Research and analysis

TB diagnosis, microbiology and drug resistance in England, 2021

Updated 3 August 2023

Applies to England

About this report

Report series

The aim of this report is to describe the diagnosis and microbiological testing of tuberculosis (TB) in England up to the end of 2021. Most health protection functions are devolved to the other UK nations’ public health teams in the UK, so this report only covers TB notifications and data from England.

It is the second in a series of 7 reports previously published as a single report, titled TB in England. This is the first year that they have been published as a series of smaller reports and each will describe different aspects of TB incidence, treatment and prevention in England:

1. TB incidence and epidemiology in England, 2021
2. TB diagnosis, microbiology and drug resistance in England, 2021
3. TB in children: incidence, epidemiology and microbiology in England, 2021
4. TB treatment in England, 2021
5. TB treatment outcomes in England, 2021
6. TB prevention in England, 2021
7. TB in children: treatment and prevention in England, 2021

Report format

Information on how this series of reports fits within the TB action plan for England 2021 to 2026 (jointly published with National Health Service (NHS) England) along with a list of important monitoring indicators for the report series, can be found in TB incidence and epidemiology in England, 2021.

Intended audience

This report is primarily aimed at healthcare professionals involved in the management of people with TB, healthcare commissioners involved in the planning and financing of TB services, public health professionals, researchers, and governmental and non-governmental organisations involved in TB control.

Main messages

Culture confirmation is critical to identify sensitivity to TB treatment, and to allow tracing of TB transmission.

Data up to the end of 2021 shows that:

• the proportion of culture confirmation for all TB notifications with pulmonary (and potentially infectious) TB disease in 2021 was 74.4%, under the target of 80%
• proportions of culture confirmation for all people with TB and in those with pulmonary disease do not show evidence of improving over time; more work is needed to identify the limiting factors in this diagnostic pathway
• regional variations in culture confirmation rates, unexplained by variations in proportions of pulmonary TB disease between regions, need addressing
• reported resistance rates for first line drugs rifampicin and isoniazid have remained broadly stable since 2011
• for the other first line drugs, reported resistance rates for ethambutol trended upwards since 2011 and resistance to pyrazinamide increased sharply between 2016 and 2018 as a result of improved methodology in detection of resistance, but has remained broadly stable since
• multidrug resistant (MDR) or rifampicin resistant (RR) TB rates have remained stable
• extensively drug resistant TB (XDR-TB) remained rare in England

Executive summary

Diagnosis of TB

TB disease is diagnosed through a combination of clinical features, radiology and laboratory testing. Laboratory tests used include microscopy, culture nucleic acid amplification techniques (for example, polymerase chain reaction (PCR) tests) and tissue histology. Confirming the diagnosis through microbiological testing and characterising the bacteria comprehensively through genomic and phenotypic testing provides understanding of antimicrobial susceptibility and transmission clusters. This optimises both individual treatment and public health control.

Laboratory confirmation of TB

In 2021, nearly 7% of people with TB did not have a laboratory result reported to the national TB surveillance system (NTBS), whilst 60.8% had a diagnosis confirmed by culture by one of the National Reference laboratories. Culture is the cornerstone of characterisation, and this is the lowest proportion of TB notifications confirmed by culture since 2013.

As in previous years, culture confirmation was higher for pulmonary (74.4% of notifications) than non-pulmonary notifications (45.6%). There was regional variation in culture confirmation proportions, being highest in the North East (69.1% of individuals) and lowest in the East of England (56.0%). These regional differences were only partly accounted for by regional differences in pulmonary TB disease proportions. For pulmonary disease, culture confirmation proportions were highest in London (79.6%), where they approached the 80% target, and lowest in the South West at 63.8%.

Resistance to drugs used to treat TB

Quadruple therapy remains the first choice in the UK according to guidance from the National Institute for Health and Care Excellence (NICE). In 2021, 9.9% of people with TB confirmed by culture were identified as having bacteria resistance to at least one of the 4 first line antibiotics through laboratory testing. This has been broadly stable since significant increases in 2018 compared with previous years. This rise in the proportion resistant to at least one of the 4 first line antibiotics was due to increased detection of resistance to pyrazinamide as a result of new testing methods introduced at this time.

Resistance to the other first line agents remains broadly stable across this period, with resistance to rifampicin in 1.9%, isoniazid in 7.3% and ethambutol in 2.0% of people with TB.

MDR, grouped with RR for treatment purposes (as in WHO definitions), made up 1.9% of culture-confirmed cases. This was slightly lower than in 2020, but consistent with previous years.

Reporting of MDR and XDR TB

MDR TB is TB which is resistant to at least rifampicin and isoniazid. This is grouped with RR TB with regard to treatment in the WHO classification.

XDR and pre-extensively drug resistant (pre-XDR) TB are mycobacterium tuberculosis (MTB) strains which are resistant to more drugs than rifampicin and isoniazid. The WHO changed its definitions of XDR and pre-XDR in 2021 and these changes are incorporated into this report. XDR and pre-XDR rates are therefore not comparable with previous years.

Diagnostic confirmation

NICE recommends that all patients in whom TB is suspected should have samples for microbiological diagnosis.

