Should NICE reconsider the 2016 UK guidelines on TB contact tracing? A cost-effectiveness analysis of contact investigations in London.

BACKGROUND: In January 2016, clinical TB guidance in the UK changed to no longer recommend screening contacts of non-pulmonary, non-laryngeal (ETB) index cases. However, no new evidence was cited for this change, and there is evidence that screening these contacts may be worthwhile. The objective of this study was to estimate the cost-effectiveness of screening contacts of adult ETB cases and adult pulmonary or laryngeal TB (PTB) cases in London, UK. METHODS: We carried out a cross-sectional analysis of data collected on TB index cases and contacts in the London TB register and an economic evaluation using a static model describing contact tracing outcomes. Incremental cost-effectiveness ratios (ICERs) were calculated using no screening as the baseline comparator. All adult TB cases (≥15 years old) in London from 2012 to 2015, and their contacts, were eligible (2465/5084 PTB and 2559/6090 ETB index cases were included). RESULTS: Assuming each contact with PTB infects one person/month, the ICER of screening contacts of ETB cases was £78 000/quality-adjusted life-years (QALY) (95% CI 39 000 to 140 000), and screening contacts of PTB cases was £30 000/QALY (95% CI 18 000 to 50 000). The ICER of screening contacts of ETB cases was £30 000/QALY if each contact with PTB infects 3.4 people/month. Limitations of this study include the use of self-reported symptomatic periods and lack of knowledge about onward transmission from PTB contacts. CONCLUSIONS: Screening contacts of ETB cases in London was almost certainly not cost-effective at any conventional willingness-to-pay threshold in England, supporting recent changes to National Institute for Health and Care Excellence national guidelines.

Understanding Tuberculosis Transmission in the United Kingdom: Findings From 6 Years of Mycobacterial Interspersed Repetitive Unit-Variable Number Tandem Repeats Strain Typing, 2010-2015.

Genotyping provides the opportunity to better understand tuberculosis (TB) transmission. We utilized strain typing data to assess trends in the proportion of clustering and identify the characteristics of individuals and clusters associated with recent United Kingdom (UK) transmission. In this retrospective cohort analysis, we included all culture-confirmed strain-typed TB notifications from the UK between 2010 and 2015 to estimate the proportion of patients that clustered over time. We explored the characteristics of patients in a cluster using multivariable logistic regression. Overall, 58.5% of TB patients were concentrated in 2,701 clusters. The proportion of patients in a cluster decreased between 2010 (58.7%) and 2015 (55.3%) (P = 0.001). Being a clustered patient was associated with being male and UK-born, having pulmonary disease, having a previous TB diagnosis, and having a history of drug misuse or imprisonment. Our results suggest that TB transmission in the UK decreased between 2010 and 2015, during which time TB incidence also decreased. Targeted cluster investigation and extended contact tracing should be aimed at persons at risk of being in a transmission chain, including UK-born individuals with social risk factors in clusters with a high proportion of patients having pulmonary disease.

Transmission events revealed in tuberculosis contact investigations in London.

Contact tracing is a key part of tuberculosis prevention and care, aiming to hasten diagnosis and prevent transmission. The proportion of case-contact pairs for which recent transmission occurred and the typical timespans between the index case and their contact accessing care are not known; we aimed to calculate these. We analysed individual-level TB contact tracing data, collected in London from 20/01/2011-31/12/2015, linked to tuberculosis surveillance and MIRU-VNTR 24-locus strain-typing information. Of pairs of index cases and contacts diagnosed with active tuberculosis, 85/314 (27%) had strain typing data available for both. Of these pairs, 79% (67/85) shared indistinguishable isolates, implying probable recent transmission. Of pairs in which both contact and the index case had a social risk factor, 11/11 (100%) shared indistinguishable isolates, compared to 55/75 (75%) of pairs in which neither had a social risk factor (P = 0.06). The median time interval between the index case and their contact accessing care was 42 days (IQR: 16, 96). As over 20% of pairs did probably not involve recent transmission between index case and contact, the effectiveness of contact tracing is not necessarily limited to those circumstances where the index case has transmitted disease to their close contacts.

