Latent tuberculosis

Also called latent tuberculosis infection, latent TB or LTBI.

Latent tuberculosis is where a patient is infected with Mycobacterium tuberculosis, but does not have active tuberculosis disease. Patients with latent tuberculosis are not infectious, and it is not possible to get TB from someone with latent tuberculosis. The main risk is that approximately 10% of these patients will go on to develop active tuberculosis at a later stage of their life. The identification and treatment of people with latent TB is an important part of controlling this disease.

=Tests for latent tuberculosis= There are currently two major classes of tests used to identify patients with latent tuberculosis: tuberculin skin tests and γ-interferon tests. The tuberculin skin tests in use include (but are not limited to) There are currently two γ-interferon tests available A description of the tests and their interpretation is given below.
 * Mantoux test
 * Heaf test
 * Tyne test
 * ELISPOT
 * QuantiFERON-TB

Tuberculin skin testing
The tuberculin skin test has its origins in the late 19th century. Crudely speaking, tuberculin (also called purified protein derivative or PPD) is a standardised killed extract of cultured TB, injected into the skin to measure the reaction that person's immune response to TB. There are three methods of testing, the Mantoux test, the Heaf test and the Tyne test. The Heaf test was preferred in the UK because it requires less training to administer and because there is less interobserver variation in its interpretation. The Heaf test was stopped in 2005 because the manufacturer did not find it financially sustainable to continue manufacturing the test.

Mantoux test

 * See: Mantoux test

The Mantoux test is now standardised by the WHO. 0.1 ml of tuberculin (100 units/ml) is given by intradermal injection into the volar surface of the forearm (subcutaneous injection results in false negative results). A waterproof ink mark is drawn around the injection site so as to avoid difficulty finding it later if the level of reaction is small. The test is read two to seven days afterwards. The area of induration (NOT erythema) is measured transversely across the forearm (left to right, not up and down) and recorded to the nearest millimetre.

Heaf test

 * See:Heaf test

The Heaf test was first described in 1951. The test uses a Heaf gun with disposable single-use heads; each head has six needles arranged in a circle. There are standard heads and pediatric heads: the standard head is used on all patients aged 2 years and older; the pediatric head is for infants under the age of 2. For the standard head, the needles protude 2 mm when the gun is actuated; for the pediatric heads, the needles protrude 1 mm. Skin is cleaned with alcohol, then tuberculin (100,000 units/ml) is evenly smeared on the skin (about 0.1 ml); the gun is then applied to the skin and fired. The excess solution is then wiped off and a waterproof ink mark is drawn around the injection site. The test is read 2 to 7 days later.
 * Grade 0: no reaction, or induration of 3 or less puncture points;
 * Grade 1: induration of four or more puncture points;
 * Grade 2: induration of the six puncture points coalesce to form a circle;
 * Grade 3: induration of 5 mm; or more
 * Grade 4: induration of 10 mm or more, or ulceration

It is not easy to translate between Heaf and Mantoux, but
 * Heaf grade 0 & 1 ~ Mantoux less than 5 mm;
 * Heaf grade 2 ~ Mantoux 5–14 mm;
 * Heaf grade 3 & 4 ~ Mantoux 15 or greater

It is essential to note that the tuberculin used for Heaf tests is 1000 times more concentrated than that used for Mantoux tests and in countries where both tests are used it is essential to note what concentration of tuberculin is available before administering the test, so as to avoid false positive and false negative results.

Tuberculin conversion
Tuberculin conversion is said to occur if a patient who has previously had a negative tuberculin skin test develops a positive tuberculin skin test at a later date. This is strong evidence for significant exposure to TB. The UK recommendation is that the two tests be done at least six weeks apart; the U.S. recommendation is that the two tests can be done as little as one week apart.

Boosting
The phenomenon of boosting occurs when people who have had previous exposure to Bacille Calmette Guerin of Mycobacterium bovis (BCG), an attenuated strain of Mycobacterium bovis that is used in some countries as a vaccine against tuberculosis are given repeated tuberculin skin tests. In these people, the first test revives or primes the immune response so that on repeat testing, the response is much stronger and the patient then looks as if he now has a positive reaction. The second tuberculin skin test result is the correct one.

The UK and U.S. guidelines approach the phenomenon of boosting differently. Under U.S. guidelines, which say to ignore previous immunisation with BCG, a person showing the phenomenon of boosting will be falsely described as a tuberculin converter. On the other hand, UK guidelines advise two tuberculin skin tests one week apart if boosting is suspected, taking the result of the second test as being the true result.

Boosting can occur up to two years after the first Mantoux test.