For tests other than culture confirmation, data was obtained from user-entered variables in NTBS. Some of these variables have large amounts of missing data, so should be interpreted with caution.

Any test confirmation

Table 1 of the TB diagnosis, microbiology and drug resistance in England dataset shows the proportions of notifications in NTBS with any diagnostic test recorded as having been performed (culture, PCR, microscopy, histology or chest X-ray) and the proportion with any positive test recorded. In 2021, the proportion of notifications with any diagnostic test reported was 92.8% (95% confidence interval (CI) 92.0% to 93.5%). It was higher in those with pulmonary disease 97.0% (95% 96.2% to 97.6%) compared with 88.1% (95% CI 86.7% to 89.5%) in those with non-pulmonary disease.

The proportion of notifications with any test performed has decreased since 2011 (97.0% (CI 96.6 to 97.3%). However, the proportion of people notified with TB with a positive test result has increased over time from 66.4% (95% CI, 65.4% to 67.4%) in 2011 to 73.8% (95% CI 72.5% to 75.1%) in 2021. In 2021, there were 1,158 people out of 4,425 (26.2%) who did not have a positive test result reported to NTBS and were either diagnosed on clinical grounds or were diagnosed abroad and or results were not reported to NTBS.

A national laboratory audit is due to be piloted early in 2023 to gather laboratory-level data and, along with the Getting it right first time (GIRFT) review, to identify if diagnostic testing is in line with NICE guidance.

PCR tests

NICE recommends that respiratory samples should have a PCR in all cases for paediatric TB. It is recommended in adults, if the patient has HIV, if the result would change management, or if a large contact tracing exercise is being planned. For non-respiratory samples, PCR is indicated if it would change management.

In 2021, data on PCR testing was not recorded in the NTBS for 85.4% of notifications (3,778 of 4,425). When limited to children (aged under than 15 years) with pulmonary disease, 90.0% of 70 children had no PCR testing information recorded. Overall, in 2021 13.0% of people with TB (573 of 4,425) were recorded as PCR positive and 3.7% (163 of 4,425) were recorded as PCR negative.

The recording of PCR results may not reflect actual diagnostic practice as it relies on user entry.

Culture confirmation and action plan indicator 11: Proportion of TB cases that were culture confirmed

Culture confirmation in pulmonary TB to target of 80%

The 2021 to 2026 TB action plan target is to increase the proportion of culture confirmation for pulmonary disease to 80% by 2024 to 2025.

Figure 1 shows the proportions of culture confirmation in persons with pulmonary TB from 2016 to 2021. In 2021, 74.4% (1,737 of 2,334) of people with pulmonary disease had their TB confirmed by culture, below the target of 80%. Culture confirmation rates over the longer period from 2002 to 2021 (TB diagnosis, microbiology and drug resistance in England dataset) demonstrate no consistent change over time.

Figure 1. Proportion culture confirmation in people with pulmonary TB, England, 2016 to 2021

Culture confirmation in non-pulmonary TB

Table 2 of the TB diagnosis, microbiology and drug resistance in England dataset shows the proportion of culture confirmed in people with non-pulmonary disease from 2000 to 2021. The proportion with culture confirmation in people with non-pulmonary disease is lower than for people with pulmonary disease. In 2021, only 45.6% of cases with non-pulmonary disease were culture confirmed in line with previous years.

Culture confirmation in all persons notified with TB: 5% year-on-year increase

In 2021, 2,690 of 4,425 (60.8%) of people notified with TB had their diagnosis confirmed by culture. The proportion has remained stable over the past 20 years (Table 2 of the TB diagnosis, microbiology and drug resistance in England dataset).

As well as the target of culture confirmation in pulmonary TB, an ambitious target for culture confirmation of all people with TB, pulmonary and non-pulmonary, was included in the collaborative action plan. A 5% year-on-year increase from an average (2020 to 2021) baseline of 61.15% is the target for culture confirmation of all people with TB. Over the next 4 years to 2025, this would result in just under 74.3% of all people with TB being culture confirmed.

In only 3 out of the last 10 years has there been a percentage increase in the proportion of people with culture confirmation compared with the previous year (Table 2 of the TB diagnosis, microbiology and drug resistance in England dataset), the largest being a 2.7% increase from 2015 to 2016. A better understanding of the factors that affect culture confirmation rates is required to inform the design of interventions to improve these rates.

Culture confirmation by UKHSA centre

Figure 2 shows the proportions of TB notifications with culture confirmation for all cases and those with pulmonary TB by UKHSA centre for 2021. London is the region closest to achieving the target of 80% culture confirmation of pulmonary TB at 79.6% (621 out of 780 people).

Table 3 of the TB diagnosis, microbiology and drug resistance in England dataset shows the proportions of culture confirmation for pulmonary and all TB disease notifications by UKHSA region over the period 2011 to 2021. Changes over time were not consistent between the regions, but there was a notable decrease for the South West for culture confirmation rates between 2020 and 2021; this may reflect changes in data feeds to NTBS and is being investigated. The London region has consistently achieved some of the highest proportions of culture confirmation with both 2020 and 2021 nearly achieving the 80% target for pulmonary TB.

