Tuberculosis in the UK. Annual report on tuberculosis surveillance in the UK 2008

Transcription

1 Tuberculosis in the UK Annual report on tuberculosis surveillance in the UK 2008

2 Acknowledgements This report was prepared by the Tuberculosis Section, Health Protection Agency Centre for Infections. This was only possible with the collaboration of the Communicable Disease Surveillance Centre (Northern Ireland), Health Protection Scotland and the National Public Health Service for Wales, along with other Centre for Infections departments, and the Agency s Local and Regional Services, Regional Microbiology Network and Centre for Emergency Preparedness and Response. Special thanks to Professor Pete Borriello who, as lead of the HPA TB Programme until September 2008, has steered the development of this and previous annual reports. We gratefully acknowledge all those who contribute information on tuberculosis cases in the UK, including physicians, nurses, microbiologists, scientists and administrative staff. Authors and contributors Main authors Charlotte Anderson, Jonathan Moore, Dr Michelle Kruijshaar, Dr Ibrahim Abubakar. Contributors to Chapter 1 Jonathan Crofts, Fiona Johnston. Contributors to Chapter 2 Prof Francis Drobniewski, Prof Phil Marsh, Dr John Magee, Jason Evans, Dr Grace Smith, Paul Howatson, Dr Ruth Gelletlie, Dr Cath Arnold, Dr Jon Green, Dr Emilia Vynnycky. Other contributors Prof John Watson, Dr Jim McMenamin, Louise Bradshaw, Prof Pete Borriello, David Quinn. Suggested citation Tuberculosis in the UK: Annual report on tuberculosis surveillance in the UK London: Health Protection Agency Centre for Infections, October

3 Contents Foreword Executive summary Introduction Chapter 1 Chapter 2 Tuberculosis cases, drug resistance and treatment outcome reported in Overall numbers of cases and rates Demographic characteristics Clinical characteristics Drug resistance Treatment outcome of UK tuberculosis cases reported in Research and development: published output of the Health Protection Agency from Centre for Emergency Preparedness and Response Centre for Infections Local and Regional Services and Regional Microbiology Network Chapter 3 What do the findings mean? What next? References Appendices Appendix A: Additional data tables and figures Appendix B: Data sources - tuberculosis surveillance systems Appendix C: Methods Appendix D: Definitions used in this report Appendix E: Contributors Other sources of information 45 3

4 Foreword The World Health Organization (WHO) reports that the overall incidence rate of tuberculosis across the world has begun to reduce slightly in recent years. The number of cases of tuberculosis, however, and the number of deaths, remains very high and a number of the other WHO targets for global tuberculosis control are not being achieved. The interaction of tuberculosis with HIV infection in some parts of the world, and the emergent problem of multi-drug resistant (MDR) and extensively drug resistant (XDR) disease in countries with a high incidence of tuberculosis, present continuing challenges to global control. To a large extent, the occurrence of tuberculosis in the United Kingdom (UK) reflects the global tuberculosis situation due to the diversity of population subgroups within the UK, particularly in urban areas. This report describes the distribution of this disease in the population resident in the UK and the trends in subgroups of the population. The report highlights not only the issue of high rates of disease in people originating from countries with a high burden of tuberculosis, but also the continuing problems of drug resistance and the challenge of achieving high rates of treatment completion in some subgroups of the population. In addition to providing an update on current trends in tuberculosis in the UK, including appendices with more detailed data, this report highlights the research and development work carried out by the Health Protection Agency, in collaboration with a wide range of partners, since the inception of the HPA in The bibliography of peer-reviewed publications provides a useful starting point for steering the future research that the HPA needs to carry out if it is to continue to contribute effectively to the development of more effective control of this major public health problem in the UK and elsewhere. PROFESSOR JOHN M WATSON MANAGER, HPA TUBERCULOSIS PROGRAMME DEPUTY DIRECTOR, RESPIRATORY AND SYSTEMIC INFECTIONS DEPARTMENT CENTRE FOR INFECTIONS PROFESSOR MIKE CATCHPOLE LEAD, HPA TUBERCULOSIS PROGRAMME INTERIM DIRECTOR, CENTRE FOR INFECTIONS 4

5 Executive summary A total of 8417 cases of tuberculosis were reported in the UK in 2007, a rate of 13.8 per 100,000 population. Overall, a small decrease was seen compared to 2006, and tuberculosis case numbers and rates appear to be stabilising. The main burden of disease remains concentrated in certain urban areas, with 39% of all cases in London, giving this region a rate of 43.2 per 100,000. The majority of cases occurred in young adults and among those born outside of the UK. Over half of all non-uk born cases were diagnosed with tuberculosis five or more years after entering the UK. Rates of tuberculosis among the UK born population remain low but have not reduced. This may reflect the changing epidemiology of tuberculosis in this population, with more cases occurring in high risk groups, such as the homeless and problem drug users. There was also variation within the UK born population, with black African and south Asian ethnic groups remaining at increased risk compared to those of white ethnicity. The proportion of cases with extra-pulmonary tuberculosis continues to increase with nearly half of all cases now presenting with disease exclusively affecting an extrapulmonary site. Overall levels of drug resistance in the UK have been stable in recent years, and within the level suggested in the Chief Medical Officer s Action Plan 1 : 7.4% were resistant to at least one first line drug, 6.8% were isoniazid resistant and 1.2% multi-drug resistant, although levels in some regions were higher. Drug resistance was more common among younger cases, those with a previous history of tuberculosis, and those born outside the UK. In some regions, however, isoniazid resistance was more common among UK born cases. In London, this is likely to be related to an ongoing outbreak of isoniazid resistant tuberculosis among hard to reach UK born populations 2. being on treatment were the most common reasons for not completing treatment. The reasons for not achieving 85% treatment completion as recommended by the CMO 1 are likely to include high levels of mortality from causes other than tuberculosis among elderly cases, and cases undergoing planned courses of treatment which exceed 12 months 3;4. The higher proportion of cases known to be drug resistant at start of treatment subsequently being lost to follow up is, however, of particular concern. While the apparent stabilisation of tuberculosis incidence in the UK is encouraging, rates remain at their highest since the late 1980s, and efforts to control and accelerate the downward trend should be continued. The research and development activity of the Agency, as exemplified in its published output, is summarised in this report and is accompanied by an electronic listing ( of the peer-reviewed publications of the Agency since The common thread in this research and development activity is the strengthening of the prevention and control of the disease through better diagnosis, surveillance, outbreak management and vaccine development. The completeness of treatment outcome reporting was the highest yet achieved, at 93%, although still short of the 95% level suggested in the Department of Health toolkit for planning, commissioning and delivering high-quality tuberculosis services in England. The proportion of cases completing treatment within 12 months has remained at around 79% since surveillance began in Death and still 5

6 Key points Scale of the problem 8417 cases of tuberculosis were reported in the UK in 2007, a rate of 13.8 per 100,000 population: numbers and rates have remained stable since % of cases were reported in England, with London accounting for the largest proportion (39% of UK cases) and the highest regional rate (43.2 per 100,000 population). 72% of cases were born outside the UK, predominantly from South Asia and sub-saharan Africa. The highest rates of tuberculosis were seen among non-uk born black African and Indian/Pakistani/ Bangladeshi ethnic groups. Nearly half (44%) of cases had extra-pulmonary disease only. Drug resistance 7.4% of cases in the UK were resistant to at least one first line drug, 6.8% were isoniazid resistant and 1.2% multi-drug resistant: similar to levels seen in recent years. Drug resistance was more common among cases born outside the UK, those with a previous history of tuberculosis, and cases aged less than 45 years. Isoniazid resistance was higher among UK born than non-uk born cases in London, the East of England, and Yorkshire and the Humber. Treatment outcomes Treatment outcomes were provided for 93% of cases reported in 2006, an increase compared to previous years. The proportion completing treatment was 79%, the same as in the previous year. Treatment completion was lower among males, older cases, the UK born and those with pulmonary disease. As in previous years, the most common reasons for not completing treatment were death (6%) and still being on treatment (6%). 6

