This can also be known as:

• Purified Protein Derivative
• PPD
• Mantoux
• Latent Tuberculosis Infection Test
• Interferon-gamma Release Assays
• IGRA
• T-Spot®.TB
• QuantiFERON®-TB Gold (QFT-G)
• QuantiFERON®-TB Gold In-Tube (QFT-GIT)
• Formal Name: Tuberculin Skin Test
• Formal Name: Interferon Gamma Release Assays

Overview

Tuberculosis (TB) remains a leading cause of morbidity and mortality in the world, especially in developing countries. A combination of factors including high costs, limited resources and the poor performance of various diagnostic tests make the diagnosis of TB difficult in developing countries. Short of demonstrating viable organisms in body tissues and fluids the tuberculin skin test (TST) is the only method of detecting M. tuberculosis infection in an individual and is used in the diagnosis of TB in individual patients, as well as in epidemiological settings, to measure the prevalence of tuberculous infection in populations. The screening tests measure the body’s immune response to antigens derived from these bacteria, either directly as a skin reaction to a tuberculin skin test (TST) or indirectly with an interferon gamma release assay (IGRA) blood test.

TB may cause an inactive (latent) infection or an active, progressive disease. The immune system of about 90% of people who become infected with TB manages to control its growth and confine the TB infection to a few cells in the body. The bacteria in these cells are inactive but still alive. The person does not have any symptoms and is not infectious but does have a “latent TB infection.”

If, after some time, the immune system of an individual with an inactive infection becomes weakened (compromised), the mycobacteria may begin to grow again, leading to an active case of tuberculosis disease. Active TB does cause illness and can be passed to others through respiratory secretions such as sputum or aerosols released by coughing, sneezing, laughing, talking, singing, or breathing.

Both the tuberculin skin test and the IGRA blood test can detect M. tuberculosis infections, but neither can distinguish between latent and active infections. Additional tests, such as AFB testing, are required to help establish a diagnosis of an active TB infection.

What Is Latent TB Infection?

There are two phases of TB. Both phases can be treated with medicine. When TB germs first enter your body, they cause latent TB infection. Without treatment, latent TB infection can become active TB disease. Anyone can get TB because it spreads from one person to another through the air.

Phase 1 – Latent TB Infection

• TB germs are “asleep” in your body. This phase can last for a very long time – even many years.
• You don’t look or feel sick. Your chest x-ray is usually normal.
• You can’t spread TB to other people.
• Usually treated by taking one medicine for 9 months.

Phase 2 – Active TB Disease

• TB germs are active and spreading. They are damaging tissue in your body.
• You usually feel sick. Your doctor will do special tests to find where TB is harming your body.
• If the TB germs are in your lungs, you can spread TB to other people by coughing, sneezing, talking, or singing.
• Treated by taking 3 or 4 medicines for at least 6 months.

How Can I Tell If I Have Latent TB Infection?

A Mantoux tuberculin skin test (TST) can show if you have latent TB infection. You could have latent TB infection if you have ever spent time close to someone with active TB disease (even if you didn’t know they were sick). Your health care provider will use a small needle to inject some harmless testing fluid (called “tuberculin”) under the skin on your arm.

How Is The TST Administered?

The standard recommended tuberculin test, known as the Mantoux test, is administered by injecting a 0.1 mL of a liquid containing 5 TU (tuberculin units) of purified protein derivative (PPD) into the top layers of skin (intradermally, immediately under the surface of the skin) of the forearm. The use of a skin area that is free of abnormalities and away from veins is recommended. The injection is typically made using a 27-gauge needle, and a tuberculin syringe. The tuberculin PPD is injected just beneath the surface of the skin. A discrete, pale elevation of the skin (a wheal) 6 mm-10 mm in diameter should be produced when the injection is done correctly. This wheal or “bleb” is generally quickly absorbed. If it is recognized that the first test was improperly administered, another test can be given at once, selecting a site several centimeters away from the original injection.

How Do I Take Care Of My Arm After The TB Skin Test?

• Don’t cover the spot with a bandage or tape.
• Be careful not to rub it or scratch it.
• If the spot itches, put a cold cloth on it.
• You can wash your arm and dry it gently.

How Is The TST Read?

The skin test reaction should be read between 48 and 72 hours after administration. A patient who does not return within 72 hours will need to be rescheduled for another skin test.

The reaction should be measured in millimeters of the induration (palpable, raised, hardened area or swelling). The reader should not measure erythema (redness). The diameter of the indurated area should be measured across the forearm (perpendicular to the long axis).

How Are TST Reactions Interpreted?

