Latent tuberculosis

Latent tuberculosis
Classification and external resources
ICD-10	R76.1
ICD-9	795.5

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—it is not possible to get TB from someone with latent tuberculosis. The main risk is that approximately 10% of these patients (5% in the first two years after infection and 0.1% per year thereafter but higher risk if immunosuppressed) will go on to develop active tuberculosis at a later stage of their life. This is particularly true under any of the following circumstances:

• if there is onset of a disease affecting the immune system (such as AIDS) or a disease whose treatment affects the immune system (such as chemotherapy in cancer or systemic steroids in asthma or Enbrel, Humira or Orencia in rheumatoid arthritis);
• malnutrition (which may be the result of illness or injury affecting the digestive system, or of a prolonged period of not eating, or disturbance in food availability such as famine, residence in refugee camp or concentration camp, or civil war;
• degradation of the immune system due to aging. 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 IFN-γ (Interferon-gamma) tests. The tuberculin skin tests in use include (but are not limited to)

• Mantoux test
• Heaf test
• Tine test (often misspelled as tyne)

There are currently three IFN-γ (interferon-gamma release assay - IGRA) tests available.

• T-SPOT.TB
• QuantiFERON-TB Gold
• QuantiFERON-TB Gold In-Tube

A description of the tests and their interpretation follows.

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 person's immune response to TB. Historically, there have been three methods of tuberculin testing: the Mantoux test, the Heaf test, and the Tine test. The Heaf test was discontinued in 2005 because the manufacturer deemed its production to be financially unsustainable. 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.

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 negatives). 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 of 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 protrude 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

The tuberculin used for Heaf tests is 1000 times more concentrated than that used for Mantoux tests. In countries where both tests are used, use of the correct concentration avoids 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 is one way of obtaining a false positive test result. Boosting can occur up to two years after the first Mantoux test. Boosting occurs when people who have had remote infection with Mycobacterium tuberculosis and/or 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.

Interpretation of tuberculin skin tests

According to the U.S. guidelines, there are multiple size thresholds for declaring a positive result of latent tuberculosis from the Mantoux test: For testees from high risk groups, such as those who are HIV positive, the cutoff is 5 mm of induration; for medium risk groups, 10 mm; for low risk groups, 15 mm. 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 diagnosed if the Heaf test is 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 many 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.

Interferon-γ (IFN-γ) testing

The role of IFN-γ tests is undergoing constant review and various guidelines have been published with the option for revision as new data comes to hand.CDC:MMWR Health Protection Agency:UK

There are currently (26 March 2009) three commercially available interferon-γ release assays (IGRAs): QuantiFERON-TB Gold, QuantiFERON-TB Gold In-Tube and T-SPOT.TB. These tests are not affected by prior BCG vaccination, and look for the body's response to specific TB antigens not present in other forms of mycobacteria and BCG (ESAT-6). Whilst these tests are new they are now becoming available globally.

CDC:

CDC recommends that QFT-G may be used in all circumstances in which the TST is currently used, including contact investigations, evaluation of recent immigrants, and sequential-testing surveillance programs for infection control (e.g., those for health-care workers).

HPA Interim Guidance:

The HPA recommends the use of IGRA testing in health care workers, if available, in view of the importance of detecting latently infected staff who may go on to develop active disease and come into contact with immunocompromised patients and the logistical simplicity of IGRA testing.

Treatment

Main article: tuberculosis 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 be 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 rifampin 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.
• 3RPT/INH - three-month (12-dose) regimen of weekly rifapentine and isoniazid.

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.

Research

Although a tuberculosis cure was developed around 1960, TB continues to kill from 2 to 3 million people every year. According to the World Health Organization (WHO), approximately one-third of the world's population are carriers of latent tuberculosis, 8 million people develop active tuberculosis every year, and approximately 36 million people will die of tuberculosis by 2020 if it is not controlled. Approximately 98 percent of those victims are from developing countries. .

Therefore, the scientific community continues its research efforts to learn more from this disease in order to develop more options for possible treatments.

Further reading

• Jasmer, RM; Nahid, P; Hopewell, PC (2002). "Latent Tuberculosis Infection". New Engl J Med 347 (23): 1860–1866. doi:10.1056/NEJMcp021045. PMID 12466511 
• Mazurek, GH; Villarino, ME (2003). "Guidelines for using the QuantiFERON-TB test for diagnosing latent Mycobacterium tuberculosis infection". Morb Mortal Wkly Rep 52 (RR–2): 15–18 
• Joint Tuberculosis Committee Of The British Thoracic Society, P; Skinner, C; Moore-Gillon, J; Davies, P; Connolly, M (2000). "BTS Guidelines:Control and prevention of tuberculosis in the United Kingdom: Code of Practice 2000". Thorax 55 (11): 887–901. doi:10.1136/thorax.55.11.887. PMC 1745632. PMID 11050256. http://thorax.bmjjournals.com/cgi/content/full/55/11/887 

 This article incorporates public domain material from websites or documents of the Centers for Disease Control and Prevention.