7 Introduction Tuberculosis has affected mankind for many centuries, but it is only in recent decades that it has grown to be such a threat to global public health. In this year, when the theme of the World TB Day is I am stopping TB, and the WHO global tuberculosis report 5 suggests that the global epidemic may be on the threshold of decline, multi and extensively drug resistant forms of the disease are an increasingly important element of the global threat of tuberculosis. The Health Protection Agency (HPA) in England and its partner health protection bodies in Scotland, Wales and Northern Ireland, continue to contribute to the global effort to control tuberculosis both by their work within the UK and their involvement in international efforts to combat the disease. The re-emergence of tuberculosis as a public health problem in the UK over the last two decades has been marked by a significant change in its epidemiology. In contrast to its occurrence in the general population in the first half of the last century, tuberculosis now largely affects population subgroups such as ethnic minorities, non-uk born individuals, the homeless and problem drug users 6;7. The highest burden is concentrated in cities and largely affects deprived communities 8;9. The national effort to control and eventually eliminate tuberculosis in the UK was strengthened by the publication of an Action Plan, Stopping Tuberculosis in England, by the Chief Medical Officer (CMO) in The Action Plan outlines measures which, if appropriately implemented, should lead to a decline in the incidence of tuberculosis in the UK. The HPA has restated, in the draft Strategic Plan 2008 to 2013, that it will support the NHS and CMO s Action Plan to achieve: At least 70% of patients with pulmonary tuberculosis have the diagnosis confirmed by laboratory culture of the organism. All patients diagnosed with tuberculosis have the outcome of their treatment recorded, and at least 85% successfully complete their treatment. Tuberculosis in the UK aims to provide an updated description of the epidemiology of tuberculosis in the UK and allow an assessment of whether these objectives are being met. This report presents data on the incidence and clinical characteristics of cases reported in 2007 and treatment outcomes for cases reported in Data on drug resistance are provided to assess the burden of first line, and multi-drug, resistance in the UK. The methods for the collection and analysis of surveillance data, as well as further tables providing additional data, are given in the appendices. Research and development form a major part of the contribution of the HPA to improving local, national and international tuberculosis control. Alongside this report, a comprehensive listing of all published research and development output since the inception of the Agency in 2003 is provided on the HPA website. This bibliography illustrates not only the breadth and depth of HPA research in the field of tuberculosis and the wide range of our collaborations, but also provides a resource which will be used by the HPA Tuberculosis Programme Board, among others, when considering priorities for future research and development. A progressive decline (of at least two per cent per year) in rates of tuberculosis in population groups born in England. A reduction in the incidence of disease among people who entered the country and became resident here within the previous five years. No more than seven per cent of new cases resistant to the anti-tuberculosis drug isoniazid and two per cent multi-drug resistant. 7

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9 C H A P T E R O N E1 Tuberculosis cases, drug resistance and treatment outcome reported in

10 1 1.1 Overall numbers of cases and rates Tuberculosis cases, drug resistance and treatment outcome reported in 2007 A total of 8417 cases of tuberculosis were reported in the UK in 2007, a rate of 13.8 cases per 100,000 population. This represents a decrease of 0.9% on the number of cases reported in 2006 (Table 1). Figures for England are presented in Appendix A i. Table 1: Tuberculosis case reports, rates and annual percentage change, UK, Year Number of cases Rate (per 100,000) Annual change in case numbers (%) England accounted for 92% (7742/8417) of cases in 2007; Scotland, Wales and Northern Ireland made up 5% (408), 2% (202) and 1% (65) respectively. Case numbers in England have shown annual increases of 2% or more from 2000 to 2005 but have since remained stable (Figure 1). Scotland, Wales and Northern Ireland have seen little annual change in case numbers. Regional trends within England can be found in Appendix A ii. 10

11 Figure 1: Tuberculosis case reports by country, UK, Number of cases England Northern Ireland Scotland Wales Country As in previous years, London accounted for the highest proportion of cases in the UK in 2007 (39%, 3265/8417) and had the highest rate (43.2 per 100,000 population) (Figure 2). The rates in all other regions and countries of the UK were below 18 per 100,000 population. Regional level data may, however, mask variations between sub-regional geographic areas (Appendix A iii). Figure 2: Tuberculosis case reports and rates by country/region, UK, 2007 Number of cases England Northern Ireland Scotland Wales East Midlands East of England 43.2 London 7.7 North East Country/Region Number of cases Rate (per 100,000) 10.8 North West 8.6 South East 5.4 South West 17.2 West Midlands 13.0 Yorkshire and the HUmber Rate (per 100,000) 11

12 1T UBERCULOSIS IN THE UK Age and Sex 1.2 Demographic characteristics More than half of reported UK cases were male (55%, 4636/8396). The largest proportion were aged between 15 and 44 years (60%, 5083/8417); those aged under 5, 5 to 14, 45 to 64, and 65 years and over accounted for 2%, 4%, 19% and 14% of cases respectively. The age and sex distribution of cases in 2007 was similar to that seen in In England, the rate of tuberculosis among children aged under five, an indicator of recent transmission, has remained stable at around 4 per 100,000 since 2000 (Appendix A iv). Place of birth Figure 3: Non-UK born tuberculosis cases by world region of birth, UK, 2007 East Mediterranean (1.3%) Central Europe (2.0%) East Asia (2.1%) Latin America & Caribbean (2.2%) West Europe (2.3%) South East Asia (4.5%) Sub-Saharan Africa (32.9%) North Africa (1.1%) East Europe (0.8%) South Asia (50.4%) North America and Oceania (0.4%) The place of birth was known for 91% (7618/8417) of cases reported in Of these, 72% (5453/7618) were born outside the UK, a similar proportion to The rate of tuberculosis among the non-uk born population was 85 per 100,000 compared to 4 per 100,000 among the UK born. Within England, the rate of tuberculosis among the non-uk born decreased to 87 per 100,000 in 2007, following annual increases from 88 per 100,000 in 2002 to 102 per 100,000 in 2005 (Appendix A v). The rate among the UK born has remained stable at 4 per 100,000 since Among cases born outside the UK, 96% (5228/5453) had information on world region of birth. The majority originated from South Asia (50%) or sub-saharan Africa (33%) (Figure 3). Proportions of cases from all world regions were comparable to those in Ethnic group Among non-uk born cases, the Indian/Pakistani/ Bangladeshi ethnic group accounted for the highest proportion (48%, 2608/5390). The highest rates were again in the black African (309 per 100,000) and Indian/Pakistani/Bangladeshi (212 per 100,000) ethnic groups. Time since entry into the UK Time since entry into the UK to tuberculosis diagnosis was known for 86% (4698/5453) of non-uk born cases. Of these, 48% were diagnosed within five years of entering the UK (19% within two years). Twenty-three percent were diagnosed between five and nine years after entry, and 30% had been in the UK for ten or more years before diagnosis. The majority of cases born in the UK were of white ethnicity (66%, 1408/2148) (Figure 4). The rate in this group was 3 per 100,000. Higher rates were seen among UK born black African (46 per 100,000) and Indian/ Pakistani/Bangladeshi (37 per 100,000) ethnic groups. 12