Large Outbreak of Neisseria meningitidis Serogroup C - Nigeria, December 2016-June 2017.

On February 16, 2017, the Ministry of Health in Zamfara State, in northwestern Nigeria, notified the Nigeria Centre for Disease Control (NCDC) of an increased number of suspected cerebrospinal meningitis (meningitis) cases reported from four local government areas (LGAs). Meningitis cases were subsequently also reported from Katsina, Kebbi, Niger, and Sokoto states, all of which share borders with Zamfara State, and from Yobe State in northeastern Nigeria. On April 3, 2017, NCDC activated an Emergency Operations Center (EOC) to coordinate rapid development and implementation of a national meningitis emergency outbreak response plan. After the outbreak was reported, surveillance activities for meningitis cases were enhanced, including retrospective searches for previously unreported cases, implementation of intensified new case finding, and strengthened laboratory confirmation. A total of 14,518 suspected meningitis cases were reported for the period December 13, 2016-June 15, 2017. Among 1,339 cases with laboratory testing, 433 (32%) were positive for bacterial pathogens, including 358 (82.7%) confirmed cases of Neisseria meningitidis serogroup C. In response, approximately 2.1 million persons aged 2-29 years were vaccinated with meningococcal serogroup C-containing vaccines in Katsina, Sokoto, Yobe, and Zamfara states during April-May 2017. The outbreak was declared over on June 15, 2017, after high-quality surveillance yielded no evidence of outbreak-linked cases for 2 consecutive weeks. Routine high-quality surveillance, including a strong laboratory system to test specimens from persons with suspected meningitis, is critical to rapidly detect and confirm future outbreaks and inform decisions regarding response vaccination.

Lack of Secondary Transmission of Ebola Virus from Healthcare Worker to 238 Contacts, United Kingdom, December 2014.

In December 2014, Ebola virus disease (EVD) was diagnosed in a healthcare worker in the United Kingdom after the worker returned from an Ebola treatment center in Sierra Leone. The worker flew on 2 flights during the early stages of disease. Follow-up of 238 contacts showed no evidence of secondary transmission of Ebola virus.

Recent household transmission of tuberculosis in England, 2010-2012: retrospective national cohort study combining epidemiological and molecular strain typing data.

BACKGROUND: We estimate the proportion of tuberculosis (TB) in England due to recent household transmission, identify factors associated with being a household transmitter, and investigate the impact that identification of a case has on time to treatment of subsequent cases. METHODS: TB cases notified between 2010 and 2012 in England in the same household as another case were identified; 24 locus MIRU-VNTR strain typing (ST) was used to identify household cases with likely recent transmission. Treatment delay in index and subsequent cases was compared. Risk factors for being a household transmitter were identified in univariable and multivariable analyses. RESULTS: Overall, 7.7% (1849/24,060) of TB cases lived in a household with another case. We estimate that 3.9% were due to recent household transmission. ST data was unavailable for 67% (1242) of household pairs. For those with ST data, 64% (386) had confirmed, 11% probable (66) and 25% (155) refuted household transmission. The median treatment delay was 65 days for index cases and 37 days for subsequent asymptomatic cases. Risk factors for being a household transmitter included being under 25 years old, UK-born with Black African, Indian or Pakistani ethnicity, or born in Somalia or Romania. CONCLUSIONS: This study has a number of implications for household TB contact tracing in low incidence countries, including the potential to reduce the diagnostic delay for subsequent household cases and the benefit of using ST to identify when to conduct source contact tracing outside the household. As 25% of TB cases in households had discordant strains, households with multiple TB cases do not necessarily represent household transmission. The additional fact that 25% of index cases within households only had extra-pulmonary TB demonstrates that, if household contact tracing is limited to pulmonary TB cases (as recently recommended in UK guidelines), additional cases of active TB in households will be missed. Our finding that no lineage of TB was associated with recent household transmission and with no increased transmissibility in the Beijing lineage compared to others, suggests that the lineage need not impact contact tracing efforts. Improvements in contact tracing have the potential to reduce transmission of TB in low incidence countries.

Optimising spatial accessibility to inform rationalisation of specialist health services.

