INFECTION

Clinical tuberculosis Key points

Adam Ainley C Tuberculosis (TB) remains one of the top 10 causes of death
Onn Min Kon globally

C Underserved populations make up 12.6% of all TB cases in the

UK, and have a rate of TB >3 times the national average
Abstract
In 1993 the World Health Organization declared tuberculosis (TB) a
C Underserved patients have higher TB-related death and lower
global public health emergency, and yet 26 years later it remains a sig-
treatment completion rates
nificant public health issue globally and nationally within the UK.
Although the overall incidence and mortality have improved, there re-
C Patients born in the UK are 2.5 times more likely to have at
mains considerable work to tackle both an underserved population
least one social risk factor associated with TB infection than
who present unique and complex challenges, and the continuing
patients who were born elsewhere
threat from drug resistance. Within the UK and worldwide, numerous
stakeholders have established networks, guidance and frameworks
C Without treatment, 5e10% of people with latent infection
to facilitate a more targeted and standardized approach to the detec-
progress to active disease during their lives, commonly within
tion, diagnosis and management of patients. Furthermore, novel diag-
the first 5 years after infection
nostic tools and treatments aim to reduce the burden of disease, with
the ultimate aim of eradicating TB.
C The pursuit of a microbiological diagnosis is important given
Keywords Latent tuberculosis; multidrug-resistant; rifapentine; the growing issue of drug resistance
tuberculosis; underserved populations; whole-genome sequencing

there is an MDR-TB profile of resistance as well as resistance to

any fluoroquinolone and at least one second-line injectable, ac-
Global and UK trends in tuberculosis (TB) counts for 7.4% of all DR-TB cases globally.1 Of significance,
treatment success in this cohort is only 55% compared with 82%
TB worldwide globally,1 further highlighting the concern regarding drug
Globally, the burden of disease from TB has fallen, with inci- resistance.
dence dropping approximately 2% per year and TB-associated
death rates falling by 29% since 2000.1 However, the decline is
still much slower than aimed for by the World Health Organi- TB in the UK
zation (WHO) ‘End TB’ strategy. TB remains one of the top 10 Up until 2017 the UK consistently reported a rising number of TB
causes of death globally. In 2017 an estimated 1.3 million (HIV- cases yearly, with an overall incidence of 13.4 per 100,000 in
negative) people died from TB while an estimated 10 million 2014.2 Since then the overall incidence has continued to fall to a
people developed the disease.1 Significantly, most cases (66%) current reported rate of 8.3 per 100,000 population, and since
were distributed across only eight countries of high TB incidence 2017 the UK has been defined as a low-incidence (<10 per
(incidence >40 per 100,000), with only 3% of global cases re- 100,000) setting. DR-TB within the UK is of a lower proportion
ported within the European Region, thus demonstrating the than that globally, with only 47 cases reported in 2018, four of
variability in epidemiology of the disease.1 which were reported as being XDR-TB. Interestingly, however,
Despite improvements in overall TB rates, drug resistance there was a rise in the proportion of isoniazid-resistant TB cases
continues to be of major concern. Up to 558,000 cases of TB that were not considered MDR cases, from an average 5.4% over
notified in 2017 were thought to be rifampicin-resistant TB (RR- the last 10 years to 6.6%. In patients with drug-sensitive TB,
TB), with 82% of these also being multidrug-resistant TB (MDR- treatment completion rates remain stable at 84.7%, with TB-
TB), in which there is resistance to rifampicin and isoniazid with related deaths in 5.3% of cases overall.2
or without resistance to other first-line medications.1 Around 3% Although the overall population data are encouraging, they
of cases of drug-resistant TB (DR-TB) were thought to represent mask a great disparity between the general population and sub-
new cases, while 18% were considered to have been previously sections of the country, in particular large urban communities
treated for TB. Extensively drug-resistant TB (XDR-TB), when such as London, Birmingham and Leicester, where rates of TB
are estimated to be >3 times the national average.3 Notably,
there is a rising proportion of persons classified as being from an
Adam Ainley MBBS BSC MRCP is a Respiratory SpR/Clinical Research ‘underserved population’, to 12.6% of overall TB cases in 2017 e
Fellow at the NIHR HPRU in Respiratory Infections, Imperial College the highest proportion since 2010 (Figure 1).3
London, UK. Competing interests: none declared. Underserved populations are likely to experience social
deprivation and/or have risk factors such as drug and alcohol
Onn Min Kon MBBS MD FRCP is a Respiratory Physician at Imperial
College London Healthcare NHS Trust, and Professor of Respiratory misuse, mental health needs, homelessness or contact with the
Medicine at Imperial College London, UK. Competing interests: none criminal justice system, or to be from specific migrant subcohorts
declared. including asylum-seekers, refugees or individuals held in