Figure 2. Proportions of culture confirmation for all people with TB and for people with pulmonary TB by UKHSA centre, England, 2021

Note: The line at 80% indicates the action plan indicator 11 target of 80% for culture confirmation of pulmonary TB.

Culture confirmation by Integrated Care Boards (ICBs)

Table 4 of the TB diagnosis, microbiology and drug resistance in England dataset shows the proportions of culture confirmation for pulmonary and all TB disease notifications for the 42 ICBs over the period 2016 to 2021. ICBs were created in July 2022 from mergers of Clinical Commissioning Groups (CCGs). Here we report data using current Integrated Care Board boundaries to support future planning and evaluation. In 2021 the proportion of people with culture confirmed pulmonary TB was more than or equal to 80% in 10 ICBs and ranged from 28.6% (with the second lowest at 51.2%) to 100%. Changes over time were not consistent between ICBs.

Predictors of culture confirmation

To better understand factors associated with the probability of culture confirmation, the proportions of people with culture confirmation were compared by potential predictive factors such as age, sex and country of birth and the differences quantified by calculation of risk ratios. These are shown in Table 1 for all TB notifications and in Table 2 limited to pulmonary TB disease. This is because the predictive factors may differ in pulmonary disease, which is also the primary focus of efforts to improve culture confirmation rates.

As can be seen in Table 1, people with pulmonary disease were 63% more likely to be culture confirmed compared with those with non-pulmonary TB. Males compared with females were 14% more likely to be culture confirmed with 64.0% culture confirmation in males (1,716 of 2,682 people) compared with 55.9% in females (974 of 1,743 people).

Compared with people aged 15 to 44 years, all age groups (both younger and older) were less likely to be culture confirmed. This was much more so for children aged under 15 years, who had a 48% decreased probability compared with 8% to 9% decreased probabilities for the older age groups.

There is no evidence of place of birth (UK versus non-UK-born) being associated with the probability of culture confirmation. Also, the probability of culture confirmation by region did not significantly differ when compared with London apart from a decreased probability of 11% in East of England and 8% in the West Midlands.

Table 1. Predictors of culture confirmation (all TB notifications), England, 2021 (univariable analysis)

Predictor	Level	% Culture positive	Risk ratio	95% CI
Sex	Female	55.9	Reference	NA
Sex	Male	64.0	1.14	1.09 to 1.20
Pulmonary disease	Non pulmonary	45.6	Reference	NA
Pulmonary disease	Pulmonary	74.4	1.63	1.55 to 1.72
Age group (years)	15 to 44	63.9	Reference	NA
Age group (years)	0 to 15	33.3	0.52	0.41 to 0.67
Age group (years)	45 to 64	58.8	0.92	0.87 to 0.97
Age group (years)	65 and over	58.0	0.91	0.84 to 0.98
UK-born	Non-UK-born	61.5	Reference	NA
UK-born	UK-born	58.6	0.95	0.90 to 1.01
UKHSA centre	London	63.2	Reference	NA
UKHSA centre	West Midlands	58.1	0.92	0.85 to 0.99
UKHSA centre	South East	58.9	0.93	0.86 to 1.01
UKHSA centre	North West	59.7	0.94	0.87 to 1.02
UKHSA centre	East of England	56.0	0.89	0.80 to 0.98
UKHSA centre	East Midlands	66.2	1.05	0.96 to 1.14
UKHSA centre	Yorkshire and the Humber	57.1	0.90	0.82 to 1.00
UKHSA centre	South West	58.6	0.93	0.81 to 1.06
UKHSA centre	North East	69.1	1.09	0.94 to 1.27

When limited to people with pulmonary TB disease (2,334, 52.7% of TB notifications), the increased probability of culture confirmation in males remained (risk ratio 1.11, 95%CI, 1.05 to 1.16). Thus, the increased probability of males of having pulmonary TB (as seen in the risk factors for pulmonary TB section of TB incidence and epidemiology in England) does not explain the increased chance of males having culture confirmed TB overall.

The probability of culture confirmation in the different age groups was similar to that for all TB disease. However, the probability of culture confirmation for people born outside of the UK decreased by 9%.

The regional differences in the probability of culture confirmation were also more pronounced for pulmonary disease. When compared with London, 4 regions have a statistically significant decreased probability of culture confirmation. This demonstrates that differences in culture confirmation rates for all TB notifications were not solely the result of regional differences in the proportion of people with TB having pulmonary disease.

