challenges because it is the most infectious disease known, it thrives among those who do not access the child health system for one reason or another, and we do not always have the information we need to identify and target communities with low immunization coverage. Outbreaks typically arise from Canadians who travel and are exposed to measles abroad. Controlling sporadic outbreaks arising from importations is time and resource intensive, which makes immunization for Canadians travelling outside the region of the Americas (where measles has been eliminated) a priority. To prevent importations of measles into Canada altogether requires other countries and regions of the world to make progress in eliminating measles.

Prolonged Pertussis Outbreak in Ontario Originating in an Under-immunized Religious Community.

Abstract. BACKGROUND: A prolonged pertussis outbreak began in Ontario in November 2011 in an under-immunized religious community and subsequently spread to the general population and a second religious community in the same region of the province. OBJECTIVE: To compare the epidemiology in the religious communities to that of the general population within the affected jurisdictions. METHODS: The analysis includes cases reported through the integrated Public Health Information System (iPHIS) between November 1, 2011 and April 15, 2013 that met the outbreak case definition. Health unit staff assessed whether cases were members of religious communities through case investigations and collected information on immunization status, treatment and outcomes. RESULTS: A total of 443 confirmed and probable outbreak cases were reported in 7 health units. The outbreak began in one religious community (138 cases), before spreading to the general population in the region (273 cases). A second under-immunized community within the region experienced 32 cases. Thirteen cases were hospitalized and no deaths were reported. Disease peaked earlier in the religious community; cases were significantly younger, more likely to be at high risk for pertussis and more likely to be unimmunized. Among the fully immunized general population, 51% of cases were between 10-14 years and with a median of 5.6 years since their last immunization. CONCLUSION: The epidemiology of pertussis in the under-immunized community is distinct from the general population. Transmission of pertussis to the general community is not unexpected during an outbreak; however, the proportion of cases up to date with immunization warrants further investigation.

Documenting the elimination of measles, rubella and congenital rubella syndrome in Ontario: 2009-12.

BACKGROUND: Under the guidance of the Pan American Health Organization (PAHO), countries of the Americas are currently documenting the elimination of measles, rubella, and congenital rubella syndrome. OBJECTIVE: This paper describes Ontario's progress in documenting the elimination of these conditions between 2009 and 2012. METHODS: All possible case classifications, including those that did not meet surveillance case definitions, were extracted from the provincial reportable disease database, the integrated Public Health Information System (iPHIS). Data were analyzed against select criteria specified by the PAHO, specifically with respect to epidemiology, vaccination coverage, and the quality of the surveillance system. RESULTS: There were no known endemic cases of measles, rubella or congenital rubella syndrome reported in Ontario during the study period. Cases were predominantly the result of importation, as these diseases remain endemic in many countries. A total of 27 confirmed cases of measles were reported over the four-year period, most of which could be verified as being directly or indirectly linked with travel outside Canada. In addition, five confirmed cases of rubella and one case of imported congenital rubella syndrome were identified. A review of immunization coverage and surveillance data quality identified gaps. The combined annual rates of suspected measles and rubella cases (between 0.7 and 1.1 cases per 100,000 population) and suspected congenital rubella syndrome cases (0.21 to 0.49 cases per 10,000 live births) were below PAHO's thresholds. Also, the frequent absence of immunization and travel histories within iPHIS was of concern (77.3% and 44.6% respectively). CONCLUSION: These results support Ontario's sustained elimination status. However, in order to satisfactorily meet PAHO's requirements for documenting the elimination of these diseases, continued vigilance is required. Efforts are currently under way within Ontario to improve reporting.

Poor seroprotection but allosensitization after adjuvanted pandemic influenza H1N1 vaccine in kidney transplant recipients.