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 INFECTION

Number and proportion of people with TB (aged ≥15 years) who had
social risk factors by place of birth 2013–2017

1600 20
1400

Proportion of people (%)

1200 15
Number of people

1000
800 10
600
400 5
200
0 0
Drug Alcohol Homeless- Prison ≥1 SRF ≥2 SRF
misuse misuse ness

Social risk factor

UK born Non-UK born Proportion

Figure 1 Number and proportion of people with TB (aged 15 years) who had social risk factors by place of birth 2013e2017. Source: Reproduced
with permission from Public Health England (2019).3

immigration centres. Patients born in the UK are 2.5 times more Latent infection (LTBI) is defined when there is no clinical ev-
likely to have at least one social risk factor than patients who idence of active disease despite a state of persistent immune
were born elsewhere.3 response to TB antigens. Although this is commonly detected by
It is important to recognize patients defined as ‘underserved’ measuring an adaptive immune response to M. tuberculosis an-
as they have a higher likelihood of developing pulmonary disease tigens using interferon-g release assays or tuberculin skin tests,
(77%) and TB-related death (6.2% versus 4%) and have also there is no clear gold standard test. A positive result suggests
been found to have lower treatment completion rates (78.7% exposure to M. tuberculosis but does not help to distinguish be-
versus 89.1%).3 ‘Underserved’ groups often find it more difficult tween active and latent infection. As a result, defining the global
to access services, subsequently leading to delays in diagnosis burden of latent infection is problematic, although the WHO
and treatment, and higher loss to follow-up rates, than those estimates one-third of the world’s population to be infected.
outside the cohort (9.2% versus 3.1%).3 Recognizing the need to Latent TB can eventually progress to active disease, the stron-
address the complex challenges posed by this population, several gest risk factor clinically in immunocompetent patients being the
approaches have been employed to allow services to be more duration since infection. Around 5e10% of people infected prog-
adaptable; these include TB-specific outreach teams, innovative ress to active disease during their lives, commonly within the first 5
methods of providing directly observed therapy and personalized years after infection. However the risk of progression is highest
local solutions. within the first 2 years, with an annual risk of 1.5%, which falls to
0.1% thereafter. Other risk factors for disease progression include
Patterns of disease immunomodulatory therapies, immune suppressive conditions
such as diabetes mellitus and HIV, and older age.
Defining disease Defining whether LTBI has been recently or remotely acquired
Mycobacterium tuberculosis can affect individuals in a spectrum has the potential to allow clinicians to more accurately assess
of ways, and our ability to define stage of disease is evolving as risk of progression and therefore stratify treatment/in-
research continues to inform our understanding (Figure 2). terventions. However, whilst many research studies have been
Broadly speaking, individuals respond to infection with M. undertaken to explore means of more accurately demonstrating
tuberculosis either by eliminating the initial infection or, if the the timeline of infection, such as the use of biomarker analysis, a
bacterium persists, developing either active or latent disease. gold standard method has yet to be established.

Active disease arises when the initial infection progresses, Clinical patterns
leading to clinical evidence of either pulmonary or other organ Pulmonary TB remains the most common presentation (57.3%
disease that may also be accompanied by positive microbiolog- cases within the UK),2 with classical symptoms involving cough,
ical culture for M. tuberculosis or consistent histological findings. fever, night sweats and weight loss. Although often considered

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 INFECTION

The spectrum of Mycobacterium tuberculosis from exposure to disease: symptomology, infectivity and
likely diagnostic test results

Exposure Infection eliminated

Latent TB Subclinical Active
to MTb Innate Adaptive infection disease disease
immune response immune response

Symptoms None None None Mild/asymptomatic Mild to severe

Infectious No No No Possibly/intermittently Yes

Smear +ve No No No Possibly Possibly

TST +ve No Yes Yes Yes Usually
IGRA +ve No Yes Yes Yes Usually
Culture +ve No No No Intermittently Yes