13 Figure 4: Tuberculosis case reports and rates by place of birth and ethnic group, UK, 2007 Number of cases Number of cases Rate (per 100,000) Rate (per 100,000) 0 White Black Caribbean Black African Indian/Pakistani /Bangladeshi Chinese White Black Caribbean Black African Indian/Pakistani /Bangladeshi Chinese 0 UK Born Place of birth / Ethnic group* Non-UK Born * Other ethnic groups not shown 1.3 Clinical characteristics Previous history of tuberculosis Eight per cent of cases had a previous history of tuberculosis (509 of 6559 cases with information reported). Site of disease Where site of disease was known, over half (56%, 4631/8287) of tuberculosis cases reported in 2007 had pulmonary disease (with or without extra-pulmonary disease). This varied, however, with place of birth: 71% (1505/2132) of UK born cases had pulmonary tuberculosis compared to 49% (2643/5386) of non-uk born cases. In England, the proportion of cases with pulmonary disease decreased steadily from 60% in 2000 to 55% in 2007 (Appendix A vi). Bacteriological results The result of a sputum smear test was known for 3190 (69%) of the 4631 cases with pulmonary disease. Of those, 1761 (55%) had a positive smear. The proportion of all UK cases that were culture confirmed in 2007 was 60% (5075/8417), slightly lower than in 2006, and 70% among pulmonary cases (3233/4631). Species identification Tuberculosis disease is caused by the Mycobacterium tuberculosis complex, which includes M. tuberculosis, M. africanum and M. bovis. The species was identified in 5014 culture confirmed cases (98.8%): the majority of these were M. tuberculosis (4954, 98.8%), with 24 identified as M. bovis (0.5%) and 36 as M. africanum (0.7%). 1.4 Drug resistance Isoniazid, rifampicin, ethambutol and pyrazinamide are considered first line drugs for the treatment of tuberculosis in the UK. Susceptibility test results for at least isoniazid and rifampicin were available for 4730 (93%) of the culture confirmed cases. Of these, 7.4% had resistance to at least one first line drug at start of treatment, 6.8% were resistant to isoniazid and 1.2% were multi-drug resistant (resistant to at least isoniazid and rifampicin) (Table 2). Resistance to the other first line drugs, ethambutol and pyrazinamide, remained very low (0.6% and 0.7% respectively). 13

14 1T UBERCULOSIS IN THE UK Table 2: Number and proportion of tuberculosis cases with first line drug resistance, UK, Isoniazid Rifampicin Ethambutol Pyrazinamide Multi-drug Resistant to any Year resistant resistant resistant resistant* resistant first line drug Total** n % n % n % n % n % n % * Excludes M. bovis cases ** Culture confirmed cases with drug susceptibility testing results for at least isoniazid and rifampicin Figure 5: Proportion of tuberculosis cases with first line drug resistance, UK, Proportion of cases (%) Isoniazid resistant Multi-drug resistant Resistant to any first line drug Recent trends Year The proportion of cases with resistance to first line drugs was similar to that seen in 2006 in the UK, with a slight decrease in resistance to any first line drug (Figure 5). Following a rise in overall drug resistance from 2000 to 2001, due to an increase in isoniazid resistance at this time, levels have remained fairly stable over the last seven years. Geographical region/country The number and proportion of tuberculosis cases with drug resistance varied by UK country/region, with nearly half of all cases with drug resistance residing in London (46%, 162 /350). As in recent years, London remained an area with high levels of isoniazid resistance in particular, but had slightly lower proportions compared to the previous year (10.4% resistant to any first line drug and 9.3% isoniazid resistant in 2006) (Table 3). High proportions of resistance were seen in some other regions, but the low number of cases in these areas can cause large fluctuations, and so regional trends outside of London should be interpreted with caution. Place of birth Overall levels of isoniazid and multi-drug resistance were higher among non-uk born cases (7.5% vs. 5.7%, and 1.5% vs. 0.4% respectively). In London, the East of England and Yorkshire and the Humber, however, isoniazid resistance was higher among UK born cases (Figure 6). Again, the results should be interpreted with care due to small numbers in some regions. Multi-drug resistance was higher among non-uk born cases in all regions. 14

15 Table 3: Number and proportion of tuberculosis cases with drug resistance by country/region, UK, 2007 * Isoniazid Multi-drug Resistant to any Country/region resistant resistant first line drug Total** n % n % n % England Northern Ireland Scotland Wales East Midlands East of England London North East North West South East South West West Midlands Yorkshire and the Humber * Variations by region and country should be interpreted with caution in view of small numbers ** Culture confirmed cases with drug susceptibility testing results for at least isoniazid and rifampicin Figure 6: Proportion of tuberculosis cases with isoniazid resistance by country/region, UK, 2007 * Proportion of cases (%) UK born Non-UK born England Northern Ireland Scotland * Variations by region and country should be interpreted with caution in view of small numbers Number of cases given above each bar Wales East Midlands East of England Country/Region London North East North West South East South West West Midlands Yorkshire and the Humber 15

16 1T UBERCULOSIS IN THE UK Age and Sex Females had higher proportions of isoniazid resistance (7.6%, 153/2006 vs. 6.2%, 167/2709) and multi-drug resistance (1.4%, 28 vs. 1.0%, 27). Younger ages had the highest proportions of drug resistance (Table 4). Of cases aged less than 15 years, 8.1% were isoniazid resistant and 1.8% multi-drug resistant, but numbers of cases in this age group were small. Among cases aged 15 to 44 years, 7.9% were isoniazid resistant and 1.5% multi-drug resistant. Previous history of tuberculosis proportions of resistance to at least one first line drug (12.4%, 31/251 vs. 7.4%, 254/3439), isoniazid resistance (10.0%, 25/251 vs. 6.9%, 238/3439) and multi-drug resistance (5.6%, 14/251 vs. 1.0%, 33/3439) compared to cases with no previous history. Among cases with a previous history of tuberculosis, isoniazid and multi-drug resistance were more common among those born outside of the UK (Figure 7). Among cases with no previous history of tuberculosis, multi-drug resistance was also higher among those born outside the UK: levels of isoniazid resistance, however, were similar for those born in and outside the UK. Cases with a previous history of tuberculosis had higher Table 4: Number and proportion of tuberculosis cases with drug resistance by age group, UK, 2007 Isoniazid Multi-drug Resistant to any resistant resistant first line drug Total * n % n % n % * Culture confirmed cases with drug susceptibility testing results for at least isoniazid and rifampicin Figure 7: Proportion of tuberculosis cases with isoniazid and multi-drug resistance by previous history of tuberculosis and place of birth, UK, 2007 Isoniazid MDR* No previous history Previous history of TB No previous history Previous history of TB Non-UK born UK born Proportion (%) *Multi-drug resistant 16