BACKGROUND: In an era of budget constraints for healthcare services, strategies for provision of services that improve quality whilst saving costs are highly valued. A proposed means to achieve this is consolidation of services into fewer specialist centres, but this may lead to reduced spatial accessibility. We describe a methodology which includes implementing a combinatorial optimisation algorithm to derive combinations of services which optimise spatial accessibility in the context of service rationalisation, and demonstrate its use through the exemplar of tuberculosis clinics in London. METHODS: Our methodology involves (1) identifying the spatial distribution of the patient population using the service; (2) calculating patient travel times to each service location, and (3) using a combinatorial optimisation algorithm to identify subsets of locations that minimise overall travel time. We estimated travel times for tuberculosis patients notified in London between 2010 and 2013 to each of 29 clinics in the city. Travel time estimates were derived from the Transport for London Journey Planner service. We identified the subset of clinics that would provide the shortest overall travel time for each possible number of clinic subsets (1-28). RESULTS: Based on the 29 existing clinic locations, mean estimated travel time to clinics used by 12,061 tuberculosis patients in London was 33 min; and mean time to their nearest clinics was 28 min. Using optimum combinations of clinic locations, and assuming that patients attended their nearest clinics, a mean travel time of less than 45 min could be achieved with three clinics; of 34 min with ten clinics, and of less than 30 min with 18 clinics. CONCLUSIONS: We have developed a methodological approach to optimise spatial accessibility which can be used to inform rationalisation of health services. In urban conurbations, this may enable service reorganisation which increases quality and efficiency without substantially affecting spatial accessibility. This approach could be used to inform planning of service reorganisations, but may not be generalisable to rural areas or smaller urban centres.

An evaluation of tuberculosis contact investigations against national standards.

BACKGROUND: Contact tracing is a key element in England's 2015 collaborative TB strategy, although proposed indicators of successful contact tracing remain undescribed. METHODS: We conducted descriptive and multivariable analyses of contact tracing of TB cases in London between 1 July 2012 and 31 December 2015 using cohort review data from London's TB Register, identifying characteristics associated with improved indicators and yield. RESULTS: Of the pulmonary TB cases notified, 60% (2716/4561) had sufficient information for inclusion. Of these, 91% (2481/2716) had at least 1 contact (median: 4/case (IQR: 2-6)) identified, with 86% (10 251/11 981) of these contacts evaluated. 4.1% (177/4328), 1.3% (45/3421) and 0.70% (51/7264) of evaluated contacts of pulmonary smear-positive, pulmonary smear-negative and non-pulmonary cases, respectively, had active disease. Cases who were former prisoners or male were less likely to have at least one contact identified than those never imprisoned or female, respectively. Cases diagnosed at clinics with more directly observed therapy or social workers were more likely to have one or more contacts identified. Contacts screened at a different clinic to their index case or of male index cases were less likely to be evaluated than those screened at the same clinic or of women, respectively; yield of active disease was similar by sex. 10% (490/4850) of evaluated child contacts had latent TB infection. CONCLUSIONS: These are the first London-wide estimates of TB contact tracing indicators which are important for monitoring the strategy's success and informing risk assessment of index cases. Understanding why differences in indicators occur between groups could improve contact tracing outcomes.

Twenty years and counting: epidemiology of an outbreak of isoniazid-resistant tuberculosis in England and Wales, 1995 to 2014.

An outbreak of isoniazid-resistant tuberculosis first identified in London has now been ongoing for 20 years, making it the largest drug-resistant outbreak of tuberculosis documented to date worldwide. We identified culture-confirmed cases with indistinguishable molecular strain types and extracted demographic, clinical, microbiological and social risk factor data from surveillance systems. We summarised changes over time and used kernel-density estimation and k-function analysis to assess geographic clustering. From 1995 to 2014, 508 cases were reported, with a declining trend in recent years. Overall, 70% were male (n = 360), 60% born in the United Kingdom (n = 306), 39% white (n = 199), and 26% black Caribbean (n = 134). Median age increased from 25 years in the first 5 years to 42 in the last 5. Approximately two thirds of cases reported social risk factors: 45% drug use (n = 227), 37% prison link (n = 189), 25% homelessness (n = 125) and 13% alcohol dependence (n = 64). Treatment was completed at 12 months by 52% of cases (n = 206), and was significantly lower for those with social risk factors (p < 0.05), but increased over time for all patients (p < 0.05). The outbreak remained focused in north London throughout. Control of this outbreak requires continued efforts to prevent and treat further active cases through targeted screening and enhanced case management.