Table 2. Culture confirmation predictors for pulmonary disease, England, 2021 (univariable analysis)

Risk factor	Level of risk factor	% Culture positive	Risk Ratio	95% CI
Sex	Female	69.7	Reference	NA
Sex	Male	77.0	1.11	1.05 to 1.16
Age group (years)	15 to 44	78.4	Reference	NA
Age group (years)	0 to 15	40.0	0.51	0.38 to 0.68
Age group (years)	45 to 64	74.4	0.95	0.90 to 1.00
Age group (years)	65 and over	67.6	0.86	0.80 to 0.93
UK-born	Non-UK-born	61.5	Reference	NA
UK-born	UK-born	58.6	0.91	0.86 to 0.96
UKHSA Centre	London	79.6	Reference	NA
UKHSA Centre	West Midlands	70.7	0.89	0.82 to 0.96
UKHSA Centre	South East	69.9	0.88	0.80 to 0.96
UKHSA Centre	North West	76.6	0.96	0.89 to 1.04
UKHSA Centre	East of England	72.0	0.90	0.83 to 0.99
UKHSA Centre	East Midlands	73.5	0.92	0.84 to 1.01
UKHSA Centre	Yorkshire and the Humber	73.0	0.92	0.84 to 1.01
UKHSA Centre	South West	63.8	0.80	0.69 to 0.93
UKHSA Centre	North East	72.0	0.90	0.76 to 1.08

These results suggests that to achieve an increase in culture confirmation in pulmonary TB, in line with the action plan target, understanding of the variation and its causes between different groups and services will need to be developed and acted on.

Determination of Mycobacterium tuberculosis complex (MTBC) species

In 2021, 2,690 people (60.8% of notifications) had their TB successfully cultured, sequenced and the species within the MTB complex identified.

In 2021:

• 97.2% (2, 615) were identified as Mycobacterium tuberculosis (M. tuberculosis)
• 0.9% (23) were identified as Mycobacterium bovis (M. bovis)
• 1.8% (49) were identified as Mycobacterium africanum (M. africanum)
• 0.04% (1) were identified as Mycobacterium microti (M. microti)

There were 2 culture positive isolates which could not be identified below the level of Mycobacterium tuberculosis complex (Table 5 of the TB diagnosis, microbiology and drug resistance in England dataset).

Identification and classification of drug resistance

All people with culture confirmed TB have drug sensitivity predictions conducted through WGS for first line drugs (rifampicin, isoniazid, pyrazinamide, and ethambutol), plus aminoglycosides and fluoroquinolones.  Identification and reporting of drug resistance using WGS is more rapid than conventional phenotypic drug susceptibility testing (pDST). However, pDST is still performed for second line drugs if first line resistance is detected by WGS, or if WGS does not give complete results for first line drugs.

Results from these tests are presented in this report, along with the total number of people who were treated with a multi-drug resistant TB regimen in the absence of laboratory confirmation of resistance.

Drug sensitivity testing

In 2021, 97.2% (2,615 out of 2,690) of people with culture confirmed TB had susceptibility results for at least isoniazid and rifampicin reported (Table 6 of the TB diagnosis, microbiology and drug resistance in England dataset). This is the lowest observed between 2011 and 2021 (the range during previous years was 99.5% in 2015 to 98.1% in 2020).

Action plan indicator 12: Proportion of culture confirmed notifications with drug susceptibility testing reported for all first-line drugs

Indicator 12 is a historic indicator retained since the previous TB Strategy for 2015 to 2020.

Figure 3 shows the proportion of persons with culture confirmed TB with results for at least isoniazid and rifampicin and for all first line drugs reported in NTBS from 2016 to 2021.

In 2021, this proportion was 97.1%, similar to the previous year (97.6%), but lower than the peak in 2015 when 99.4% were reported.

Figure 3. Proportion of persons with culture confirmed TB with results reported for all first-line drugs, England, 2016 to 2021

Action plan indicator 13: Proportion of culture confirmed notifications with any first-line drug resistance

Indicator 13 is a historical indicator retained since the previous TB strategy 2015 to 2020.

Figure 4 shows the proportions of persons with culture confirmed TB with resistance to any first line drug (rifampicin, isoniazid, pyrazinamide or ethambutol) for those with reported sensitivities for all 4 drugs. In 2021, 9.9% (267 out of 2,690) people had resistance to at least one first line drug, similar to 2020 at 10.6%.

Figure 4. Proportions of persons with culture confirmed TB with resistance to any first-line drug (rifampicin, isoniazid, pyrazinamide or ethambutol), England, 2016 to 2021

In 2021, for individual first line antibiotics in the 2,690 people with culture confirmed TB:

• 7.3% of people had resistance to isoniazid
• 1.9% of people had resistance to rifampicin
• 2.0% of people had resistance to ethambutol
• 3.2% of people had resistance to pyrazinamide

Table 7 of the TB diagnosis, microbiology and drug resistance in England dataset shows these proportions over time from 2011 to 2021. The proportion of TB cultures resistant to ethambutol has generally increased over this period from 0.9% in 2011. Pyrazinamide resistance has increased since 2017 corresponding with the introduction of new methodology due to the recognition that TB strains from a particular branch (‘lineage 1- East African-Indian Ocean’) have resistance mechanisms which were not detected by the previous genotypic methods. No clear trends were apparent over this period for isoniazid or rifampicin.

Isoniazid resistance without MDR-TB at diagnosis

Figure 5 and Table 8 of the TB diagnosis, microbiology and drug resistance in England dataset show the numbers and proportions of people with isoniazid resistance without MDR or RR TB (hereafter referred to as isoniazid monoresistance (INH-R)) and with MDR or RR TB for the period 2011 to 2021. The proportion of people with initial INH-R in 2021 was 5.6% (150 out of 2,690) people, a decrease compared with the previous 3 years at 6.4% or 6.5%.

