Diagnosis of active and latent tuberculosis: summary of NICE guidance
BMJ 2012; 345 doi: https://doi.org/10.1136/bmj.e6828 (Published 17 October 2012) Cite this as: BMJ 2012;345:e6828
- Ibrahim Abubakar, professor of infectious disease epidemiology1,
- Chris Griffiths, professor of primary care2,
- Peter Ormerod, professor of respiratory medicine3
- on behalf of the Guideline Development Group
- 1Research Department of Infections and Population Health, University College London, London
- 2Centre for Primary Care and Public Health, Queen Mary University of London
- 3Royal Blackburn Hospital, Blackburn, UK
- Correspondence to: I Abubakar i.abubakar{at}ucl.ac.uk
Tuberculosis is a major preventable infectious cause of morbidity and mortality globally, which has re-emerged in high risk groups such as migrants, homeless people, problem drug users, and prisoners in the UK.1 This article summarises the most recent recommendations (2011) from the National Institute for Health and Clinical Excellence (NICE)2 on the diagnosis of latent tuberculosis (including the use of new tests) and of active tuberculosis. Although this summary focuses on diagnosis, the full guidelines cover the public health and clinical management of tuberculosis and replaced the guidelines published in 2006.3
Recommendations
NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the Guideline Development Group’s experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets.
Diagnosing latent tuberculosis (New/updated recommendations)
All contacts of tuberculosis cases, aged 5 years or older
Offer Mantoux testing in line with the Department of Health’s Green Book4 to:
-Household contacts of all people with active tuberculosis
-Non-household contacts (other close contacts, such as in workplaces and schools).
A positive Mantoux test is an induration of ≥6 mm diameter for those who have not been vaccinated with BCG and ≥15 mm diameter for those who have been vaccinated.
Consider interferon-γ release assay (IGRA) for people whose Mantoux test shows positive results, or in people for whom Mantoux testing may be less reliable (such as those who have been vaccinated with BCG).
Refer people with a positive IGRA or an inconclusive Mantoux test to a tuberculosis specialist.
Household contacts aged 2–5 years
Offer Mantoux testing.
If the initial test is positive (taking into account BCG vaccination history), refer to a tuberculosis specialist to exclude active disease and consider treating latent tuberculosis.
If the initial Mantoux test is negative but the child is a contact of a person with disease that is positive for acid fast bacilli on a sputum smear, offer an IGRA after six weeks and repeat the Mantoux test to reduce the rate of false negative results for latent infection.
Household contacts younger than 2 years and older than 4 weeks
If contact was with a person whose sputum smear is positive for acid fast bacilli:
-For children not vaccinated with BCG, perform a Mantoux test and offer isoniazid
If the Mantoux test is positive, assess the child for active tuberculosis. If active tuberculosis is excluded, offer full treatment for latent infection
If the Mantoux test is negative (<6 mm induration), continue isoniazid for six weeks, and then repeat the Mantoux test together with an IGRA. If the repeat tests are negative, isoniazid may be stopped and BCG vaccination performed. If either repeat test is positive, assess the child for active tuberculosis and consider treating for latent tuberculosis
-For vaccinated children, perform a Mantoux test. If the Mantoux reaction is <15 mm, repeat the Mantoux test after six weeks, together with an IGRA. If both repeat tests are negative, no further action is needed. If either test is positive, exclude active tuberculosis and follow with treatment for latent tuberculosis.
Contacts in outbreak
If large numbers of individuals need to be screened, consider a single IGRA for people aged ≥5 years.
New entrants from countries with a high incidence of tuberculosis
For children under 5 years, offer a Mantoux test. If strongly positive, refer to consider treating latent tuberculosis.
For children aged 5–15 years, offer a Mantoux test. If positive, follow with an IGRA.
For people aged 16–35 years, offer either an IGRA alone or a dual strategy (Mantoux test followed by IGRA).
For people over 35 years, consider the individual risks and benefits of likely subsequent treatment before offering testing.
People who are immunocompromised
If latent tuberculosis is suspected in children who are immunocompromised, refer to a tuberculosis specialist.
For people with HIV infection and CD4 counts <200 cells/mm3 (<200×106/L), offer concurrent IGRA and Mantoux tests. If either test is positive, perform a clinical assessment to exclude active tuberculosis and consider treating latent tuberculosis.
For people with HIV and CD4 counts of 200–500 cells/mm3, offer an IGRA alone or concurrent IGRA and Mantoux tests. If either test is positive, perform a clinical assessment to exclude active tuberculosis and consider treating latent tuberculosis.