17 1.5 Treatment outcome of UK tuberculosis cases reported in 2006 Completeness of treatment outcome information Information on the outcome of treatment at 12 months was received for 7885 (93%) of the 8495 tuberculosis cases reported in This represents an increase in the completeness of treatment outcome information compared to previous years, and a continuation of an upward trend since reporting began in 2001 (Table 5). Of these 7885, 197 cases were identified as not having tuberculosis (often subsequently diagnosed with non-tuberculous mycobacteria). Therefore, 7688 treatment outcomes were eligible for analysis. The completeness of treatment outcome reporting varied by region, ranging from around 75% in the West Midlands and the South West, to nearly 100% in London (Figure 8). Table 5: Proportion of reported treatment outcomes at 12 months, UK, Year Reported cases n Treatment outcomes Reported outcomes n % Identified as not TB n Among cases eligible for analysis, 79% were known to have completed treatment within 12 months, although this varied by region (Figure 9). Figure 8: Proportion of treatment outcomes reported by country/region, UK, 2006 tion (%) Propor Toolkit target 95% England Northern Ireland Scotland Wales East Midlands East of England London Country/Region North East North West South East South West 91.2 West Midlands Yorkshire and the Humber 17

18 1T UBERCULOSIS IN THE UK CMO's target 85% Figure 9: Proportion of tuberculosis cases who completed treatment within 12 months by country/region, UK, 2006 Proportion (%) England Northern Ireland Scotland Wales East Midlands East of England London Country/Region North East North West South East South West West Midlands Yorkshire and the Humber The most common reasons for not completing treatment were death (6%) and being still on treatment (6%) (Table 6). Table 6: Treatment outcomes at 12 months, UK, 2006 Treatment outcome n % Treatment completed Died Still on treatment Lost to follow up Treatment stopped Transferred out Reason for non-completion not reported Outcome unknown Total outcomes received * * Excludes 197 cases identified as not tuberculosis from outcome reports The relationship between tuberculosis disease and death was reported for 57% of deaths (278/487). Tuberculosis was reported as causing or contributing directly to 34% of all deaths (167/487), and incidental to 23% (111/487). For 20% of deaths, tuberculosis was diagnosed post mortem (97 of 474 deaths with available information). The proportion of cases completing treatment was the same as for cases reported in 2005, and has remained stable since The proportion still on treatment, however, increased to 5.7% (from 4.4% in 2005), while cases lost to follow up decreased to 4.5% (from 5.7% in 2005). Age and Sex Treatment completion was higher among females (81%, 2836/3486 vs. 77%, 3215/4184, among males), and declined with age from 88% among cases under 15 years old to 62% among those aged 65 and over (Table 7). Among older cases (65 years or older), more than a quarter died before completing treatment (26%, 285/1092), with just 26% of these deaths linked to tuberculosis. 18

19 Table 7: Number and proportion of tuberculosis cases completing treatment by age group, UK, 2006 Age group Place of birth Completed treatment n % Total outcomes Cases born outside the UK completed treatment more often than those born in the UK (80% vs. 77%). Death was the most common reason for not completing treatment among UK born cases (12%), who tend to be older than non-uk born cases. Still being on treatment (6%) and being lost to follow up (5%) were the most common reasons for not completing treatment among non-uk born cases (Figure 10). Site of disease A slightly lower proportion of pulmonary tuberculosis cases completed treatment than cases with extra-pulmonary disease (77%, 3275/4230 vs. 81%, 2722/3371). Among sputum smear positive pulmonary cases, the level of completion was 76% (1255/1650). Drug resistance Treatment completion was lower in cases identified with isoniazid resistant strains of tuberculosis than in cases with isoniazid susceptible strains (54%, 174/325 vs. 80%, 3446/4302). Almost a third of isoniazid resistant cases (31%, 100/325) were still on treatment at 12 months and 6% (20) were lost to follow-up. Figure 10: Treatment outcome at 12 months by place of birth, UK, UK born 70 Non-UK born Proportion (%) Treatment Died Still on Lost to follow Treatment Transferred Non- Outcome completed treatment up stopped out completion unknown reason not reported Treatment outcome 19

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21 C H A P T E R2T W O Research and development: published output of the Health Protection Agency from

22 2 Research and development: published output of the Health Protection Agency from 2003 The research and development activity of the HPA in the field of tuberculosis relates directly to the remit of the Agency to protect the population from infection. Thus the work aims to improve prevention and control of the disease through better diagnostic methods, strengthened surveillance, effective approaches to the control of the disease at the local level (including management of outbreaks) and the production of better vaccines. This activity is summarised below by each of the main groupings within the Agency engaged in research and development work. Almost all of this work involves collaboration across the Agency and with external partners. A comprehensive listing of the peer-reviewed papers, relating to this work, published since the inception of the Agency in 2003, is published on the HPA website at: Centre for Emergency Preparedness and Response The tuberculosis group at the Centre for Emergency Preparedness and Response (CEPR) has a major programme of research that contributes to the global effort to develop more effective interventions to reduce the prevalence of tuberculosis. Research interests include understanding more fully the behaviour of pathogenic mycobacteria during the infection process and in latency, and the host responses to this bacterial challenge, so as to identify possible new vaccine or drug targets, biomarkers of disease or correlates of protection. A major focus of the group is on tuberculosis vaccine development and evaluation, including the discovery of in-house vaccine candidates. In addition, CEPR is supporting the two major EU-funded vaccine consortia, TB VAC and MUVAPRED, by performing critical pre-clinical 22

23 assessments on the leading European tuberculosis vaccine candidates. The data generated help inform decisions on selecting the most promising candidates for evaluation in human clinical trials. The principal sources of funding are from the HPA, the European Union, and the Veterinary Laboratories Agency (Department for Environment, Food and Rural Affairs (DEFRA). 2.2 Centre for Infections The Centre for Infections is involved in a broad range of work relating to the prevention of tuberculosis, including surveillance, specialist and reference microbiology, co-ordinating the investigation of national and uncommon outbreaks, providing advice to government and responding to international health alerts. Within this Division are the Mycobacterium Reference Unit and Tuberculosis Section of the Respiratory and Systemic Infections Department, the Applied and Functional Genomics Unit, and the Statistics, Modelling and Bioinformatics Department Mycobacterium Reference Unit (Respiratory and Systemic Infections Department) The HPA Mycobacterium Reference Unit (MRU), a World Health Organization (WHO) SupraNational Reference Laboratory, moved to the Institute of Cell and Molecular Sciences at Barts and The London School of Medicine and Dentistry, where it forms part of the Clinical Tuberculosis and HIV Group. The MRU is the national reference laboratory for mycobacterial infections, and also provides local primary diagnostic NHS services and regional services for London and the South East. Its research interests and activities focus on the diagnosis and molecular epidemiology of tuberculosis and other mycobacteria, understanding drug resistance and disease tropisms, the interplay between tuberculosis and HIV, and broader related public health problems, both in the UK and internationally, particularly in eastern Europe and Africa. The principal sources of funding are from the HPA with external grant income in recent years coming from the European Union, Department for International Development, British Lung Foundation, King s College Joint Research Committee, Department of Health, DEFRA, WHO, Drinking Water Inspectorate, National Health Service Research and Development, European Respiratory Society, and British Council Tuberculosis Section (Respiratory and Systemic Infections Department) The Tuberculosis Section, based at the Colindale site of the HPA Centre for Infections, is the national group responsible for tuberculosis and other mycobacterial infections surveillance. The Section has a leading role in supporting the Department of Health to formulate policy on tuberculosis prevention and control, contributes to international surveillance and tuberculosis control and advises various government agencies on tuberculosis research priorities. Activities include improving the quality of epidemiological information on tuberculosis cases through development of surveillance methodology, and providing evidence on trends and high risk groups to inform targeted interventions for tuberculosis control. Other research interests include the role of BCG vaccination, the impact of tuberculosis and HIV coinfection and the use of molecular epidemiology to inform tuberculosis control. The Section is also involved in public health measures against tuberculosis including the role of specific interventions in hard-to-reach groups and migrants. Principal sources of funding are from the HPA, Department of Health, National Institute for Health Research (NIHR) Health Technology Assessment and the NIHR programme grants scheme. 23

