Optimal symptom combinations to aid COVID-19 case identification: Analysis from a community-based, prospective, observational cohort.

OBJECTIVES: Diagnostic work-up following any COVID-19 associated symptom will lead to extensive testing, potentially overwhelming laboratory capacity whilst primarily yielding negative results. We aimed to identify optimal symptom combinations to capture most cases using fewer tests with implications for COVID-19 vaccine developers across different resource settings and public health. METHODS: UK and US users of the COVID-19 Symptom Study app who reported new-onset symptoms and an RT-PCR test within seven days of symptom onset were included. Sensitivity, specificity, and number of RT-PCR tests needed to identify one case (test per case [TPC]) were calculated for different symptom combinations. A multi-objective evolutionary algorithm was applied to generate combinations with optimal trade-offs between sensitivity and specificity. FINDINGS: UK and US cohorts included 122,305 (1,202 positives) and 3,162 (79 positive) individuals. Within three days of symptom onset, the COVID-19 specific symptom combination (cough, dyspnoea, fever, anosmia/ageusia) identified 69% of cases requiring 47 TPC. The combination with highest sensitivity (fatigue, anosmia/ageusia, cough, diarrhoea, headache, sore throat) identified 96% cases requiring 96 TPC. INTERPRETATION: We confirmed the significance of COVID-19 specific symptoms for triggering RT-PCR and identified additional symptom combinations with optimal trade-offs between sensitivity and specificity that maximize case capture given different resource settings.

Optimal symptom combinations to aid COVID-19 case identification: analysis from a community-based, prospective, observational cohort.

OBJECTIVES: Diagnostic work-up following any COVID-19 associated symptom will lead to extensive testing, potentially overwhelming laboratory capacity whilst primarily yielding negative results. We aimed to identify optimal symptom combinations to capture most cases using fewer tests with implications for COVID-19 vaccine developers across different resource settings and public health. METHODS: UK and US users of the COVID-19 Symptom Study app who reported new-onset symptoms and an RT-PCR test within seven days of symptom onset were included. Sensitivity, specificity, and number of RT-PCR tests needed to identify one case (test per case [TPC]) were calculated for different symptom combinations. A multi-objective evolutionary algorithm was applied to generate combinations with optimal trade-offs between sensitivity and specificity. FINDINGS: UK and US cohorts included 122,305 (1,202 positives) and 3,162 (79 positive) individuals. Within three days of symptom onset, the COVID-19 specific symptom combination (cough, dyspnoea, fever, anosmia/ageusia) identified 69% of cases requiring 47 TPC. The combination with highest sensitivity (fatigue, anosmia/ageusia, cough, diarrhoea, headache, sore throat) identified 96% cases requiring 96 TPC. INTERPRETATION: We confirmed the significance of COVID-19 specific symptoms for triggering RT-PCR and identified additional symptom combinations with optimal trade-offs between sensitivity and specificity that maximize case capture given different resource settings.

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.

Adult encephalitis surveillance: experiences from an Australian prospective sentinel site study.

Few countries routinely collect comprehensive encephalitis data, yet understanding the epidemiology of this condition has value for clinical management, detecting novel and emerging pathogens, and guiding timely public health interventions. When this study was conducted there was no standardized diagnostic algorithm to aid identification of encephalitis or systematic surveillance for adult encephalitis. In July 2012 we tested three pragmatic surveillance options aimed at identifying possible adult encephalitis cases admitted to a major Australian hospital: hospital admissions searches, clinician notifications and laboratory test alerts (CSF herpes simplex virus requests). Eligible cases underwent structured laboratory investigation and a specialist panel arbitrated on the final diagnosis. One hundred and thirteen patients were initially recruited into the 10-month study; 20/113 (18%) met the study case definition, seven were diagnosed with infectious or immune-mediated encephalitis and the remainder were assigned alternative diagnoses. The laboratory alert identified 90% (102/113) of recruited cases including six of the seven cases of confirmed encephalitis suggesting that this may be a practical data source for case ascertainment. The application of a standardized diagnostic algorithm and specialist review by an expert clinical panel aided diagnosis of patients with encephalitis.

Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium.

BACKGROUND: Encephalitis continues to result in substantial morbidity and mortality worldwide. Advances in diagnosis and management have been limited, in part, by a lack of consensus on case definitions, standardized diagnostic approaches, and priorities for research. METHODS: In March 2012, the International Encephalitis Consortium, a committee begun in 2010 with members worldwide, held a meeting in Atlanta to discuss recent advances in encephalitis and to set priorities for future study. RESULTS: We present a consensus document that proposes a standardized case definition and diagnostic guidelines for evaluation of adults and children with suspected encephalitis. In addition, areas of research priority, including host genetics and selected emerging infections, are discussed. CONCLUSIONS: We anticipate that this document, representing a synthesis of our discussions and supported by literature, will serve as a practical aid to clinicians evaluating patients with suspected encephalitis and will identify key areas and approaches to advance our knowledge of encephalitis.