Table 3 shows the proportions of people with INH-R by demographic and disease characteristics for 2021. INH-R was more common in females (6.4%) compared with males (5.1%). It was highest in those aged 45 to 64 years (6.8%) compared with other age groups. The most frequent countries of birth for individuals with INH-R TB were the UK (37), India (35) and Pakistan (16).

The UKHSA centre with the highest proportion of INH-R between 2017 and 2021 (aggregated numbers) was London at 7.6% or 392 out of 5,168 culture confirmed cases (Table 9 of the TB diagnosis, microbiology and drug resistance in England dataset). Just over a quarter of these cases (27.2%) were in the single largest INH-R cluster.

Figure 5. Number and proportion of people notified with culture confirmed TB with initial drug resistance to isoniazid alone and with multidrug resistant or rifampicin resistant TB (MDR or RR TB), England, 2011 to 2021

Table 3. Number and proportion of people with drug resistant TB by demographic and TB disease characteristics for those with culture confirmed TB, England, 2021

Characteristic	Total number	Isoniazid resistance without MDR-TB	MDR or RR TB
Sex: Female	974	62 (6.4%)	16 (1.6%)
Sex: Male	1,716	88 (5.1%)	35 (2.0%)
Age: 0 to 14 years	43	0 (0.0%)	4 (9.3%)
Age: 15 to 44 years	1,586	89 (5.6%)	28 (1.8%)
Age: 45 to 64 years	703	48 (6.8%)	16 (2.3%)
Age: 65 years and over	358	13 (3.6%)	3 (0.8%)
Country of birth: India	596	35 (5.9%)	12 (2.0%)
Country of birth: United Kingdom	588	37 (6.3%)	7 (1.2%)
Country of birth: Pakistan	267	16 (6.0%)	3 (1.1%)
Country of birth: Romania	160	4 (2.5%)	1 (0.6%)
Country of birth: Somalia	67	0 (0.0%)	4 (6.0%)
Country of birth: Nigeria	47	5 (10.6%)	1 (2.1%)
Country of birth: Lithuania	25	2 (8.0%)	4 (16.0%)
At least one social risk factor	433	35 (8.1%)	8 (1.8%)
No social risk factors	2,257	115 (5.1%)	43 (1.9%)
No previous TB diagnosis	2,388	134 (5.6%)	40 (1.7%)
Previous TB diagnosis	111	4 (3.6%)	7 (6.3%)
Pulmonary TB: No	953	58 (6.1%)	14 (1.5%)
Pulmonary TB: Yes	1,737	92 (5.3%)	37 (2.1%)

Note: 1. Only the most frequent countries of birth are analysed.
2. Country of birth is included if 4 or more people had either isoniazid resistance without MDR-TB or MDR or RR TB, ordered by number of people with a result.
3. Total number is 2,690, number isoniazid resistance without MDR-TB is 150, number MDR or RR TB is 51.
4. Data is missing for 191 people for previous TB diagnosis.

MDR or RR TB (at diagnosis)

Figure 5 (and Table 8 of the TB diagnosis, microbiology and drug resistance in England dataset) shows the numbers and proportions of people with MDR or RR TB for the period 2011 to 2021. In 2021 the proportion of MDR or RR TB decreased to 1.9% (51 people) from a peak prevalence in 2020 of 2.1% (54 people) but with no evidence of a clear trend over the period 2011 to 2021.

Table 3 shows the numbers and proportions of MDR or RR TB by demographic and TB disease characteristics. The proportion of MDR or RR TB was slightly higher in males compared with females and in those with pulmonary TB. It was considerably higher in those with a reported history of a previous TB diagnosis, compared with those with no previous TB diagnosis and in children. The most common country of birth for those with MDR or RR TB was India with 12 people. The majority of people with MDR or RR TB were not born in the UK (86.3%).

Table 9 of the TB diagnosis, microbiology and drug resistance in England dataset shows the aggregated numbers and proportions of MDR or RR TB by UKHSA centre for the period 2017 to 2021. The East of England had the highest proportion of people with MDR or RR TB at 2.5%. This is compared with 1.5% of people in the South East, 1.6% in the South West and 1.7% in London, the West Midlands, the East Midlands and the North East.

Table 10 of the TB diagnosis, microbiology and drug resistance in England dataset shows the numbers and most common countries of birth for those with MDR-RR TB sub-divided into extended groupings of drug resistant TB (resistant to all first line drugs, pre-XDR and XDR-TB) aggregated across 2017 to 2021. Whilst most people notified with MDR or RR TB from 2017 to 2021 were born in India (53 notifications), a greater proportion of people with MDR or RR TB born in Lithuania (23 notifications) and Romania (13 notifications) were resistant to all first line drugs (65.2% and 64.3%).

Acquired resistance to rifampicin or MDR TB

Table 4a shows the numbers of people who acquired MDR or RR TB after initial diagnosis from 2011 to 2021. In 2021 there were no cases of acquired resistance.