24 2.2.3 Applied and Functional Genomics Unit 2The Applied and Functional Genomics Unit, based at the Colindale site of the HPA Centre for Infections, in collaboration with the Regional Microbiology Network and international groups, works on the development of novel molecular methods to define the global phylogeny of modern M. tuberculosis. Evidence is accumulating that hyper-virulent strains exist and this will enable the development of markers for rapid detection of these important lineages. Other related developmental work includes rapid molecular diagnostics and speciation methods Statistics, Modelling and Bioinformatics Department Bioinformatics Unit The Bioinformatics Unit has worked in collaboration with the Regional Centres for Mycobacteriology (RCM), the Mycobacterium Reference Unit and the Tuberculosis Section at Centre for Infections, and colleagues in Local and Regional Services to establish the National M. tuberculosis Strain Typing Database. This is a web-enabled resource ( hosted at the Centre for Infections which allows RCMs to identify potentially linked cases of tuberculosis outside their own region and provides those involved in tuberculosis detection and control with the ability to determine the prevalence and geographic distribution of specific tuberculosis strain types. Currently, the database contains information on 18,725 strains from recent years, representing 7,495 strain profiles. A total of 3,246 records were submitted by the five RCMs in Work is ongoing to link the strain typing database with the Enhanced Tuberculosis Surveillance system and to develop additional analytical tools for local and regional use. The Bioinformatics Unit is also involved in collaborative work across the HPA to determine optimal typing methods and develop novel mathematical modelling methods and reporting systems. Modelling and Economics Unit The Modelling and Economics Unit, in collaboration with the Bioinformatics Unit, the Respiratory and Systemic Infections Department and the RCMs, works on the development of novel mathematical modelling methods to interpret national genotyping data of M. tuberculosis strains to elucidate the extent of recent transmission. It is also involved in collaborative work with outside institutes on appropriate interventions against tuberculosis in high incidence settings. 2.3 Local and Regional Services and Regional Microbiology Network Local and Regional Services (LaRS) provides specialist health protection services to a wide range of partners including the NHS, local authorities and the public. Its activities are backed by the conduct and publication of high quality translational health and health service research. Staff from the division contribute to HPA-wide research projects and also undertake studies such as detailed epidemiological analysis to inform local control, literature reviews to draw together the evidence for their specialist practice, and the publication of studies identifying key lessons from the investigation of incidents and outbreaks. Previously part of LaRS, the Regional Microbiology Network (RMN) was established as a separate Division of the Agency in April Diagnostic and public health mycobacteriology services are provided by two centres in the RMN, the North of England and West Midlands Regional Centres for Mycobacteriology (RCMs), to NHS Trusts and HPA Health Protection Units in the surrounding areas. North of England Regional Centre for Mycobacteriology Research and publications by the North of England RCM in collaboration with HPA, academic and other colleagues address the issues of the appropriateness of culture methods, particularly in the isolation of less common mycobacterial species and in their epidemiology, 24

25 occurrence and significance in non-respiratory sites. They have also focussed on the rapid detection of drug resistance using molecular techniques. Publications on the taxonomy of the Mycobacteriaceae and on the applications of DNA fingerprinting are currently in preparation. West Midlands Regional Centre for Mycobacteriology The publications from the West Midlands RCM and collaborators highlight the development of DNA fingerprinting, using variable number tandem repeat (VNTR) typing, of all M. tuberculosis complex isolates in the Midlands. This ranges from initial validation against the gold standard for typing (IS6110 restriction fragment length polymorphism), and evaluation of the performance of automated VNTR analysis, to being part of a global study on the origin of strains (with a particular focus on the south Asian strain). The utility and impact of prospective DNA fingerprinting during public health investigations was highlighted by the cluster of six M. bovis cases between 2004 and

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27 C H A P T E R T H R E E3 What do the findings mean? 27

28 3 What do the findings mean? This report shows that the stabilisation of tuberculosis rates in the UK observed since 2006 continues. This is the second consecutive year without a rise in the incidence of tuberculosis after nearly two decades of increase. While this is encouraging, rates remain high with the UK having one of the highest incidence rates of tuberculosis in western Europe 10.The direction of future changes remains unknown, and efforts to control and accelerate the downward trend should be continued. The main burden of disease remains concentrated in certain urban areas. Over 90% of UK tuberculosis cases were found in England, and London in particular accounted for a considerable proportion (39%). The rate of disease in the capital (43.2 per 100,000) was comparable to rates in some eastern European and South American countries (Estonia, Bulgaria, Croatia, Colombia, Venezuela and Argentina) 5. As in previous years, the majority of cases occurred in young adults aged 15 to 44 years, and among those born outside of the UK. The CMO s Action Plan 1 proposes that, for tuberculosis to be controlled, a decline in incidence, among (a) the UK born population and (b) people who entered the UK and became resident within the previous five years, is required. The incidence of tuberculosis in the UK born has not increased, but neither has there been a reduction. This may reflect the changing epidemiology of tuberculosis in this population, with more cases occurring in high risk groups, such as the homeless and problem drug users, as opposed to cases resulting from reactivation of previously acquired infection in the elderly. There was also variation within the UK born population, with black African and south Asian ethnic groups remaining at increased risk compared to those of white ethnicity. The rate among the non-uk born population appeared to have decreased. Care needs to be taken in interpreting these data as the rates rely on sample-based population estimates. 28

29 The decrease in rates may reflect changes in migration patterns, with fewer migrants originating from countries with a high burden of tuberculosis. Among those cases born outside the UK, however, over half were diagnosed with tuberculosis more than five years after entering the UK. Future trends will continue to be influenced by recent immigration patterns, but the control of tuberculosis in UK born groups and non-uk born populations resident in the UK for more than five years remains important. In particular, clinicians should note that the risk of tuberculosis remains high among persons born in high incidence countries for many years after arrival. An important marker of disease transmission within the UK is the incidence of tuberculosis in children. Recent trends suggest that rates in children under the age of five years remain stable and low. Much of the disease in this age group affects children whose parents or grandparents originate from countries with a high burden of tuberculosis, among whom rates are high compared to those of indigenous white children 11. This report identifies changes in the epidemiology of tuberculosis with clinical implications. The proportion of cases with extra-pulmonary tuberculosis continues to increase with nearly half of all cases now presenting with disease exclusively affecting an extra-pulmonary site. The majority of these cases occur in non-uk born individuals. A high index of suspicion is warranted in patients presenting with symptoms suggestive of extra-pulmonary tuberculosis. The proportion of pulmonary cases in which the diagnosis is confirmed by culture, at 70%, meets the goal in the HPA s proposed five year strategic health plan, although the proportion in England itself falls just below 70%. Among all cases, which include both pulmonary and non-pulmonary cases, the proportion confirmed by culture is 60%. This is mainly due to the high proportion of cases with extra-pulmonary disease from whom obtaining suitable specimens for culture may often be more difficult. Nevertheless, every effort should be maintained to increase the proportion of patients from whom suitable specimens are obtained. Although the absolute burden of disease due to M. bovis is low, in view of the recent increase in bovine tuberculosis in cattle, further investigation is needed, including the use of molecular typing, of those cases likely to have been infected recently in this country. Despite an earlier increase in isoniazid resistant tuberculosis in the UK 12 and a global rise in MDR tuberculosis 13, levels of resistance to first line anti-tuberculosis drugs in the UK overall have remained stable in recent years. Of initial isolates, 6.8% were reported as resistant to isoniazid and 1.2% as multi-drug resistant: these are within the levels suggested in the CMO s Action Plan 1. The target level of no more than 7% of cases resistant to isoniazid was, however, exceeded in two regions in England. In particular, since 1999, in London more than 7% of tuberculosis cases have been reported to be resistant to isoniazid. The increases in proportions resistant reported in other regions were likely to be due to fluctuations in small numbers of cases. Overall, drug resistance was more common among younger patients with tuberculosis, and those born outside the UK. In some regions, however, resistance to isoniazid was more common among UK born cases. This was likely to be partly due to an ongoing outbreak of isoniazid resistant tuberculosis among hard to reach UK born populations in London 2. A previous history of tuberculosis was associated with an increased proportion of drug resistance, reflecting the likely development of drug resistance in these cases through inadequate treatment. This was more common among cases born outside the UK, and in 2007 no cases which were multi-drug resistant at start of treatment were born in the UK. 29