Multiple large clusters of tuberculosis in London: a cross-sectional analysis of molecular and spatial data.

Large outbreaks of tuberculosis (TB) represent a particular threat to disease control because they reflect multiple instances of active transmission. The extent to which long chains of transmission contribute to high TB incidence in London is unknown. We aimed to estimate the contribution of large clusters to the burden of TB in London and identify risk factors. We identified TB patients resident in London notified between 2010 and 2014, and used 24-locus mycobacterial interspersed repetitive units-variable number tandem repeat strain typing data to classify cases according to molecular cluster size. We used spatial scan statistics to test for spatial clustering and analysed risk factors through multinomial logistic regression. TB isolates from 7458 patients were included in the analysis. There were 20 large molecular clusters (with n>20 cases), comprising 795 (11%) of all cases; 18 (90%) large clusters exhibited significant spatial clustering. Cases in large clusters were more likely to be UK born (adjusted odds ratio 2.93, 95% CI 2.28-3.77), of black-Caribbean ethnicity (adjusted odds ratio 3.64, 95% CI 2.23-5.94) and have multiple social risk factors (adjusted odds ratio 3.75, 95% CI 1.96-7.16). Large clusters of cases contribute substantially to the burden of TB in London. Targeting interventions such as screening in deprived areas and social risk groups, including those of black ethnicities and born in the UK, should be a priority for reducing transmission.

Recent TB transmission, clustering and predictors of large clusters in London, 2010-2012: results from first 3†years of universal MIRU-VNTR strain typing.

BACKGROUND: The incidence of TB has doubled in the last 20 years in London. A better understanding of risk groups for recent transmission is required to effectively target interventions. We investigated the molecular epidemiological characteristics of TB cases to estimate the proportion of cases due to recent transmission, and identify predictors for belonging to a cluster. METHODS: The study population included all culture-positive TB cases in London residents, notified between January 2010 and December 2012, strain typed using 24-loci multiple interspersed repetitive units-variable number tandem repeats. Multivariable logistic regression analysis was performed to assess the risk factors for clustering using sociodemographic and clinical characteristics of cases and for cluster size based on the characteristics of the first two cases. RESULTS: There were 10 147 cases of which 5728 (57%) were culture confirmed and 4790 isolates (84%) were typed. 2194 (46%) were clustered in 570 clusters, and the estimated proportion attributable to recent transmission was 34%. Clustered cases were more likely to be UK born, have pulmonary TB, a previous diagnosis, a history of substance abuse or alcohol abuse and imprisonment, be of white, Indian, black-African or Caribbean ethnicity. The time between notification of the first two cases was more likely to be <90 days in large clusters. CONCLUSIONS: Up to a third of TB cases in London may be due to recent transmission. Resources should be directed to the timely investigation of clusters involving cases with risk factors, particularly those with a short period between the first two cases, to interrupt onward transmission of TB.

Outcomes analysis of new entrant screening for active tuberculosis in Heathrow and Gatwick airports, United Kingdom 2009/2010.