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.

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.

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.

Hepatitis A surveillance in England--how many cases are not reported and does it really matter?

Underreporting of hepatitis A infection in England may be high and a number of outbreaks have occurred undetected by routine surveillance. We evaluated surveillance of hepatitis A cases by employing capture-recapture analysis on data from two distinct outbreaks of hepatitis A. The overall reporting of cases of hepatitis A was 81.7% (95% CI 55.3-95) in the first outbreak in North East England and reporting through Lab Base was 65.7% (95% CI 42.8-76.4). In the second outbreak in the East Midlands the overall reporting of hepatitis A cases was 27.8% (95% CI 19-38.7) and through Lab Base 16.6% (95% CI 11.4-23.1). Underreporting of hepatitis A cases is high. Public health interventions exist to prevent and control outbreaks of hepatitis A. The lack of reliable data on incidence and prevalence hampers effective public health management of this disease.

Investigating the aetiology of and evaluating the impact of the Men C vaccination programme on probable meningococcal disease in England and Wales.

The aims were to (1) investigate the aetiology of probable meningococcal disease, where a clinical diagnosis is made in the absence of laboratory data, and (2) evaluate the impact of the Men C vaccination programme in England and Wales. Multiple linear regression analyses were carried out using data reported to Enhanced Surveillance of Meningococcal Disease (ESMD) and laboratory reports of isolates of organisms causing symptoms that mimic meningococcal disease. Confirmed meningococcal disease appeared to be a significant predictor of probable disease. Thus, an additional reduction in meningococcal disease attributable to the serogroup C vaccination campaign was evident in probable disease over and above that observed in confirmed cases alone. Enteroviruses were a significant contributor to cases of probable meningitis and influenza appeared to be a significant contributor to probable cases of septicaemia. This analysis confirms the success seen following the Men C vaccination campaign and gives an indication of the aetiologies of other causes of probable meningitis and septicaemia reported to ESMD.

Vaccine coverage in England: the impact of health service reorganisation.

AIM: To evaluate the impact of reorganisation of the health service and a change in the definition used to collect immunisation coverage statistics on vaccine coverage data in England. METHODS: Denominator data from the Cover Of Vaccination Evaluated Rapidly (COVER) programme, the national programme for the collection of immunisation coverage statistics, were compared to the Office for National Statistics (ONS) population data; the impact of any discrepancies between the two data sources on vaccine coverage was assessed. RESULTS: ONS populations were generally larger than COVER populations. This was particularly true for 2002, the year Primary Care Trusts (PCTs) came into existence, suggesting that some children are being missed by the COVER programme. On average, in 1998-2001 around 10,000 children per year (approximately 2%) were lost to the COVER population estimates compared to data from ONS. This increased to around 20,000-40,000 (approximately 3-8%) children in 2002, but decreased again in 2003 to 2000-8000 (approximately 1%) children. Assuming all the "lost" COVER children were vaccinated, vaccine coverage appeared very similar to that seen in the COVER programme for all antigens. However, assuming all the "lost" children were unvaccinated, coverage would be substantially lower for all antigens (range 2.7-3.5%). DISCUSSION: This analysis provides a quantitative example of how changes such as restructuring of the health service directly impact on public health surveillance. Such changes have potential risks for information and may affect important data used to inform public health policy.

Clusters of meningococcal disease in educational establishments in the United Kingdom: April 2001 to March 2002.

Clusters of meningococcal disease in school and pre-school settings generate high levels of public anxiety. Thus, cluster detection and reporting is crucial to trigger prompt public health measures, and detailed study is essential to shape future public health policy. In 2001/02, most clusters were of group B meningococcal disease and most occurred in pre-school or secondary school settings. No clusters of group C meningococcal disease occurred in this time period.

Changing epidemiology of hepatitis A: should we be doing more to vaccinate injecting drug users?

Since 2001 there have been significant outbreaks of hepatitis A virus (HAV) across South Yorkshire, largely in intravenous drug users, and HAV infection has been reported to be an increasing problem in England and Scotland during this time. This paper reports a brief investigation to clarify current HAV epidemiology in England and Wales. The epidemiology of HAV in England, but not yet Wales, has recently changed. Laboratory reports now show that most cases are occurring in young adults, mainly young men, and that the commonest reported risk group is injecting drug users. That cases may now be concentrated in injecting drug users is supported by reports from consultants in communicable disease control (CsCDC). These detail fourteen outbreaks in England in 2002 alone, all involving injecting drug users. Links to prisons and to the homeless, usually those in hostels, were also common. A combined Hepatitis A/B vaccine is readily available and we recommend that this now be used to extend the national immunisation programme against Hepatitis B in injecting drug users to include HAV.