Figure 2

typical, haemoptysis may not be a feature and the cough is often, validation of molecular methods since many assays have the
especially within early stages of onset, non-productive in nature. benefit of allowing for detection of both M. tuberculosis and
Spread elsewhere constitutes extrapulmonary disease (EP-TB); associated resistance in a more clinically relevant time frame.
this can present in virtually any organ, with lymph nodes being
the most common site (Table 1).
In the UK culture confirmation is most commonly achieved in Number of people with TB by site of disease, England
patients with pulmonary disease (74%, versus 44% in patients 2018
with EP-TB). Diagnosis is made based on the clinical and/or
Site of diseasea Number of cases Percentageb
radiological features only in 31% of patients.2 It is important that
clinicians pursue a microbiological diagnosis if possible, given Pulmonary 2664 57.3
the growing issue of drug resistance. Miliary 116 2.5
Laryngeal 12 0.3
TB diagnostics e where are we now? Extra-pulmonary 2759 59.3
One key pillar of the WHO ‘End TB’ strategy is directed at the Extra-thoracic lymph nodes 958 20.6
development and uptake of newer diagnostic tools, in particular Intra-thoracic lymph nodes 575 12.4
rapid point-of-care diagnostics. Despite several molecular and Unknown extra-pulmonary 735 15.8
immune-based diagnostic approaches having been used in the Pleural 418 9.0
UK, microbiological diagnosis is still only established in 69% of Other extra-pulmonary 410 8.8
cases.2 Currently, only 8% of diagnoses are made by means other Gastrointestinal 254 5.5
than culture, including by polymerase chain reaction (PCR), Bone (spine) 147 3.2
microscopy or histology.2 With the continuing threat from DR- Bone (not spine) 90 1.9
TB, tests that facilitate an early, accurate and comprehensive CNS (meningitis) 98 2.1
profile of resistance are vital in a time when only 30% globally of CNS (other) 76 1.6
overall notified TB cases are tested for rifampicin resistance.1 As Genitourinary 93 2.0
a means of standardizing approaches, the WHO has implemented Cryptic disseminated 31 0.7
an endorsement process by which diagnostic tests are reviewed CNS, central nervous system.
by a panel of experts before they can be recommended for use. a
With or without disease at another site.
b
Proportion of people with TB for which sites of disease were known
Molecular approaches (4,651): total may exceed 100% due to disease at more than one site.
Although sputum smear and culture are still used, results can Source: Reproduced from Public Health England. Tuberculosis in England:
take up to 2 days and 8 weeks, respectively. Furthermore, drug 2018. London: Public Health England, London. Page 36 with permission.
sensitivity testing takes significantly longer, adding an additional
2e3 weeks. As a result, focus remains on the development and Table 1

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 INFECTION

The XpertÒ MTB/RIF (Cephid, CA, USA), an automated rapid centralized laboratories. The FluoroTypeÒ MTBDR (Hain, Life-
assay that detects genetic material and mutations within M. science, Germany) is one such assay. It uses a multiplex PCR and
tuberculosis, is currently the most used first-line method for fluorescence-based detection approach to detect M. tuberculosis
diagnosis, particularly for smear-positive cases. Whilst having a complex and isoniazid and rifampicin resistance, and has been
lower sensitivity in patients who are smear negative or suspected shown to be useful in smear-negative samples. A number of further
of having EP-TB it is important to note that the XpertÒ MTB/RIF molecular methods are in development, including the XpertÒ XDR-
is still considered to be a more effective means of diagnosis than TB cartridge (Cepheid) and FluoroTypeÒ XDR-TB Assay (Hain
smear testing. In 2017, the WHO recommended the use of an Lifescience, Germany); these feature assays that allow a broader
updated assay, the XpertÒ MTB/RIF Ultra test; despite a 2% spectrum of resistance profiling to include XDR cases.
reduction in specificity, this demonstrated an improved sensi- In keeping with the WHO ‘End TB’ strategy, a number of
tivity overall, in particular for central nervous system disease point-of-care strategies aimed at decentralizing diagnostic ap-
(70% for Ultra versus 43% with XpertÒ MTB/RIF) and in HIV- proaches have been endorsed. These include methods such as
positive patients. The detection of rifampicin resistance is urinary detection of lipoarabinomannan, a substrate TB protein
similar for both tests, at 95%. A further version of the assay, the which has been shown to improve diagnosis and guide initiation
XpertÒ XDR, is awaiting WHO endorsement and offers the ability of anti-tuberculosis treatment in patients with HIV and low CD4
to detect not only M. tuberculosis, but also resistance mutations counts. As a means of decentralizing molecular assays and
to isoniazid, second-line injectables and fluoroquinolones. allowing molecular methods to be implemented in remote and
Other molecular methods using nucleic acid amplification low/middle income settings Cepheid is developing benchtop
methods and line probe assays that detect drug resistance have also point-of-care platforms such as the GeneXpertÒ Omni and have
been employed; however, these are currently available only in already launched the GeneXpertÒ Edge a portable system for