BACKGROUND: In 2012, the United Kingdom (UK) Government announced that the new entrant screening for active tuberculosis (TB) in Heathrow and Gatwick airports would end. Our study objective was to estimate screening yield and diagnostic accuracy, and identify those at risk of active TB after entry. METHODS: We designed a retrospective cohort study and linked new entrants screened from June 2009 to September 2010 through probabilistic matching with UK Enhanced TB Surveillance (ETS) data (June 2009 to December 2010). Yield was the proportion of cases reported to ETS within three months of airport screening in the screened population. To estimate screening diagnostic accuracy we assessed sensitivity, specificity, positive and negative predictive values. Through Poisson regression we identified groups at increased risk of TB diagnosis after entry. RESULTS: We identified 200,199 screened entrants, of these 59 had suspected TB at screening and were reported within 3 months to ETS (yield = 0.03 %). Sensitivity was 26 %; specificity was 99.7 %; positive predictive value was 13.2 %; negative predictive value was 99.9 %. Overall, 350 entrants were reported in ETS. Persons from countries with annual TB incidence higher than 150 cases per 100,000 population and refugees and asylum seekers were at increased risk of TB diagnosis after entry (population attributable risk 77 and 3 % respectively). CONCLUSION: Airport screening has very low screening yields, sensitivity and positive predictive value. New entrants coming from countries with annual TB incidence higher than 150 per 100,000 population, refugees and asylum seekers should be prioritised at pre- or post-entry screening.

Olympics and Paralympics 2012 mass gathering in London: time-series analysis shows no increase in attendances at sexual health clinics.

OBJECTIVE: To determine whether the 2012 Olympic and Paralympic Games were associated with a change in the number of patients attending or diagnosed with a new sexually transmitted infection (STI) at sexual health clinics in London and Weymouth. METHODS: We undertook an interrupted time-series analysis of surveillance data from the Genitourinary Medicine Clinic Activity Dataset (GUMCAD) collected at 33 genitourinary medicine (GUM) clinics in London and Weymouth (where Games events were concentrated) between 2009 and 2012. Mixed-effects linear regression models of weekly attendance and diagnoses, incorporating temporal trends, bank holidays, categorical month and clinic closures, were used to test for the effect of the 'Olympic-Paralympic' period. We subdivided the 9-week 'Olympic-Paralympic' period (16 July 2012 to 17 September 2012) into five periods, including three Olympic weeks, two Paralympic weeks, pre-, post- and inter-Games weeks. We also compared characteristics of patients attending during the Olympic-Paralympic period and those attending during the same period in 2011. RESULTS: During the 3 weeks of the Olympics, there was a significant reduction in the number of new episode attendances (2020 fewer, 5.6% reduction (95% CI -8.2 to -2.9)) and the number of patients diagnosed with an STI (267 fewer, 4.8% reduction (95% CI -8.6 to -0.9)) compared to expected. There were no important differences in the profile of patients attending during the 2012 Olympic-Paralympic period and those attending during the same period in 2011. CONCLUSIONS: We conclude that a 'business-as-usual' approach to managing local sexual health clinics during the 2012 Olympic and Paralympics would have been appropriate.

Prospective evaluation of a complex public health intervention: lessons from an initial and follow-up cross-sectional survey of the tuberculosis strain typing service in England.

BACKGROUND: The national tuberculosis strain typing service (TB-STS) was introduced in England in 2010. The TB-STS involves MIRU-VNTR typing of isolates from all TB patients for the prospective identification, reporting and investigation of TB strain typing clusters. As part of a mixed-method evaluation, we report on a repeated cross-sectional survey to illustrate the challenges surrounding the evaluation of a complex national public health intervention. METHODS: An online initial and follow-up questionnaire survey assessed the knowledge, attitudes and practices of public health staff, physicians and nurses working in TB control in November 2010 and March 2012. It included questions on the implementation, experience and uptake of the TB-STS. Participants that responded to both surveys were included in the analysis. RESULTS: 248 participants responded to the initial survey and 137 of these responded to the follow-up survey (56% retention). Knowledge: A significant increase in knowledge was observed, including a rise in the proportion of respondents who had received training (28.6% to 67.9%, p = 0.003), and the self-rated knowledge of how to use strain typing had improved ('no knowledge' decreased from 43.2% to 27.4%). Attitudes: The majority of respondents found strain typing useful; the proportion that reported strain typing to be useful was similar across the two surveys (95.7% to 94.7%, p = 0.67). Practices: There were significant increases between the initial and follow-up surveys in the number of respondents who reported using strain typing (57.0% to 80.5%, p < 0.001) and the proportion of time health protection staff spent on investigating TB (2.74% to 7.08%, p = 0.04). CONCLUSIONS: Evaluation of a complex public health intervention is challenging. In this example, the immediate national roll-out of the TB-STS meant that a controlled survey design was not possible. This study informs the future development of the TB-STS by identifying the need for training to reach wider professional groups, and argues for its continuation based on service users' perception that it is useful. By highlighting the importance of a well-defined sampling frame, collecting baseline information, and including all stakeholders, it provides lessons for the implementation of similar services in other countries and future evaluations of public health interventions.