30 3The occurrence of drug resistance in patients at the start of their treatment, when no history of previous tuberculosis is reported, is likely to be a result of transmission of a drug resistant strain. Proportions of cases with no previous history of tuberculosis that were isoniazid resistant were similar for UK born and non-uk born cases, suggesting some transmission of drug resistant strains is occurring in the UK. Again, this has been demonstrated to be occurring in London, with transmission of an indistinguishable isoniazid resistant strain of M. tuberculosis 2. The emergence of multi-drug resistant and extensively drug resistant tuberculosis (XDR TB) as a global public health issue calls for greater surveillance of these forms of tuberculosis and the maintenance of strong laboratory capacity to rapidly identify these cases as well as contribute to the development of mycobacterial diagnostics internationally. The completeness of treatment outcome reporting was the highest yet achieved, at 93%. Ideally, however, all incident tuberculosis cases should have a treatment outcome reported and the Department of Health toolkit for planning, commissioning and delivering high-quality tuberculosis services in England 14 states that 95% of incident cases should have this information reported by clinical services to the Health Protection Agency. Only two to three of the English regions reached these national standards for tuberculosis surveillance. The proportion of patients who successfully complete treatment has remained at around 79% since surveillance began in 2001, which is below the 85% level suggested by the CMO 1. Previous reports 3;4 have suggested reasons for this, including high levels of mortality from causes other than tuberculosis among elderly cases, and patients undergoing planned courses of treatment which exceed 12 months. Lower levels of treatment completion among the UK born and white ethnic group may be explained in part by the older average age of these cases 3. Although national surveillance may underestimate mortality 15, the number of deaths among tuberculosis cases has remained stable in recent years. Most of these deaths occur in the elderly population, but further investigation of factors associated with mortality is needed. In comparison to previous years, the proportion of cases still on treatment increased, while those lost to follow up decreased. These observed changes may be, at least in part, artefactual as a result of changes in data collection practices in the London region. Due to this and the small magnitude of the change, this finding should be interpreted with caution. The higher proportion of cases known to be drug resistant at start of treatment subsequently being lost to follow up is, however, of particular concern. Following agreement at the European level for improved monitoring of patients undergoing treatment for multi-drug resistant disease, a revised surveillance system for England, Wales and Northern Ireland has been developed which will monitor treatment outcomes at 24 months for appropriate cases. The research and development activity of the Health Protection Agency described in this report, and illustrated by the listing of peer reviewed publications since 2003, demonstrates the commitment of the Agency to strengthening the prevention and control of tuberculosis in this country and globally. This work includes basic scientific research to inform the development of a future tuberculosis vaccine to applied health service research supporting the NHS in controlling tuberculosis. Other areas of research include the development and application of new diagnostics, use of molecular strain typing, strengthening of surveillance methods and systems, and application of all of these to understanding the epidemiology of the disease and more effective approaches to its control. An assessment of current progress against the measures of success suggested in the CMO s Action Plan (restated in the draft HPA Strategic Plan 2008 to 2013) is summarised in the text box below. Much work remains to be done if the most effective control of tuberculosis in the UK is to be achieved: 30

31 Indicator A progressive decline (of at least 2% per year) in rates of tuberculosis in population groups born in England. No more than 7% of new cases resistant to the anti-tuberculosis drug isoniazid. No more than 2% of new cases multi-drug resistant. At least 70% of patients with pulmonary tuberculosis have the diagnosis confirmed by laboratory culture of the organism. All patients diagnosed with tuberculosis have the outcome of their treatment recorded. At least 85% successfully complete their treatment. * Not met in two regions Status Not met Met* Met Met Not met Not met Further investigation of the epidemiology of tuberculosis disease due to M. bovis in humans in the UK should be undertaken. Further recommendations supported by the HPA, consistent with the WHO Stop TB Strategy 16, the CMO s Action Plan 1 and the HPA draft Strategic Plan for 2008 to 2013, include: - To the HPA and NHS The systematic use of prospective strain typing data should be implemented to improve tuberculosis control. TB-HIV collaborative activities should be strengthened. The current efforts to enhance the control of tuberculosis among hard to reach groups should be maintained. What next? Recommendations arising from this report include: - To the HPA and NHS in England (separate recommendations in Scotland will follow the publication of a detailed report by Health Protection Scotland later this year) Tuberculosis surveillance systems should be fully strengthened by ensuring the implementation of the recently developed national web-based system. Measures should be continued to ensure that tuberculosis can be recognised and diagnosed early among migrants who are at increased risk of developing tuberculosis in the years after their arrival in the UK. Clinicians should have a higher index of suspicion among non-uk born persons presenting with symptoms suggestive of extra-pulmonary tuberculosis. The proportion of cases of tuberculosis that are culture confirmed should be further increased. - Research and Development Further research into latency of M. tuberculosis in humans and the development of new tools with a high positive predictive value for active disease among those latently infected should be encouraged. The efficacy of treatment regimes for latent tuberculosis infection due to drug resistant strains should be evaluated. Further investigation to improve our understanding of the factors associated with diagnostic delay should be undertaken. The effectiveness of awareness raising measures should be assessed. Interventions to improve tuberculosis control in hard to reach groups should be evaluated. Research into new agents for the treatment of drug resistant tuberculosis is needed. The development of an effective vaccine remains a priority and current collaborative research effort by the Agency and other partners should be supported. 31