BACKGROUND: Seasonal and pandemic influenza virus infections in renal transplant patients are associated with poor outcomes. During the pandemic of 2009-2010, the AS03-adjuvanted monovalent H1N1 influenza vaccine was recommended for transplant recipients, although its immunogenicity in this population was unknown. We sought to determine the safety and immunogenicity of an adjuvant-containing vaccine against pandemic influenza A H1N1 2009 (pH1N1) administered to kidney transplant recipients. METHODS: We prospectively enrolled 124 adult kidney transplant recipients in the fall of 2009 at two transplant centers. Cohort 1 (n = 42) was assessed before and after pH1N1 immunization, while Cohort 2 (n = 82) was only assessed post immunization. Humoral response was measured by the hemagglutination inhibition assay. Vaccine safety was assessed by adverse event reporting, graft function, and human leukocyte antigen (HLA) alloantibody measurements. RESULTS: Cohort 1 had a low rate of baseline seroprotection to pH1N1 (7%) and a low rate of seroprotection after immunization (31%). No patient <6 months post transplant (n = 5) achieved seroprotection. Seroprotection rate was greater in patients receiving double as compared with triple immunosuppression (80% vs. 24%, P = 0.01). In Cohort 2, post-immunization seroprotection was 35%. In both cohorts, no confirmed cases of pH1N1 infection occurred. No difference was seen in estimated glomerular filtration rate before (54.3 mL/min/1.73 m(2) ) and after (53.8 mL/min/1.73 m(2) ) immunization, and no acute rejections had occurred after immunization at last follow-up. In Cohort 1, 11.9% of patients developed new anti-HLA antibodies. CONCLUSION: An adjuvant-containing vaccine to pH1N1 provided poor seroprotection in renal transplant recipients. Receiving triple immunosuppression was associated with a poor seroresponse. Vaccination appeared safe, but some patients developed new anti-HLA antibodies post vaccination. Alternative strategies to improve vaccine responses are necessary.

Diagnostic strategy used to establish etiologies of encephalitis in a prospective cohort of patients in England.

The laboratory diagnostic strategy used to determine the etiology of encephalitis in 203 patients is reported. An etiological diagnosis was made by first-line laboratory testing for 111 (55%) patients. Subsequent testing, based on individual case reviews, resulted in 17 (8%) further diagnoses, of which 12 (71%) were immune-mediated and 5 (29%) were due to infection. Seventy-five cases were of unknown etiology. Sixteen (8%) of 203 samples were found to be associated with either N-methyl-d-aspartate receptor or voltage-gated potassium channel complex antibodies. The most common viral causes identified were herpes simplex virus (HSV) (19%) and varicella-zoster virus (5%), while the most important bacterial cause was Mycobacterium tuberculosis (5%). The diagnostic value of testing cerebrospinal fluid (CSF) for antibody was assessed using 139 samples from 99 patients, and antibody was detected in 46 samples from 37 patients. Samples collected at 14 to 28 days were more likely to be positive than samples taken 0 to 6 days postadmission. Three PCR-negative HSV cases were diagnosed by the presence of virus-specific antibody in the central nervous system (CNS). It was not possible to make an etiological diagnosis for one-third of the cases; these were therefore considered to be due to unknown causes. Delayed sampling did not contribute to these cases. Twenty percent of the patients with infections with an unknown etiology showed evidence of localized immune activation within the CNS, but no novel viral DNA or RNA sequences were found. We conclude that a good standard of clinical investigation and thorough first-line laboratory testing allows the diagnosis of most cases of infectious encephalitis; testing for CSF antibodies allows further cases to be diagnosed. It is important that testing for immune-mediated causes also be included in a diagnostic algorithm.

Screening for Corynebacterium diphtheriae and Corynebacterium ulcerans in patients with upper respiratory tract infections 2007-2008: a multicentre European study.