Evaluation of the measles, mumps and rubella vaccination catch-up campaign in England in 2013.

In January-March 2013 in England, confirmed measles cases increased in children aged 10-16 years. In April-September 2013, the National Health System and Public Health England launched a national measles-mumps-rubella (MMR) campaign based on data from Child Health Information Systems (CHIS) estimating that approximately 8% in this age group were unvaccinated. We estimated coverage at baseline, and, of those unvaccinated (target), the proportion vaccinated up to 20/08/2013 (mid-point) to inform further public health action. We selected a sample of 6644 children aged 10-16 years using multistage sampling from those reported unvaccinated in CHIS at baseline and validated their records against GP records. We adjusted the CHIS MMR vaccine coverage estimates correcting by the proportion of vaccinated children obtained through sample validation. We validated 5179/6644 (78%) of the sample records. Coverage at baseline was estimated as 94.7% (95% confidence intervals, CI: 93.5-96.0%), lower in London (86.9%, 95%CI: 83.0-90.9%) than outside (96.1%, 95%CI 95.5-96.8%). The campaign reached 10.8% (95%CI: 7.0-14.6%) of the target population, lower in London (7.1%, 95%CI: 4.9-9.3) than in the rest of England (11.4%, 95%CI: 7.0-15.9%). Coverage increased by 0.5% up to 95.3% (95% CI: 94.1-96.4%) but an estimated 210,000 10-16 year old children remained unvaccinated nationally. Baseline MMR coverage was higher than previously reported and was estimated to have reached the 95% campaign objective at midpoint. Eleven per cent of the target population were vaccinated during the campaign, and may be underestimated, especially in London. No further national campaigns are needed but targeted local vaccination activities should be considered.

Factors associated with travel to non-local genitourinary medicine clinics for gonorrhoea: an analysis of patients diagnosed in London, 2009-10.

We analysed factors associated with travelling to non-local genitourinary medicine clinics for gonorrhoea care in London. We used surveillance data on London residents attending genitourinary medicine clinics in 2009-10 and calculated distances between patients' areas of residence and both the nearest genitourinary medicine clinic and the clinic attended. Non-local clinics were attended by 5408 (46.7%) patients. Men having sex with men attended non-local services more than heterosexuals (OR 3.83, p < 0.001). Among heterosexual men, black Africans and black Caribbeans were more likely, and South Asians less likely, to attend non-local services compared to whites (OR [95%CI] 1.33 [1.04-1.72], 1.36 [1.11-1.67] and 0.46 [0.31-0.70] respectively). Similar associations, although not statistically significant, were found in women. People were more likely to attend local services if their local clinic provided walk-in and young people's services, weekend consultations and long opening hours. These findings could help design services meeting local population needs and facilitate prompt and equitable access to care.

Identifying men at ultra high risk of psychosis in a prison population.

BACKGROUND: The prevalence of psychotic disorders among prisoners is relatively high. We sought to investigate the prevalence of men who have a very high risk of developing psychosis in a prison population. METHODS: The Prodromal Questionnaire - Brief Version (Loewy, Pearson, Vinogradov, Bearden and Cannon, 2011), was used to screen newly-arrived prisoners in a London prison for features associated with an increased risk of psychosis. Concurrent validity was evaluated using the Comprehensive Assessment for At Risk Mental State (Yung et al., 2005). RESULTS: 750 prisoners were screened and 301 were underwent further clinical assessment. 5% the total number of those screened met diagnostic criteria for the ARMS and 3% had recently developed a first episode of psychosis. Using endorsement of items that also caused distress, the PQ-B predicted an ARMS or a psychotic disorder with 90% sensitivity and 44% specificity. CONCLUSIONS: The PQ-B is effective in identifying people who are vulnerable to developing psychosis in a prison population.