32

33 References 33

34 References 1 Department of Health. Stopping Tuberculosis in England: An Action Plan from the Chief Medical Officer London, Department of Health. 2 Ruddy MC, Davies AP, Yates MD, Yates S, Balasegaram S, Drabu Y, et al. Outbreak of isoniazid resistant tuberculosis in north London. Thorax 2004;59: Ditah IC, Reacher M, Palmer C, Watson JM, Innes J, Kruijshaar ME, et al. Monitoring tuberculosis treatment outcome: analysis of national surveillance data from a clinical perspective. Thorax 2008;63(5): Antoine D, French CE, Jones J, Watson JM. Tuberculosis treatment outcome monitoring in England, Wales and Northern Ireland for cases reported in J Epidemiol Community Health. 2007;61: World Health Organization. Global tuberculosis control - surveillance, planning, financing. World Health Organization Report Geneva, World Health Organization. 6 French CE, Antoine D, Gelb D, Jones JA, Gilbert RL, Watson JM. Tuberculosis in non-uk-born persons, England and Wales, Int J Tuberc Lung Dis 2007;11(5): Story A, Murad S, Verheyen M, Roberts W, Hayward AC. Tuberculosis in London - the importance of homelessness, problem drug use and prison. Thorax 2007;62: French CE, Kruijshaar ME, Jones JA, Abubakar I. The influence of socio-economic deprivation on tuberculosis treatment delays in England, Epidemiol Infect. 2008;8: Abubakar I, Crofts JP, Gelb D, Story A, Andrews N, Watson JM. Investigating urban-rural disparities in tuberculosis treatment outcome in England and Wales. Epidemiol Infect. 2008;136: EuroTB and the national coordinators for tuberculosis surveillance in the WHO European Region. Surveillance of Tuberculosis in Europe: Report on tuberculosis cases notified in Abubakar I, Laundy M, French CE, Shingadia D. Epidemiology and treatment outcome of childhood Tuberculosis in England and Wales: 1999 to Arch Dis Child E-pub ahead of print. 12 Kruijshaar ME, Watson JM, Drobniewski F, Anderson C, Brown TJ, Magee JG, et al. Increasing antituberculosis drug resistance in the United Kingdom: analysis of national surveillance data. BMJ 2008;366: The World Health Organization /International Union Against Tuberculosis and Lung Disease Global Project on Anti-Tuberculosis Drug Resistance Surveillance. Anti- Tuberculosis Drug Resistance in the World Geneva, World Health Organization. 14 Department of Health. Tuberculosis prevention and treatment: a toolkit for planning, commissioning and delivering high-quality services in England London, Department of Health. 15 Crofts JP, Pebody R, Grant A, Watson JM, Abubakar I. Estimating tuberculosis case mortality in England and Wales, Int J Tuberc Lung Dis. 2008;12: The World Health Organization Stop TB Partnership. The Stop TB Strategy Geneva, World Health Organization. 34

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37 Appendices 37

38 Appendix A: Additional data tables and figures Appendices i) Tuberculosis case reports, rates and annual percentage change, England, Year Number of cases Rate (per 100,000) Annual change in case numbers (%)

39 ii) Tuberculosis case reports by region, England, Number of cases East Midlands East of England London North East North West South East South West West Midlands Yorkshire and the Humber Region iii) Rates of tuberculosis in England by Local Authority,

40 iv) Number of tuberculosis cases aged less than 5 years, and rate, England, Year Number of cases Rate (per 100,000) v) Tuberculosis case reports, rates and annual percentage change by place of birth, England, UK Born Non-UK Born Year Number of Rate per Annual change Number of Rate per Annual change cases 100,000 in rate (%) cases 100,000 in rate (%) vi) Number and proportion of tuberculosis cases by site of disease, England, Year Pulmonary* Extra-pulmonary** Total*** n % n % * With or without extra-pulmonary disease ** Extra-pulmonary disease only *** Where site of disease was known 40

41 vii) Number and proportion of tuberculosis cases with first line drug resistance, England, Isoniazid Rifampicin Ethambutol Pyrazinamide Multi-drug Resistant to any Year resistant resistant resistant resistant** resistant first line drug Total* n % n % n % n % n % n % * Culture confirmed cases with drug susceptibility testing results for at least isoniazid and rifampicin ** Excludes M. bovis cases Appendix B: Data sources - tuberculosis surveillance systems Case reports Enhanced Tuberculosis Surveillance (ETS) was introduced on 1 January 1999 in England and Wales, and the following year in Northern Ireland. The equivalent scheme in Scotland, Enhanced Surveillance of Mycobacterial Infections (ESMI), was introduced in Results from the two systems are compiled for the purpose of UK reporting. Enhanced Tuberculosis Surveillance (ETS) England, Wales and Northern Ireland Clinical teams are asked to provide information on tuberculosis cases on a case report form. Data include notification details, demographic information, clinical and microbiological information. This form is sent to the local tuberculosis co-ordinator and either entered onto a database locally, or forwarded on to the regional level for entry. Regional data are subsequently collated at the national level by the Tuberculosis Section at the Health Protection Agency Centre for Infections. Collation and finalisation of national data is a multi-step process. Firstly the data are checked, and duplicates are identified. This information is then fed back to the regions, which in turn feed back to the local level, before returning finalised data to the national level. Notifications and denotifications that are reported after the dataset has been finalised are not included at the national level. Enhanced Surveillance of Mycobacterial Infections (ESMI) - Scotland The ESMI scheme provides the clinical surveillance system for tuberculosis in Scotland and is co-ordinated by Health Protection Scotland (HPS). Information collected on each case includes notification details, demographic information, clinical characteristics, and microbiological investigations. Each NHS Board Public Health Team notifies HPS of a case via a completed questionnaire. HPS collates the information to a national level and reports findings annually. The data are updated with late notifications and denotifications continuously. 41

42 Treatment outcome monitoring (TOM) Since 2002, treatment outcome information has been collected for cases reported to ETS/ESMI in the previous year. For all cases reported in the previous year, clinicians and/or nurses are asked to complete a short form detailing the patient s status 12 months after starting treatment or being notified. This includes patients who were diagnosed at post mortem. The definitions for treatment outcome are based on World Health Organization (WHO) and European definitions, but adapted to the UK context 4. UK Mycobacterial Surveillance Network Information on Mycobacterium tuberculosis complex isolates in the UK is obtained from seven mycobacterial reference laboratories. Data collected includes species (Mycobacterium tuberculosis, Mycobacterium bovis or Mycobacterium africanum), drug susceptibility, and some minimal demographic and clinical data. Datasets received from the reference laboratories are cleaned. The cleaning includes removal of duplicate records and of further reports of isolates from the same individual within a 12-month period. These data are then matched to the ETS/ESMI dataset, through a computerised matching process based on patient identifiers common to both systems, in order to improve the completeness and validity of microbiological information in ETS/ESMI. UK mycobacterial reference laboratories The mycobacterial reference laboratories in the UK are: HPA National Mycobacterium Reference Unit (MRU), London. HPA Regional Centre for Mycobacteriology, Birmingham. HPA Regional Centre for Mycobacteriology, Newcastle. Royal Brompton Hospital Microbiology Department, London. Wales Centre for Mycobacteriology, Penarth. Northern Ireland Public Health Laboratory, Belfast. Scottish Mycobacteria Reference Laboratory (SMRL), Edinburgh. Appendix C: Methods Tuberculosis rates Overall tuberculosis rates per 100,000 population as well as those by age, sex and region of reporting, are calculated using the mid-year estimates provided by the Office for National Statistics (ONS). Rates by place of birth and by ethnic group have been calculated using population estimates from the Labour Force Survey (LFS). In 2001/2, the ethnic group classifications used in the LFS changed. Furthermore, in 2006, the Labour Force Survey moved from producing data for seasonal quarters to calendar quarters, and in 2007 LFS estimates were reweighted in line with revised Census data. Rates by place of birth and by ethnic group presented in this report are therefore from 2002 only and are not directly comparable to rates presented in previous reports. The LFS is based on a population sample, thus estimates are liable to sampling errors, particularly for smaller population subgroups. Rates by ethnic group and by place of birth are therefore presented as whole numbers and should be interpreted with caution. Proportions All proportions in this report are calculated among cases with known information or a known result, except where otherwise stated. Drug resistance is reported as the proportion of tuberculosis case reports resistant at the start of treatment, using as denominator cases with available drug susceptibility results for at least isoniazid and rifampicin. M. bovis is usually resistant to pyrazinamide, and so cases with disease due to this organism are excluded when calculating resistance to this drug. The proportion of treatment completion is calculated using as the denominator all cases with an outcome reported (including post mortem cases), minus cases whose treatment was stopped because they were subsequently recognised not to have tuberculosis. In this report, proportions are presented as whole numbers except in Chapter 1, Section 2 (and elsewhere when proportions are very small) where they are presented to one decimal place. 42