CHOOSING THE MDR-TB TREATMENT REGIMEN IN PATIENTS WITH

CONFIRMED RIFAMPICIN-RESISTANT OR MDR-TB

CRITERIA: Do any of the following apply ?

regimen (except isoniazid resistance)

Exposure to ≥1 second-line medicines in the shorter MDR-TB regimen for >1 month
Intolerance to ≥1 medicines in the shorter MDR-TB regimen or risk or toxicity (e.g. drug–drug interactions)
Pregnancy
Extrapulmonary disease
At least one medicine in the shorter MDR-TB regimen not available in the programme

NO YES
FAILING REGIMEN, DRUG INTOLERANCE,
RETURN AFTER INTERRUPTION >2 MONTHS, Individualized
Shorter MDR-TB REGIMEN EMERGENCE OF ANY EXCLUSION CRITERION ( ’conventional’)
MDR/RR-TB REGIMENS

Intensive phase Intensive phase

Duration: 4–6 months Duration: Up to 8 months
Composition: 4 second-line drugs Composition: 4 or more second-line drugs

Continuation phase Continuation phase

Duration: 5 months Duration: 12 months or more
Composition: 2 second-line drugs Composition: 3 or more second-line drugs

Supported by selected first-line TB drugs Supported by selected first-line TB drugs

Figure 3 Choosing the MDR-TB treatment regimen in patients with confirmed rifampicin-resistant or MDR-TB. Source: Reproduced from The
Shorter MDR-TB Regimen, WHO FACT SHEET. Geneva: Reproduced from World Health Organization; 2016 with permission.