Total MDR or RR TB treatment cohort

Tables 4a and 4b shows the number and proportion of the total MDR or RR TB cohort out of all TB notifications for years 2011 to 2021. This includes those with culture confirmed resistance at diagnosis, acquired during treatment and those who were treated for MDR or RR TB in the absence of culture confirmation. The latter may occur if MDR or RR TB was diagnosed abroad or if the person was a close contact of another person with MDR or RR TB. The number of people treated for MDR or RR TB in 2021 was 77, the highest since 2013. The proportion of all cases treated for MDR or RR in 2021 was 1.7% (CI 1.4 to 2.2), the highest of any year from 2011 apart from 2020.

Table 4a. Number of people with MDR or RR TB confirmed by culture (at diagnosis and acquired), England, 2011 to 2021

Year	Initial resistance	Acquired resistance	Total
2011	89	4	93
2012	86	2	88
2013	78	1	79
2014	58	4	62
2015	54	1	55
2016	60	1	61
2017	55	1	56
2018	44	2	46
2019	52	0	52
2020	54	1	55
2021	51	0	51

Table 4b. Number of people treated as MDR or RR with proportion as percentage of all people notified with TB, England, 2011 to 2021

Year	Number	Proportion	Lower CI	Upper CI	Total cases
2011	100	1.2	1.0	1.5	8,281
2012	95	1.2	0.9	1.4	8,087
2013	86	1.2	0.9	1.5	7,265
2014	75	1.2	0.9	1.5	6,470
2015	65	1.1	0.9	1.4	5,734
2016	70	1.2	1.0	1.6	5,618
2017	65	1.3	1.0	1.6	5,067
2018	54	1.2	0.9	1.5	4,610
2019	68	1.4	1.1	1.8	4,705
2020	75	1.8	1.4	2.3	4,123
2021	77	1.7	1.4	2.2	4,425

Note: 1. Rifampicin resistant or MDR includes people with culture confirmed TB with a result of resistant (drug sensitivity testing or WGS) for at least rifampicin at diagnosis (initial resistance).
2. Acquired resistance can occur after a result of resistant to at least rifampicin after a result of sensitive or unknown at diagnosis.
3. Total MDR or RR cohort includes people with initial or acquired MDR or RR TB and people treated with a second line regimen in the absence of culture confirmed resistance in NTBS.

Pre-XDR and XDR TB

In 2021, of 51 people with culture confirmed MDR-TB, there were 14 (27.4%) that were confirmed as pre-XDR (resistant to rifampicin and fluoroquinolones). There were 2 cases that were XDR (3.9%), both resistant to linezolid. The proportions are not directly comparable to 2020 as this report uses the new WHO definitions of pre- XDR and XDR TB.

For the years 2017 to 2021, the most common countries of birth for those with pre-XDR and XDR was the UK, but with a greater proportion of those born in Lithuania having pre-XDR (39.1% of 23 people). The 2 cases of XDR occurred in people born in the UK (Table 10 of the TB diagnosis, microbiology and drug resistance in England dataset).

Identification of isolates in a cluster

WGS was introduced to all of England in 2018 and is used to identify people with TB whose isolates cluster together.

Table 5 shows the number of people identified whose TB was in a cluster with at least one other person’s sample(s) between 2018 and 2021. 22.1% (3,938 of 17,863) of individuals were allocated to a cluster between 2018 and 2021. The proportion of individuals in a cluster in 2021 was 19.8%. This is the lowest number and proportion of people with TB that were part of a cluster since 2018 when country-wide sequencing started and is significantly lower than 2018 and 2019. This may be a result of a change in transmission patterns during the pandemic, or less culture confirmation of clustered individuals.

Table 5. Number of people notified, proportion with culture confirmation and proportion of notifications identified in a cluster with more than one other person in England, 2018 to 2021

Year	Total notified	Total cultured	Number (%) identified in a cluster with more than one person	95% CI
2018	4,610	2,866 (62.2%)	1,070 (23.2%)	22.0 to 24.5
2019	4,705	2,897 (61.6%)	1,108 (23.6%)	22.3 to 24.8
2020	4,123	2,537 (61.5%)	882 (21.4%)	20.1 to 22.7
2021	4,425	2,690 (60.8%)	878 (19.8%)	18.7 to 21.0
Total	17,863	10,990 (61.5%)	3,938 (22.1%)	21.4 to 22.7

Species in clusters

Between 2018 and 2021, 98.2% of isolates that clustered were identified as M. tuberculosis (3,878 of 3,938). There were 40 clustered isolates of M. bovis (1% of clustered isolates) and 20 of M. africanum (0.5%). In 2021, there were 864 clustered isolates of M. tuberculosis, and 7 each of M. bovis and M. africanum.

Resistance in clusters

In 2018 to 2021, INH-R was the most common drug resistance pattern found in 229 (5.8%) of clustering isolates. A single large cluster contributed 59 (25.8%) of these cases. The next 3 largest INH-R clusters contributed a further 12% of cases.

Of 684 isolates with INH-R, a third were in a cluster. This shows that while there were several large isoniazid resistant clusters in England, there were also multiple circulating INH-R strains causing clustering and a majority of INH-R isolates that did not cluster, suggesting frequent generation or importation of new INH-R strains.

In 2018 to 2021 MDR or RR TB occurred in 64 (1.6%) of clustering isolates, representing 31.8% of all MDR or RR notifications in this period.