Skin test interpretation depends on two factors:

• Measurement in millimeters of the induration
• BPerson’s risk of being infected with TB and of progression to disease if infected

Classification Of The Tuberculin Skin Test Reaction

An induration of 5 or more millimeters is considered positive in

• HIV-infected persons
• A recent contact of a person with TB disease
• Persons with fibrotic changes on chest radiograph consistent with prior TB
• Patients with organ transplants
• Persons who are immunosuppressed for other reasons (e.g., taking the equivalent of >15 mg/day of prednisone for 1 month or longer, taking TNF-aantagonists)

An induration of 10 or more millimeters is considered positive in

• Recent immigrants (< 5 years) from high-prevalence countries
• Injection drug users
• Residents and employees of high-risk congregate settings
• Mycobacteriology laboratory personnel
• Persons with clinical conditions that place them at high risk
• Children less than 4 years of age
• Infants, children, and adolescents exposed to adults in high-risk categories

An induration of 15 or more millimeters is considered positive in any person, including persons with no known risk factors for TB. However, targeted skin testing programs should only be conducted among high-risk groups.

What Are False-Positive Reactions?

Some persons may react to the TST even though they are not infected with M. tuberculosis. The causes of these false-positive reactions may include, but are not limited to, the following:

• Infection with nontuberculosis mycobacteria
• Previous BCG vaccination
• Incorrect method of TST administration
• Incorrect interpretation of reaction
• Incorrect bottle of antigen used

What Are False-Negative Reactions?

Some persons may not react to the TST even though they are infected with M. tuberculosis. The reasons for these false-negative reactions may include, but are not limited to, the following:

• Cutaneous anergy (anergy is the inability to react to skin tests because of a weakened immune system)
• Recent TB infection (within 8-10 weeks of exposure)
• Very old TB infection (many years)
• Very young age (less than 6 months old)
• Recent live-virus vaccination (e.g., measles and smallpox)
• Overwhelming TB disease
• Some viral illnesses (e.g., measles and chicken pox)
• Incorrect method of TST administration
• Incorrect interpretation of reaction

The absence of cell mediated immunity to tuberculin may be due to the lack of previous sensitization or due to a false-negative result for various reasons or due to anergy because of immune suppression. Most children with negative result have not been infected with M. tuberculosis. A small proportion of otherwise normal children with M. tuberculosis infection remain PPD-negative for unknown reasons. From the time of infection to the development of CMI there is a window period of some two to six weeks, when the Mantoux test would be negative. Those that are immunologically compromised, especially those with HIV and low CD4 T-cell counts, frequently show negative results from the PPD test. This is because the immune system needs to be functional to mount a response to the protein derivative injected under the skin.

Negative tests can be interpreted to mean that the person has not been infected with the TB bacteria or that the person has been infected recently and not enough time has elapsed for the body to react to the skin test. A repeat test is not advocated before one week as the tuberculin injected for the first test has a booster effect on the subsequent dose. TST may convert to positive ≤eight weeks after Mycobacterium tuberculosisinfection, an interval that is usually referred to as the “window period”. A negative TST obtained less than eight weeks before does not exclude infection, and a second test is recommended after eight weeks. Also, because it may take longer than 72 h for an elderly individual to develop a reaction, it may be useful to repeat the TB skin test after 96 h and again at one week to adequately screen these individuals. Immunocompromised persons may be unable to react sufficiently to the Mantoux test, and either a chest X-ray or sputum sample may be required.

Interpretation in children: A correctly applied Mantoux test can be invaluable in the assessment of a child with suspected TB. The interpretation of the result, however, is often difficult, with different workers using different induration sizes to indicate a positive reaction. Although the test itself is neither 100% sensitive nor 100% specific, the predictive value of a positive reaction is very high in such a group. Malnutrition has previously been shown to affect the results of tuberculin testing. As in other studies, underweight children in this study were significantly more likely to have a negative Mantoux result.

Who Can Receive A TST?

Most persons can receive a TST. TST is contraindicated only for persons who have had a severe reaction (e.g., necrosis, blistering, anaphylactic shock, or ulcerations) to a previous TST. It is not contraindicated for any other persons, including infants, children, pregnant women, persons who are HIV-infected, or persons who have been vaccinated with BCG.
You should have a TB skin test if:

• you have had frequent close contact with someone who has active TB disease,
• you have lived in a country where many people have TB,
• you work or live in a nursing home, clinic, hospital, prison, or homeless shelter, or
• you have HIV infection or certain other health problems.

What if I’ve had BCG vaccine?
Even if you have had BCG vaccine, you can have a TB skin test.