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 INFECTION

processing both the XpertÒ MTB/RIF and XpertÒ MTB/RIF ultra- that injectables containing short regimens are no longer used.
assays, which is currently under review by the WHO. Data from the South African TB programme suggested signifi-
cantly better treatment success and a considerable reduction in
Whole-genome sequencing loss to follow-up irrespective of HIV status with the use of the all-
Although targeted molecular methods continue to play a sub- oral shorter regimen. A short regimen of pretomanid, linezolid
stantial role in TB diagnostics, a broader approach harnessing the and bedaquiline (BPal regimen) has also recently shown very
technique of whole-genome sequencing was commissioned for promising outcomes in the management of treatment intolerant
use within the UK in 2018. Using the ability to sequence the M. or non-reponsive cases of MDR-TB and cases of XDR-TB and this
tuberculosis genome, species can be identified and resistance regimen is now recognized by the US Food and Drug Adminis-
profiles can be determined via detection of single-nucleotide tration although is not currently licensed for use within the UK.
polymorphisms. An additional benefit to sequencing is the abil- A longer regimen, previously defined as conventional ther-
ity to analyse clinical isolates, which can be used to determine apy, is given for a minimum 18 months and includes a minimum
disease strain relatedness and subsequently transmission poten- number of second-line drugs based on patient history and drug
tial. This information can inform vital public health interventions resistance. The longer regimen is recommended for MDR/RR-TB
such as contact tracing and outbreak management. However, patients with extensive disease, severe extrapulmonary disease,
although promising, the impact of this service is still being those with fluoroquinolone resistance or who have been
evaluated and, in keeping with whole sequencing services, it exposed to treatment with second-line drugs. The longer
requires intensive centralized services and bioinformatic regimen should comprise four drugs, including all three group A
expertise. agents and at least one group B reagent (Table 2).4 It is rec-
ommended that sputum culture be repeated at monthly intervals
Therapy regimens to guide treatment response. A duration of 15e17 months after
culture conversion is recommended, and overall duration is
Although newer drugs options such as bedaquiline and guided by response to therapy defined as a negative smear and
delamanid have become available during the last decade, culture.
standard regimens for drug-susceptible TB remain the same, For cases with only isoniazid resistance, recent data have
consisting of four main drugs given over 6 months e isoniazid shown that treatment success is more likely with a short
(H), rifampicin (R), pyrazinamide (Z) and ethambutol (E). regimen.4 As such, it has been recommended that a 6-month
These are given in combination (HRZE) for 2 months, with regimen including RZE and levofloxacin can be used for iso-
treatment completed using two drugs (HR) for a further 4 lated isoniazid-resistant individuals. The use of streptomycin or
months unless there is evidence of central nervous system other injectable antibiotics is no longer recommended.
disease where durations are extended up to 12 months. Varying
regimens using three times a week drug treatment have been
previously suggested but are now associated with worse out- Grouping of medicines recommended for use in longer
comes in terms of pulmonary disease; the WHO therefore MDR-TB regimens
continues to recommend a fixed-dose daily combination with
polypills such as Rifinah (RH) or Rifater (HRZ). Studies have Groups and steps Medicine
previously found that patient satisfaction was improved with
Group A: Include all three Levofloxacin OR Lfx
regimens using polypills secondary to a reduced pill burden
medicines moxifloxacin Mfx
whilst treatment adherence, failure and adverse side effects
Bedaquiline Bdq
were similar to single drug regimens. With regards to longer
Linezolid Lzd
term outcomes no difference has been shown in end of treat-
Group B: Add one or both Clofazimine Cfz
ment culture conversion however a minimal improvement in 2
medicines Cycloserine OR Cs
month culture conversion has been noted with fixed dose daily
terizidone Trd
combinations.
Group C: Add to complete the Ethambutol E
regimen and when medicines from Delamanid Dlm
MDR-TB regimens
Groups A and B cannot be used Pyrazinamide Z
While regimens for drug-susceptible disease have remained
Imipenemecilastatin IpmeCln
consistent, the WHO recently updated its recommendations for
OR
the management of MDR-TB and LTBI. In December 2019 the
meropenem Mpm
WHO issued a rapid communication following on from the
Amikacin Am
publication of its March 2019 consolidated guideline on the
(OR streptomycin) (S)
management of DR-TB. These recommend, for the first time, use
Ethionamide Eto
of a shorter 9e12-month regimen for MDR-TB and RR-TB
OR prothionamide Pto
(Figure 3)4 in patients who have not been previously treated
p-Aminosalicylic acid PAS
with a second-line agent, have extensive disease, severe extrap-
ulmonary disease and in whom resistance to fluoroquinolones Source: World Health Organization (WHO) consolidated guidelines on drug-
and a second-line injectable has been excluded.4 As of December resistant tuberculosis treatment. Geneva: WHO, 2019. Reproduced with
permission.
2019 the WHO recommends that the shorter regimen should
contain an all-oral course of bedaquiline in place of amkican and Table 2