For other people who are immunocompromised, offer an IGRA test alone or concurrent IGRA and Mantoux tests. If either test is positive, perform a clinical assessment to exclude active tuberculosis and consider treating latent tuberculosis.
Healthcare workers
Offer a Mantoux test to new NHS employees who will be in contact with patients or clinical materials if the employees are not new entrants from high incidence countries and have not had BCG vaccination (they do not have a vaccination scar, other documentation. or reliable history). If the Mantoux test is negative, refer to the Green Book for BCG immunisation guidance. If the Mantoux test is positive, offer an IGRA.
For new NHS employees who have recently arrived from high incidence countries or who have had contact with patients in settings where tuberculosis is highly prevalent, offer an IGRA.
Screen healthcare workers who are immunocompromised in the same way as other people who are immunocompromised.
Hard to reach groups
Offer people from hard to reach groups a single IGRA (see NICE guidelines on the control of tuberculosis in hard to reach groups5).
[All the above recommendations on latent tuberculosis are based on a review of moderate to poor quality observational studies, economic analysis and the experience and opinion of the Guideline Development Group(GDG)]
Diagnosis of active tuberculosis
Active respiratory tuberculosis
Take a posterior-anterior chest x ray. If the x ray appearance suggests tuberculosis carry out further diagnostic investigation.
Send multiple sputum samples (at least three, with one early morning sample) for tuberculosis microscopy and culture for suspected respiratory tuberculosis, before starting treatment if possible or, failing that, within seven days of starting.
[The above two recommendations are based on moderate quality observational studies]
If possible obtain spontaneously produced sputum; otherwise use induction of sputum or bronchoscopy and lavage.
In children unable to expectorate sputum, consider induction of sputum if it can be done safely; consider gastric washings as third line. [Based on high quality observational studies]
Use rapid diagnostic tests for Mycobacterium tuberculosis complex (M tuberculosis, M bovis, M africanum) on specimens obtained from patients only if rapid confirmation of a tuberculosis diagnosis in a person whose sputum smear is positive would alter the patient’s care or before conducting a large contact tracing initiative. Do not use such tests for pleural fluid, cerebrospinal fluid, or urine to exclude the diagnosis of tuberculosis as they have a high false negative rate. [Based on the experience and opinion of the GDG]
Active non-respiratory tuberculosis
Discuss the advantages and disadvantages of both biopsy and needle aspiration with the patient, with the aim of obtaining adequate material for diagnosis. [Based on high quality observational studies]
If non-respiratory tuberculosis is a possibility, place part or all of any of the following samples in a dry pot (do not place in formalin) and send for tuberculosis culture: lymph node biopsy, pus aspirated from lymph nodes, pleural biopsy, any surgical sample sent for routine culture, any radiological sample sent for routine culture, histology sample, aspiration sample, autopsy sample.
Microbiology staff should routinely perform tuberculosis culture on the above samples (even if it is not requested).
Take a chest x ray of all patients with non-respiratory tuberculosis to exclude or confirm coexisting respiratory tuberculosis. In addition, consider imaging, biopsy, and histopathology as well as bacterial culture depending on the affected organ.
[The above three recommendations are based on the experience and opinion of the GDG]
If clinical signs and other laboratory findings are consistent with tuberculosis meningitis, start treatment, even if a rapid diagnostic test is negative, because the potential consequences for the patient are severe.
Carry out rapid diagnostic tests for M tuberculosis complex on biopsy material only if all the sample has been inappropriately placed in formalin and acid-fast bacilli are visible on microscopy.
Large scale contact investigation
With a positive result by microscopy or tuberculosis culture, confirm the species of mycobacterium to be M tuberculosis complex by rapid diagnostic tests on material before starting large scale contact tracing (such as in a school or hospital). Use clinical judgment if tests are inconclusive or delayed.
Multiple drug resistant (MDR) tuberculosis
Undertake a risk assessment for MDR tuberculosis. Risk factors for MDR tuberculosis include prior tuberculosis drug treatment; prior tuberculosis treatment failure; contact with a known case of drug resistant tuberculosis; birth in a foreign country, particularly one with a high incidence of tuberculosis as defined by the Health Protection Agency; HIV infection; residence in London; age profile (with highest rates between the ages of 25 and 44 years); and male sex.
If a risk assessment suggests a patient has MDR tuberculosis, carry out rapid diagnostic tests for rifampicin resistance and start infection control measures and treatment for MDR tuberculosis pending the result of the tests.