Diphtheria is now rare in most European countries but, when cases do arise, the case fatality rate is high (5-10%). Because few countries continue to routinely screen for the causative organisms of diphtheria, the extent to which they are circulating amongst different European populations is largely unknown. During 2007-2008, ten European countries each screened between 968 and 8551 throat swabs from patients with upper respiratory tract infections. Six toxigenic strains of Corynebacterium diphtheriae were identified: two from symptomatic patients in Latvia (the country with the highest reported incidence of diphtheria in the European Union) and four from Lithuania (two cases, two carriers); the last reported case of diphtheria in Lithuania was in 2002. Carriage rates of non-toxigenic organisms ranged from 0 (Bulgaria, Finland, Greece, Ireland, Italy) to 4.0 per 1000 (95% CI 2.0-7.1) in Turkey. A total of 28 non-toxigenic strains were identified during the study (26 C. diphtheriae, one Corynebacterium ulcerans, one Corynebacterium pseudotuberculosis). The non-toxigenic C. ulcerans strain was isolated from the UK, the country with the highest reported incidence of cases due to C. ulcerans. Of the eleven ribotypes detected, Cluj was seen most frequently in the non-toxigenic isolates and, amongst toxigenic isolates, the major epidemic clone, Sankt-Petersburg, is still in circulation. Isolation of toxigenic C. diphtheriae and non-toxigenic C. diphtheriae and C. ulcerans in highly-vaccinated populations highlights the need to maintain microbiological surveillance, laboratory expertise and an awareness of these organisms amongst public health specialists, microbiologists and clinicians.

Challenge of the unknown. A systematic review of acute encephalitis in non-outbreak situations.

BACKGROUND: The threat of emerging infections and recognition of novel immune-mediated forms of encephalitis has raised the profile of this condition in recent years. Incidence is poorly defined and most cases have an unknown cause. There is currently much interest in identification of new microbial agents of encephalitis, but no work has investigated systematically reasons for lack of pathogen identification in studies. METHODS: We systematically reviewed published literature on incidence and etiology of encephalitis in non-outbreak settings and explored possible explanations for the large number of cases of unknown etiology. RESULTS: Annual incidence ranged from 0.07 to 12.6 cases per 100,000 population with an evident decrease over time (p = 0.01). The proportion of cases with unknown etiology was high across studies (>50% in 26 of 41 studies), with strong evidence of heterogeneity in study findings (p < 0.001). Our meta-regression identified study period, setting, and subsyndrome to be the main contributors to between-study variation, rather than methodologic factors such as study design, case definitions, sample types, and testing strategies. CONCLUSIONS: Our findings support the hypothesis that new and emerging infectious agents, or new forms of immune-mediated encephalitis, may be responsible for cases currently of unknown cause and encourage the ongoing global effort to identify these. Our review highlights research areas that might lead to a better understanding of the causes of encephalitis and ultimately reduce the morbidity and mortality associated with this devastating condition.

Diphtheria in the United Kingdom, 1986-2008: the increasing role of Corynebacterium ulcerans.

Diphtheria is an uncommon disease in the UK due to an effective immunization programme; consequently when cases do arise, there can be delays in diagnosis and case-fatality rates remain high. We reviewed 102 patients with infections caused by toxigenic corynebacteria (an average of four per year) reported in the UK between 1986 and 2008: 42 Corynebacterium diphtheriae, 59 C. ulcerans and one C. pseudotuberculosis, as well as 23 asymptomatic carriers. Five fatalities were reported, all in unvaccinated patients. The major risk factor for C. diphtheriae infection continued to be travel to an endemic country. C. ulcerans infections became more common than C. diphtheriae infections in the UK; they were associated with contact with companion animals. The occurrence of indigenous severe C. ulcerans infections and imported C. diphtheriae cases highlights the need to maintain UK routine vaccination coverage at the 95% level in the UK, as recommended by the World Health Organization.

Causality in acute encephalitis: defining aetiologies.

Defining the causal relationship between a microbe and encephalitis is complex. Over 100 different infectious agents may cause encephalitis, often as one of the rarer manifestations of infection. The gold-standard techniques to detect causative infectious agents in encephalitis in life depend on the study of brain biopsy material; however, in most cases this is not possible. We present the UK perspective on aetiological case definitions for acute encephalitis and extend them to include immune-mediated causes. Expert opinion was primarily used and was supplemented by literature-based methods. Wide usage of these definitions will facilitate comparison between studies and result in a better understanding of the causes of this devastating condition. They provide a framework for regular review and updating as the knowledge base increases both clinically and through improvements in diagnostic methods. The importance of new and emerging pathogens as causes of encephalitis can be assessed against the principles laid out here.