Interpretation of tuberculin skin tests
According to the U.S. guidelines, latent tuberculosis is diagnosed on a Mantoux test if there is more than 10 mm of induration. In high risk groups, such as those who are HIV positive, the cut-off is 5 mm on induration. The U.S. guidelines recommend that a history of previous BCG vaccination should be ignored. For details of tuberculin skin test interpretation, please refer to the CDC guidelines (reference given below).

The UK guidelines are formulated according to the Heaf test: In patients who have had BCG previously, latent TB is diagnosed if the Heaf test is grade 3 or 4 and have no signs or symptoms of active TB; if the Heaf test is grade 0 or 1, then the test is repeated and. In patients who have not had BCG previously, latent TB is the Heaf test if grade 2, 3 or 4, and have no signs or symptoms of active TB. Repeat Heaf testing is not done in patients who have had BCG (because of the phenomenon of boosting). For details of tuberculin skin test interpretation, please refer to the BTS guidelines (references given below).

Given that the US recommendation is that prior BCG vaccination be ignored in the interpretation of tuberculin skin tests, false positives are possible as a result of: (1) people who have previously had BCG (even may years ago) may still have a false positive Mantoux test, and (2) serial testing with tuberculin skin tests boosts the immunological response in those people who have previously had BCG, so these people will falsely appear to be tuberculin converters. This may lead to treating more people than necessary, with the possible risk of those patients suffering adverse drug reactions. However, as Bacille_Calmette-Guérin vaccine is not 100% effective, and is less protective in adults than pediatric patients, not treating these patients could lead to a possible infection. The current US policy seems to a reflect a desire to err on the side of safety (of the general public).

The U.S. guidelines also allow for tuberculin skin testing in immunosuppressed patients (those with HIV, or who are on immunosuppressive drugs), whereas the UK guidelines recommend that tuberculin skin tests should not be used for such patients because it is unreliable.

γ-interferon testing
The role of gamma interferon tests has yet to be clearly defined.

There are currently (24 Feb 2006) two commercially available γ-interferon tests: QuantiFERON-GOLD and ELISPOT. These tests seek to avoid interference by prior BCG vaccination, and look for the body's response to TB antigens not present in BCG (ESAT-6). The tests are new and are not currently used widely.

CDC: From a medical and public health prospective, QFT-G testing is indicated for diagnosing infection with M.tuberculosis, including both TB disease and LTBI.

Treatment
The treatment of latent tuberculosis infection (LTBI) is essential to controlling and eliminating TB by reducing the risk that TB infection will progress to disease. The gold standard of treatment is nine months of isoniazid, and this regimen is still widely used in the U.S. (but not elsewhere).

Terminology
There is no agreement regarding terminology: the terms preventive therapy and chemoprophylaxis have been used for decades, and are preferred in the UK because it involves giving medication to people who have no disease and are currently well: the reason for giving medication is primarily to prevent people from becoming unwell. In the U.S., physicians talk about latent tuberculosis treatment because the medication does not actually prevent infection: the person is already infected and the medication prevents existing silent infection from becoming active disease. There are no convincing reasons to prefer one term over the other.

Treatment regimens
It is essential that assessment to rule out active TB is carried out before treatment for LTBI is started. To give treatment for latent tuberculosis to someone with active tuberculosis is a serious error: the tuberculosis will not be adequately treated and there is a serious risk of developing drug-resistant strains of TB.

There are several treatment regimens currently in use:
 * 9H — Isoniazid for 9 months is the gold standard (93% effective).
 * 6H — Isoniazid for 6 months might be adopted by a local TB program based on cost-effectiveness and patient compliance. This is the regimen currently recommended in the UK for routine use. The U.S. guidance excludes this regimen from use in children or persons with radiographic evidence of prior tuberculosis (old fibrotic lesions) (69% effective).
 * 6 to 9H2 — An intermittent twice-weekly regimen for the above 2 treatment regimens is an alternative if administered under Directly observed therapy (DOT).
 * 4R — Rifampin for 4-months is an alternative for those who are unable to take isoniazid or who have had known exposure to isoniazid-resistant TB.
 * 3HR — Isoniazid and rifamipin may be given daily for three months.
 * 2RZ — The two month regimen of rifampin and pyrazinamide is no longer recommended for treatment of LTBI because of the greatly increased risk of drug-induced hepatitis and death.

Multi-drug-resistant TB
There is no evidence for any regimen used for persons with known exposure to MDR-TB and no consensus on optimal treatment. A regimen consisting of ethambutol and PAS has been used before. It would appear sensible to choose a combination of antibiotics based on the known sensitivities of the organism. The CDC have recommended a combination of pyrazinamide and ethambutol, with either pyrazinamide or fluoroquinolone. Immunocompetent contacts should be treated for 6 months; immunocompromised contacts should be treated for 12 months.

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