• People who have had BCG vaccine still can get latent TB infection and active TB disease.
• BCG vaccine may help protect young children from getting very sick with TB. This protection goes away as people get older.
• BCG vaccine sometimes causes a positive TB skin test reaction. But if you have a positive reaction to the TB skin test, it probably is from TB germs in your body – not from your BCG vaccine.

How Often Can TSTs Be Repeated?

In general, there is no risk associated with repeated tuberculin skin test placements. If a person does not return within 48-72 hours for a tuberculin skin test reading, a second test can be placed as soon as possible. There is no contraindication to repeating the TST, unless a previous TST was associated with a severe reaction.

What Is A Boosted Reaction?

In some persons who are infected with M. tuberculosis, the ability to react to tuberculin may wane over time. When given TST years after infection, these persons may have a false-negative reaction. However, the TST may stimulate the immune system, causing a positive or boosted reaction to subsequent tests. Giving a second TST after an initial negative TST reaction is called two-step testing. When sensitization to mycobacteria has occurred many years earlier, an initial intradermal injection of tuberculin may produce a negative or weakly positive response due to there being too few sensitized lymphocytes in circulation to produce a significant local response. If the test is repeated, a larger reading may be obtained due to the immune response being ‘recalled‘ or ‘boosted’ by the first test. The second boosted reading is the correct one – that is, the result that should be used for decision-making or future comparison. Boosting is maximal if the second test is placed between one and five weeks after the initial test, and it may continue to be observed for up to two years.

Mantoux Reversion

Reversion is defined as the change to a negative Mantoux result following a previous positive result. Generally this phenomenon is uncommon in healthy individuals, occurring in less than 10% of such people with a previously positive Mantoux.
Reversion is more common

• in older adults (estimated at 8% per year)
• when the initial Mantoux is less than 14 mm
• in those where the initial positive reaction was a boosted result (identified by two-step testing).

Mantoux Conversion

Whereas boosting is a recall of the hypersensitivity response in the absence of new Infection, conversion is the development of new or enhanced hypersensitivity due to infection with tuberculous or non-tuberculous mycobacteria, including BCG vaccination.
Mantoux conversion is defined as a change (within a two-year period) of Mantoux reactivity which meets either of the following criteria:

• a change from a negative to a positive reaction
• an increase of greater than or equal to 10 mm.
• conversion has been associated with an annual incidence of TB disease of 4% in adolescents or 6% in contacts of smear-positive cases

There is debate about the time required for the immunological changes that produce Mantoux conversion following infection. After inadvertent vaccination with M. tuberculosis (the Lubeck disaster), children developed positive reactions in three to seven weeks. Other studies have shown clinical illness, with a positive tuberculin test, from 19 to 57 days after exposure, with a mean of 37 days.
Therefore, when testing TB contacts for conversion, the second tuberculin test is done eight weeks after the date of last contact with the source case. (In the past, the traditional window period, or interval, of 12 weeks was used.)

Why Is Two-Step Testing Conducted?

Two-step testing is useful for the initial skin testing of adults who are going to be retested periodically, such as health care workers or nursing home residents. This two-step approach can reduce the likelihood that a boosted reaction to a subsequent TST will be misinterpreted as a recent infection.

Can TSTs Be Given To Persons Receiving Vaccinations?

Vaccination with live viruses may interfere with TST reactions. For persons scheduled to receive a TST, testing should be done as follows:

• Either on the same day as vaccination with live-virus vaccine or 4-6 weeks after the administration of the live-virus vaccine
• At least one month after smallpox vaccination

Adverse Effects

Though rare there have been reports of anaphylactic reaction and foreign body reaction involving a Mantoux test site. There is a very slight risk of having a severe reaction to the test, including swelling and redness of the arm, particularly in people who have had TB or been infected previously and in those who have previously had the BCG vaccine. Allergic reactions are also rare complications. Live bacteria are not used in the test so there is no chance of developing TB from the test. Local reactions such as regional lymphangitis and adenitis may also occur on rare occasions.

Can TSTs Be Given To Persons Receiving Vaccinations?

Mantoux testing is not recommended in the following situations:

• Past Mantoux reactions greater than or equal to 15 mm: repeating the test will provide no new diagnostic information and will create discomfort
• Previous TB disease: no useful diagnostic information will be gained and significant discomfort is likely
• Infants under 12 weeks old: a positive reaction is very important, but a negative reaction may indicate that the child is too young to mount a response, and the test will need to be repeated if exposure has occurred. Pre-vaccination Mantoux testing before 12 weeks of age is not necessary unless the baby has been exposed to TB