Clustering of isolates by UKHSA centre

Figure 6 and Table 11 of the TB diagnosis, microbiology and drug resistance in England dataset show the number and proportion of isolates in a cluster in each UKHSA centre. In 2021, the highest proportion of isolates in a cluster was in the West Midlands (26.6%) and the lowest in the North East (16.1%). However, the proportion of cases clustering is also dependent on the numbers and proportions of culture confirmed notifications that varies by UKHSA centre. Also, because this analysis looks at clustering with a previous case from any date, it is likely that the proportions were higher for the West Midlands due to the longer time period of routine WGS in this region, as this is where routine WGS was piloted.

Figure 6. The proportion of people in a cluster by UKHSA centre, England 2018 to 2021

Predictors of being in a cluster

Table 12 of the TB diagnosis, microbiology and drug resistance in England dataset shows risk ratios of potential risk factors for being in a cluster using aggregated data from 2018 to 2021. Isolates from people with pulmonary TB were more than 3 times more likely to be clustered. Isolates from people with social risk factors were also more likely to be in a cluster, with the exception of people who were asylum seekers. Isolates from people in less deprived areas were less likely to be clustered. Individuals with pulmonary disease are the most likely to be infectious and so transmit TB to other people, resulting in clustering.

Clustered cases between 2018 and 2021 were less likely to be aged under 15 years or reside in the least deprived areas and more likely to have social risk factors. Public health interventions to interrupt transmission need to focus on the highest risk groups for clustering.

Recommendations

Recommendation 1

UKHSA should complete a national audit of diagnostic laboratories planned for 2023 to 2024. Diagnostic pathway should be included in the GIRFT review planned for 2023 to 2024, best practice identified and disseminated to TB services.

Recommendation 2

Local services should use outcome of laboratory audit and GIRFT report to optimise microbiological diagnosis.

Recommendation 3

Baseline for culture confirmation proportions for regions and services should be set on 2021 data and performance against baseline incorporated into future reporting.

Recommendation 4

Local services should identify actions to improve their culture confirmation rates from baseline. This may require increased focus on groups with lower culture confirmation rates. Efforts should be intensified by the UKHSA national team to develop systems for access to clustering data for local TB services in 2023 to 2024.

Recommendation 5

UKHSA health protection teams should ensure systems are in place for reviewing clustering data and public health actions needed with local teams.

How these recommendations support the action plan priorities

These recommendations will support the following action plan priorities.

3.3.1a: Monitor and report annually on the target of 100% compliance in PCR use in accordance with NICE guidance in all pathology networks or TB services (paediatrics and adults) for all pulmonary or infectious TB cases.

3.3.2: Increasing the proportion of culture confirmed cases, nationally and regionally.

3.4.1: Through the use of surveillance data and WGS diagnostic capabilities, monitor and reduce transmission of TB.

3.4.2a: 100% culture positive TB cases have WGS relatedness data reviewed as part of decisions around contact tracing or public health intervention annually.

Methodology and important definitions

General methodology for TB notifications, data production, cleaning and reporting are described in the methodology and definitions section of TB incidence and epidemiology an England in 2021.

Diagnostic and laboratory tests

Data for TB isolates from the National Mycobacterial Reference Service (NMRS) are matched to TB notifications. Isolates are de-duplicated and summarised to only count one isolate per TB notification per notification period.

NTBS also includes user-entered fields to record whether a culture sample and other diagnostic tests, such as PCR, were undertaken and the results of these tests. These data fields are combined to generate a final test status variable for the different tests for all the notified cases.

Culture and other diagnostic test results are then reported as follows.

Any test performed

Yes: Any value recorded in NTBS of any test type variables (culture, PCR, microscopy, histology, or chest X-ray), test result and date of test regardless of result.

No: No recorded value of variables of test type, test result and date of test.

Any test positive

Yes: Positive test result recorded for any test type (culture, PCR, microscopy, histology or chest x-ray).

No: No results or negative test result recorded to all test types (as above).

Culture confirmed

Culture confirmed: Supported by NMRS laboratory result of a positive culture for MTBC.

Culture unconfirmed: Negative culture, or no NMRS results for culture, surveillance system states no culture undertaken, no other supporting information.

Speciation

Species defined as M. tuberculosis, M. bovis, M. microti, M. africanum or Mycobacterium tuberculosis complex (MTBC).

MTBC is assigned to those not fully speciated by previous PCR based methods or WGS. The introduction of WGS has decreased the number of notifications in this category.

Drug resistance

The resistance reported follows this classification. All resistance proportions use the number of culture positive cases as the denominator.

• rifampicin resistance or multidrug resistant TB (RR or MDR TB) is defined as resistance to rifampicin with or without isoniazid resistance
• isoniazid mono-resistance is defined as resistant to isoniazid but not reported as resistant to rifampicin
• pre-extensively drug resistant TB (pre-XDR TB) is TB strains which fulfil the definition of multidrug resistant or rifampicin-resistant TB (MDR or RR TB) and which are also resistant to any fluoroquinolone (levofloxacin and or moxifloxacin plus historically used levofloxacin and ofloxacin)
• extensively drug resistant TB (XDR TB) are strains that fulfil the definition of MDR or RR TB and which are also resistant to any fluoroquinolone and at least one additional Group A drug in the WHO updated classification (Group A drugs are the most potent group of drugs in the ranking of second-line medicines for the treatment of drug-resistant forms of TB using longer treatment regimens and comprise levofloxacin, moxifloxacin, bedaquiline and linezolid)

Isolates may be resistant to other antibiotics in addition to those described above.

