Five to ten per cent of Tuberculin skin test (TST) positive individuals will progress from this clinically asymptomatic state (here termed latent TB infection (LTBI) to active disease. The use of anti-TNF? agents increases the risk of LTBI progressing to active TB by approximately fivefold. This is often rapid and aggressive, occurring at a median of 12 weeks from anti-TNF? initiation in the earliest reports. Thus, the onset of new respiratory symptoms, particularly within 3 months of commencing anti-TNF treatment, should be investigated promptly

Thus, all patients should be screened for latent TB before initiating anti-TNF treatment.

How to diagnose latent tuberculosis?

All patients should have:

1. Careful history: Previous h/o TB or TB treatment
2. CXR: within 3/12 of starting biologics. An abnormal chest radiograph suggestive of old TB (calcification >5 mm, pleural thickening, or linear opacities) should also be considered suggestive of latent TB even if other criteria are absent.
3. TB IFN? release assays (IGRA)

If any of the above 1, 2 or 3 is positive, the patient should be referred for assessment to a specialist with an interest in TB. If IGRA is indeterminate or equivocal, it could be repeated after 2-3 weeks and if still indeterminate or equivocal- the patient should be referred for assessment to a specialist with an interest in Tb

Discuss the treatment of latent TB?

There are two potential chemoprophylaxis regimens: isoniazid for 6 months (6H) or rifampicin plus isoniazid for 3 months (3RH).

It should be noted that no chemoprophylaxis regimen is wholly effective; protective efficacies of 60% have been reported for 6H and of 50% for 3RH. If patients who have had chemoprophylaxis develop symptoms suggestive of clinical TB, they should be promptly and appropriately investigated.

Discuss monitoring with latent TB treatment?

Isoniazid-related hepatotoxicity occurs in approximately 0.15% of patients. It may occasionally be severe and life threatening. Minor transaminase elevations (3-fold) are common (10–20%) during isoniazid therapy and of no consequence.

Most advise monitoring liver function at intervals, with cessation or alteration of therapy if the transaminases exceed >3-fold elevation associated with hepatitis symptoms or jaundice, or >5-fold in the absence of symptoms.

If a patient needs to start Latent TB treatment, when can they safely start anti-TNF? agents?

Patients with active TB should receive a minimum of 2 months full chemotherapy directed by a specialist in TB before starting anti-TNF-a treatment.

Discuss the disadvantages of TST?

• Diagnosis of latent TB by TST may be distorted by prior BCG vaccination, because vaccinated individuals may become positive reactors to purified protein derivate (PPD). This distortion is almost insignificant in adults >30 years of age, irrespective of age at vaccination or re-vaccination.
• TST may also be negative in patients on steroids (>20mg/day) for >1 month, or thiopurines or methotrexate for >3 months. The TST cannot adequately be interpreted if corticosteroids are not discontinued for >1 month and immuno modulators for >3 months.
• A false negative TST may also occur during active IBD without immuno suppression.

Thus, NICE recommends an interferon-gamma test in immunosuppressed patients and in BCG vaccinated people

Discuss IFN? release assays (IGRAs) tests for TB?

Principle: T cells of individuals who have been exposed to TB (and hence its antigens) will produce IFN? when they are re-challenged with mycobacterial antigens contained within the test kit.

Mycobacterial antigens used for the test: ‘early secretion antigen target 6? (ESAT-6), ‘culture filtrate protein 10? (CFP-10) and tb7.7. These antigens are not present in BCG, and are found in only a few species of environmental mycobacteria.

Tests available: There are currently three interferon-gamma immunological tests commercially available: QuantiFERON-TB Gold, QuantiFERON-TB Gold In tube and T-SPOT.TB.

QuantiFERON-TB Gold measures the release of interferon-gamma in whole blood in response to stimulation by ESAT-6 and CFP-10. The In tube version measures ESAT-6, CFP-10 and tb7.7.

T SPOT-TB measures IFN? production (using ESAT-6 and CFP-10 antigens) from a fixed number of blood mononuclear cells via an ex vivo overnight enzyme linked immunospot (ELISPOT) assay.

Results: Each time that a test is run on a blood sample, a negative control (which contains no stimulating antigen) and a positive control (with mitogen) are also tested against the blood sample. Indeterminate results occur when either the negative control records a positive result, (i.e., the blood sample’s T cells release IFN? without specific stimulation) or the mitogen does not stimulate the cells as expected (and no IFN? is produced). Indeterminate results are particularly common in the populations where a clear-cut result would be most helpful, such as the immunosuppressed, patients in an intensive care unit, children and older adults.

Advantages of IGRA tests over TST:

Results are usually available within 24–48 h

More specific than the TST in BCG-vaccinated populations

No follow-up visit is required

More sensitive and specific than TST

References

1. British Thoracic Society Guidelines (hyperlink to

http://www.brit-thoracic.org.uk/Portals/0/Clinical%20Information/Tuberculosis/Guidelines/antitnf.pdf

2. Greveson K et al . Interferon ?-release assays for detecting latent tuberculosis infection in patients scheduled for anti-TNF? therapy. Frontline Gastroenterology 2011;2:26–31. doi:10.1136/fg.2009.000356

3. NICE guidance 2011 (link it to http://www.nice.org.uk/nicemedia/live/13422/53638/53638.pdf