43 Appendix D: Definitions used in this report Case definition The following cases are reported through ETS/ ESMI (the final total number of cases reported each year excluding denotified cases and cases reported outside the calendar year): - Confirmed cases: Culture confirmed case, due to M. tuberculosis complex infection (including M. tuberculosis, M. bovis and M. africanum). - Other than culture confirmed case: In the absence of culture confirmation, a case that meets the following criteria: A clinician s judgement that the patient s clinical and/or radiological signs and/or symptoms are compatible with tuberculosis and A clinician s decision to treat the patient with a full course of anti-tuberculosis treatment. Persons receiving preventive chemoprophylaxis are not reported through ETS/ ESMI. Treatment outcome definitions Treatment completion A patient is defined as having completed treatment if the case: a) was reported, b) completed a full course of treatment, and c) was officially discharged by the attending physician. Death The outcome death is used for patients who died before or during treatment, and includes cases diagnosed post mortem. Death does not have to be related to tuberculosis. Four subcategories were used to provide information on the nature of the link between death and tuberculosis: 1) tuberculosis caused death 2) tuberculosis contributed to death 3) tuberculosis incidental to death (tuberculosis was not related to death) 4) relationship between tuberculosis and death unknown. Still on treatment This category is used for patients still on treatment at one year after starting treatment. Subcategories are used to provide reasons for still being on treatment: 1) still on initially planned treatment (regimen longer than initial 12 months planned) 2) treatment interrupted (non-completion of initially planned treatment regimen for 12 months or less) 3) treatment changed as a result of any of the following: intolerance or side effects, initial drug resistance, development of new drug resistance, failure to culture convert and poor clinical response to treatment. Treatment stopped A patient is classified in this category when he or she did not complete treatment for reasons other than death or still being on treatment. Transferred out The patient is classified as transferred out if responsibility for his/her care was transferred to another clinical team. Lost to follow up The patient is classified in this category if he/she was lost to follow up before the end of treatment. Unknown When no treatment details (including outcome) are available (e.g. lost patient notes) or when treatment is not completed for unknown reasons, the patient is classified as having an unknown outcome. Other definitions and classifications Pulmonary tuberculosis A pulmonary case is defined as a case with tuberculosis involving the lungs and/or tracheo-bronchial tree, with or without extra-pulmonary tuberculosis diagnosis. Sputum smear result A sputum smear positive tuberculosis case is defined as a tuberculosis case with a positive microscopy result on spontaneously produced or induced sputum. Multi-drug resistance Multi-drug resistance (MDR) is defined as resistance to at least isoniazid and rifampicin (with or without resistance to other drugs). 43

44 New case versus previously diagnosed case Information on previous tuberculosis diagnosis is collected. A case with no previous tuberculosis diagnosis is referred to as a new tuberculosis case in this report. Ethnic group The classification of ethnic group is based on the definitions used by the ONS. Regions and countries The data are presented according to the nine HPA regions in England (as from April 2002), plus Scotland, Wales and Northern Ireland. Information on region is based on the place where the patient was reported. World regions Information on the country of birth of tuberculosis cases is collected. Countries were grouped into world regions based on the United Nations (UN) classifications, adjusted to take into account the global epidemiology of tuberculosis and migration patterns to the UK. For example, the five African regions defined by the UN were grouped into two regions (north Africa and sub-saharan Africa). North America and Oceania were grouped together based on the similar epidemiology of tuberculosis in these areas. Appendix E: Contributors Tuberculosis data are provided at the local level by physicians, nurses, microbiologists, scientists and administrative staff. Those who co-ordinate the provision of data at the regional/ country level are listed below. Stefanie Davies, HPA North West Jacqui Carless and Lamya Kanfoudi, HPA London Daniel Thomas and Rhian Hughes, Communicable Disease Surveillance Centre and National Public Health Service for Wales Dr Brian Smyth and Eileen Morelli, Communicable Disease Surveillance Centre Northern Ireland Dr Jim McMenamin, Eisin Shakir and Fiona Johnston, Health Protection Scotland Laboratory data Prof Francis Drobniewski, Phil More and Dr Tim Brown, HPA National Mycobacterium Reference Unit (MRU), London Dr Grace Smith, Janet Mowbray and Jason Evans, HPA Regional Centre for Mycobacteriology, Birmingham Dr John Magee and Debbie Osborne, HPA Regional Centre for Mycobacteriology, Newcastle Carmel Prendergast, Royal Brompton Hospital Microbiology Department, London Dr Michael Ruddy and Rhian Hughes, Wales Centre for Mycobacteriology, Penarth / Mark Thomas, Communicable Disease Surveillance Centre Wales, Cardiff Timothy Stanley, Northern Ireland Public Health Laboratory, Belfast Dr Ian Laurenson, Scottish Mycobacteria Reference Laboratory (SMRL), Edinburgh Tuberculosis case reports and treatment outcome data Angela Cox, HPA North East Madeline Cox and Ivan Probert, HPA Yorkshire and the Humber Paul Clowry and Jonathan Lloyd, HPA East Midlands Katie Anders, HPA South East Helen Bagnall, HPA West Midlands Liz Tempest, HPA South West Caroline Black and Iain Roddick, HPA East of England 44

45 Other sources of information Public Health Organisations in the UK Health Protection Agency Tuberculosis Health Protection Agency / National Knowledge Service - TB Pilot Department of Health Tuberculosis National Public Health Service for Wales Tuberculosis Communicable Disease Surveillance Centre (Northern Ireland) Tuberculosis Health Protection Scotland Tuberculosis International Organisations The European Centre for Disease Prevention and Control EuroTB Centers for Disease Control and Prevention Division of Tuberculosis Elimination The International Union Against Tuberculosis and Lung Disease World Health Organization Stop TB Department World Health Organization Health Topics: Tuberculosis Stop TB Partnership Clinical Guidance National Institute for Health and Clinical Excellence - Tuberculosis British Thoracic Society Tuberculosis guidelines Immunisation/BCG National Health Service Immunisation website: BCG Immunisation Against Infectious Disease 2006 "The Green Book": Tuberculosis Chapter (updated November 2007) TB-VAC Mucosal Vaccines for Poverty Related Diseases (MUVAPRED) UK Statistics Office for National Statistics Northern Ireland Statistics and Research Agency General Register Office for Scotland Other Relevant Websites All-Party Parliamentary Group on Global Tuberculosis The British Lung Foundation Target Tuberculosis TB Alert TB Alliance Adfam The National Treatment Agency 45

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