Laboratory confirmed resistance

Resistance is reported as either resistant or sensitive. Testing is by whole genome sequencing alone or in combination with phenotypic testing. Discordances between the 2 testing methods were resolved by the reference laboratory and the reported value is used for this data analysis. The denominator for all resistance proportions is culture positive notifications, for example known resistance reported as a proportion of culture positive cases (regardless of whether the others were sensitive or unknown resistance).

M. bovis is intrinsically resistant to pyrazinamide.

The designation of resistance using genomics relies on a database of known resistance. A change in the pncA gene (gene encoding pyrazinamidase) associated with lineage 1 confers resistance to pyrazinamide. Isolates that are lineage 1 with changes in above gene are checked using phenotypic methods and coded as resistant if resistant by phenotype and sensitive by WGS.

Where ethambutol and pyrazinamide results are missing or unknown (and not lineage 1 for pyrazinamide) but results are known to be sensitive for isoniazid and rifampicin, these are coded as sensitive for ethambutol and pyrazinamide.

Acquired resistance

This is resistance in a person with more than one sample over time where the first sample shows sensitivity to a given drug and second sample is resistant.

Treated as resistant

This includes notifications that have no culture result but are recorded in NTBS, or the multidrug resistance database, or comments in NTBS indicate the individual has been treated as MDR with a second line drug regimen (for example, contacts of MDR individuals with active TB treated for MDR).

Total MDR or RR cohort

This includes both those with culture confirmed MDR or RR TB and those who were treated as resistant with second line drug regimen.

Clustering isolates

WGS was implemented for all of England in 2018. Results are available only if the isolate was successfully cultured. An isolate is defined as being in a cluster if it has 12 or fewer genetic differences (known as single nucleotide polymorphisms or SNPs) between it and another isolate that has previously been sequenced.

More detail on UKHSA’s approach to WGS-based typing is found in the WGS handbook.

The current database includes samples from devolved nations and research samples; therefore, we report positive clusters where there is more than one person in the cluster from England. The definition for clustered is:

Yes: 12 SNPs or fewer from another person’s sample and there is more than 1 person resident in England in the cluster.

No: The sample is 12 SNPs or more from any other person’s sample that has been sequenced in the UKHSA database.

However, the proportions of notifications clustered are reported as the percentage of clustered isolates (corresponding to a single notification) as a percentage of all notifications. This is also used for the risk ratio analysis of risk of a notification being in a cluster.

Note that contacts may be identified and assumed to be in clusters based on epidemiological information obtained through contact tracing. However, only those with active disease and WGS information are reported here.

Statistical methods

Confidence intervals

95% confidence intervals are model derived and were calculated using assumptions of the binomial distribution for proportions.

Risk ratios

Risk ratios are model derived using the binomial distribution for proportions.

Software packages

All statistical analysis was carried out using Stata SE 17.0. ArcGIS 10.5 was used to produce all maps shown in the report.

Glossary

Pulmonary TB

A person with pulmonary TB is defined as having TB involving the lungs and/or tracheo-bronchial tree, with or without extra-pulmonary TB diagnosis. In this report, in line with the WHO’s recommendation and international reporting definitions, miliary TB is classified as pulmonary TB due to the presence of lesions in the lungs, and laryngeal TB is also classified as pulmonary TB.

Social risk factor

Social risk factors for TB include current alcohol misuse, current or history of homelessness, current or history of imprisonment, current or history of drug misuse, current mental health needs, or current status as an asylum seeker or detainee in an immigration removal centre. Please see the reporting methodology in TB incidence and epidemiology in England for further details of these variables.

95% confidence Interval

In this report, model derived 95% confidence intervals (CI) are often presented alongside percentages and rates. For example, the percentage of TB notifications with pulmonary disease is 52.7% (95% CI 51.3 to 54.2%). This can be loosely interpreted as having a 95% confidence that the true but unknown value of this percentage in the population lies within the range of 51.3% to 54.2%. 

Risk ratios

Risk ratios quantify the relative risk of the outcome we are interested in between 2 different groups. For example, the relative risk of pulmonary disease in males compared with females. This is calculated as the proportion of males with pulmonary disease divided by the proportion of females with pulmonary disease, which is a risk ratio of 1.18 (95% CI 1.11 to 1.25). This is interpreted that males have an 18% increased risk of pulmonary disease compared with females and we have 95% confidence that the true increased risk lies within the range of 11% to 25%.

If a 95% CI for a risk ratio includes the value of 1.0 then we cannot infer that the true RR is different from 1. Thus, we would say that these results are not providing any evidence that the observed magnitude of the risk ratio is ‘statistically important’.

If a risk ratio of less than 1.0 is reported, such as risk ratio 0.85, this is interpreted that the group of interest have a 15% reduced risk of the outcome.