[The above four recommendations are based on the experience and opinion of the GDG]
Starting treatment
If clinical signs and symptoms are consistent with a diagnosis of tuberculosis, start treatment without waiting for culture results. Continue the standard recommended regimen in patients whose subsequent culture results are negative.
[Based on moderate quality observational studies]
Overcoming barriers
Primary care can and should play a key role in promoting early diagnosis of both active and latent tuberculosis through a systematic approach to screening for tuberculosis. Studies indicate that screening in primary care can contribute to the detection of latent tuberculosis in high risk groups.6 However, the resources available for the necessary tests are limited, with consequent variation in the extent to which interferon-γ release assays (IGRA) are implemented,7 as too often screening is not prioritised by commissioners. Demonstration of the potential impact of this intervention on local tuberculosis rates and of more pragmatic thresholds for screening migrants8 are the most effective ways to improve funding.
The application of the tests outlined in this article to achieve prompt diagnosis of active tuberculosis requires early recognition and referral of individuals with symptoms and signs of tuberculosis by general practitioners. Greater awareness of the clinical presentation of tuberculosis and risk factors among healthcare providers remains the primary route to achieve early diagnosis and avert transmission and adverse outcomes for the patient.
Further information on the guidance
The re-emergence of tuberculosis as a public health problem in the UK,1 its changing epidemiology,9 and the development of interferon-γ release assays (IGRA) for latent tuberculosis10 prompted the development of NICE guidelines in 2006 and their subsequent revision in 2011. The revision aimed to keep practice up to date with emerging evidence on the diagnostic accuracy of IGRA in various patient groups.
Methods
The 2011 revision of the tuberculosis guideline was developed in accordance with NICE guideline development methods (www.nice.org.uk/guidelinesmanual) supported by a guideline development group which included lay representatives, guideline method experts, an immunologist, microbiologists, an occupational physician, epidemiologist, respiratory physician, paediatrician, infectious disease physician, general practitioner, nurse specialist, and independent chair (consultant psychiatrist). A systematic appraisal of the literature was undertaken with subsequent health economic analysis using NICE standard methods to inform recommendations. The scope, and drafts, of the guidelines were circulated to stakeholders for consultation.
Future research
The GDG identified some important questions that need to be answered:
What are the positive and negative predictive values of interferon-γ tests for the subsequent development of active tuberculosis in patients investigated for latent tuberculosis?
What, if any, is the role of interferon-γ tests in the diagnosis of active tuberculosis?
What is the cost effectiveness of routine or universal use of molecular tests to diagnose active tuberculosis and drug resistance?
Notes
Cite this as: BMJ 2012;345:e6828
Footnotes
This is one of a series of BMJ summaries of new guidelines based on the best available evidence; they highlight important recommendations for clinical practice, especially where uncertainty or controversy exists.
The members of the Guideline Development Group for the 2011 revision were Ibrahim Abubakar, Christine Bell, Steve Bradley, Ann Chapman, Timothy Collyns, Francis Drobniewski, Damien Longson (chair), Tessa Marshall, Pamela Mellors, Sandy Moffitt, Peter Ormerod, and Sarath Ranganathan. The NICE Internal Clinical Guidelines Team in 2011 comprised Kathryn Chamberlain, Sarah Glover, Edward Mwarangu, Yaminah Rajput, Alfred Sackeyfio, Abitha Senthinathan, Mark Baker, Nicole Elliott, Michael Heath, Prashanth Kandaswamy, Beth Shaw, Phil Alderson, Emma Banks, Caroline Keir, Stefanie Reken, Nick Staples, and Judith Thornton. The team in 2006 comprised Sue Appleby, Gerry Bryant, Ian Campbell, Michael Carter, Malcolm Cocksedge, Sue Dart, Peter Davies, Bernadette Ford, Rob Grant, Ashley Green, Chris Griffiths, Andy Hall, Andrew Hayward, John Hayward, Bernard Higgins (consensus chair), John Innes, Jane Jones, Ian Lockhart, Joanne Lord, John Magee, Jonathan Mant, John Moore-Gillon, Helen Murshali, Ndidi Okonta, Peter Ormerod (clinical advisor), Delane Shingadia, Caroline Trevithick, Susan Varney, Irving Wells, and Martin Wiselka.
Contributors: All authors contributed to the conception and writing of this manuscript and have agreed on the final version of the paper. IA is guarantor.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work. IA is funded through an NIHR senior research fellowship. The views expressed in this publication are those of the authors and not necessarily those of the NHS, National Institute for Health Research, or Department of Health.
Provenance and peer review: Not commissioned; not externally peer reviewed.