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 INFECTION

months of isoniazid monotherapy (relative risk 0.73, 95% con-

Recommended regimens for the treatment of LTBI. fidence interval 0.23e2.30). In the rifapentine cohort there was
WHO 2018 and NICE 2019 latent tuberculosis infection therapy found to be a lower risk of hepatotoxicity in both HIV-negative
recommendations and HIV-positive patients, and treatment completion rates were
A. 6 months of isoniazid monotherapy (WHO/NICE) higher.5
B. 9 months of isoniazid (WHO)
C. 3 months of weekly rifapentine plus isoniazid (WHO) What does the future hold?
D. 3e4 months of isoniazid plus rifampicin (WHO/NICE) Advances in diagnostics, drug therapies and clinical management
E. 3e4 months of rifampicin alone (WHO) continue to help improve the incidence and mortality of a disease
Old WHO recommendations are in black, with the updated 2018 recommenda-
that has significant burden on a global and national scale. Stra-
tions highlighted in red. tegies to raise awareness of the continuing public health issue
continue. Although some way off from eradicating TB, as tar-
Table 3 geted in the WHO ‘End TB’ strategy and championed by the
collaborative TB strategy for England, trends are improving. As
rates decline, continued awareness by medical professionals of
LTBI therapy the possibility of TB needs to be maintained. If we are to continue
The use of pre-entrant active TB screening and also new entrant making strides in combating the rising threat of MDR-TB and the
latent infection screening appears to have made an impact on TB complexities of the patient cohorts being managed, further work
rates in the UK. As of 2018, based upon systematic evidence must be undertaken to address the needs of those currently un-
reviews, the WHO updated recommendations regarding the derserved, throughout the world. A
treatment of LTBI with further national guidance being provided
by the National Institute for Health and Care Excellence (NICE) KEY REFERENCES
(Table 3).5 The main difference between both guidelines is the 1 World Health Organization. Global tuberculosis report 2018.
use of rifapentine. Whilst recommended within the WHO guid- Geneva: WHO, 2018.
ance rifapentine is not currently licensed for use within the UK 2 Public Health England. Tuberculosis in the UK 2019 report. Lon-
and is therefore not recommended by NICE for use in LTBI. NICE don: Public Health England, 2019.
recommends LTBI treatment in patients <65 years in age who 3 Public Health England. Tackling TB in under-served populations: a
have evidence of LTBI and a history of close contact with patients resource for TB control boards and their partners. London: Public
who have been diagnosed with suspected or confirmed drug- Health England, 2019.
sensitive pulmonary/laryngeal disease. Caution is advised in 4 World Health Organization. Latent tuberculosis infection: updated
patients aged 35e65 due to the higher risk of drug-related and consolidated guidelines for programmatic management.
hepatotoxicity. Geneva: WHO, 2018.
The systematic reviews found that in countries with a low 5 World Health Organization. WHO consolidated guidelines on drug-
incidence, and also in a setting with a high incidence (adults with resistant tuberculosis treatment. Geneva: WHO, 2019.
HIV from South Africa), there was no significant difference in the
incidence of active TB in patients given a 3-month weekly
regimen of rifapentine plus isoniazid, compared with 6 or 9

TEST YOURSELF
To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the
end of the issue or online here.

Question 1 Based on the current UK guidance, what is the most appro-

A 34-year-old man was referred to the TB clinic having sought priate treatment to offer?
advice from his local GP having been in contact with a suspected A. 6 weeks of isoniazid monotherapy
case of pulmonary tuberculosis. He himself had recently moved B. 6 months of isoniazid and rifampicin
to the UK from China a year ago. He was well with no significant C. 3 months of weekly rifapentine plus isoniazid
past medical history. A chest X-ray undertaken has been reported D. 2 months of quadruple therapy with isoniazid, rifampicin,
as normal. pyrazinamide and ethambutol (HRZE), followed by 4
months of isoniazid and rifampicin (HR)
Investigation E. A 6-month regimen including rifampicin, pyrazinamide,
 Interferon-g release assay undertaken was positive and ethambutol (RZE) and levofloxacin
chest X-ray undertaken has been reported as normal.

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 INFECTION

Question 2 Question 3
A 52-year-old woman presented with a positive screen for TB A 22-year-old woman presented with a 6-month history of pro-
upon arriving to the UK. She was well. She had lived and worked ductive cough with associated weight loss, fevers and night
in South Africa for 30 years prior to returning to the UK 6 months sweats. She had been unemployed for the past year and was
previously. She lived with her husband and two children. She living in a hostel, having previously lived on the streets. She had
had no co-morbidities. She may have had a possible contact with a history of intravenous drug use and a 10-packeyear smoking
a colleague who was subsequently treated for pulmonary TB 12 history.
months previously but has no other history of exposure as far as
she is aware. Clinical examination was normal. She was con- Investigations
cerned that she would develop active disease.  Chest X-ray showed right upper lobe consolidation
 Sputum was positive for Mycobacterium tuberculosis on
Investigations direct smear
 Tuberculin skin test was positive
 Chest X-ray was clear
What test would be most useful to help determine her drug
 Interferon-g release assay (IGRA) positive
regimen in the shortest timeframe?
A. Tuberculin skin test
Given the history what is her risk of progression to active B. XpertÒ MTB/rifampicin assay
disease most likely to be? C. Interferon-g release assay
A. Her risk of progression to active disease will continue to D. Sputum culture
rise cumulatively each year with age after exposure E. Whole-genome sequencing
B. Her risk of progression starts to increase 5 years after
exposure
C. She is unlikely to develop active disease since she is
immunocompetent
D. She has already progressed to active disease
E. She is at highest risk of progression within the next year

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