About Tuberculosis

Tuberculosis disease is caused by a bacterium that can affect any part of the body, but most commonly the lungs. Only TB of the lungs or throat is infectious. The infection is generally transmitted by prolonged and/or frequent contact with an infected individual who is coughing bacteria droplets into the surrounding air. The bacteria are breathed in through the lungs, but can travel in the blood to other organs which become infected. Diagnosis of these non-pulmonary forms can be more difficult, as the person will not have the cough so commonly associated with TB.

A few years ago TB was thought to be a disease of the past, particularly in the developed world. However, for a number of reasons, the disease has failed to be eliminated and in 1993 was declared as a global emergency by the World Health Organisation (WHO).

Tuberculosis Infection and Tuberculosis Disease

Tuberculosis infection (latent TB infection) occurs when people carry Mycobacterium tuberculosis bacilli in their body but the bacteria are being controlled by the infected person’s immune system and so are still in small numbers. These bacteria do not cause disease or any TB symptoms. Individuals with latent TB infection are not infectious. They are negative to most TB tests including culture, Nucleic Acid Amplification Tests (NAAT), and smear microscopy. Small nodules are occasionally seen on chest x-ray or CT scan. Until recently the only test capable of identifying LTBI has been the tuberculin skin test.

Tuberculosis disease (active disease) occurs when the bacterial load increases and overcomes the body’s immune defence. Tuberculosis disease may be infectious and is often characterised by one or more of the following symptoms:

  • severe cough for 2 or more weeks (often involving blood loss)
  • weight loss
  • night sweats
  • poor appetite
  • weakness or fatigue (tiredness)
  • chills
  • fever
  • pain in the area infected

Active disease can often (but not always) be identified by culture, smear microscopy, NAAT or chest x-ray. The number of people with active TB at a given time is just the tip of the iceberg, as many more are infected with TB and are therefore at a risk of developing the disease.

To view the relationship between active disease and latent infection click on the thumbnail.

 natural_history_TB_Thumb

Importance of Identifying Latent TB Infection (LTBI)

TB control methods are based on three strategies:

  1. Vaccination using BCG. However, the vaccination is being used in fewer countries as its long term efficacy has been questioned.
  2. The diagnosis and treatment of active disease is important for individuals who have TB. It also reduces the onward transmission of the disease once diagnosis and subsequent treatment has been instigated.
  3. The diagnosis and treatment of Latent TB Infection (LTBI).

Active disease occurs following a variable time during which the subject has LTBI. Therefore, the European framework for tuberculosis control and elimination in countries with a low incidence recently recommended that “Tuberculosis control and elimination strategies must aim at diminishing the incidence and prevalence of latent infection to reduce the pool of those with tuberculosis infection from which future cases of tuberculosis will emanate1.”

Latent infection can only be reduced by firstly identifying those who are infected. This is achieved by testing specific groups with:

  • Greater risk of transmitting the disease (healthcare workers, military personnel, immigrants, contacts of index cases)
  • Higher risk of progression to active disease (immunocompromised subjects, including HIV infected, renal patients, transplant patients, haematological disorders and those taking immunosuppressive drugs).

Once people with latent infection have been identified they can be given preventative therapy which will eliminate the Mycobacteria tuberculosis and so prevent conversion to active disease and eliminate the onward progression of the disease.

1Broekmans J, et al Eur Respir J 2002; 19: 765-775

Diagnostics for Tuberculosis:  Global Demand and Market Potential/TDR, FIND SA.  WHO 2006: p. 21.
Diagnostics for Tuberculosis: Global Demand and Market Potential/TDR, FIND SA. WHO 2006: p. 21.

Diagnostic Tests for Detecting Latent Tuberculosis

Until recently, the only test available to diagnose LTBI has been the tuberculin skin test (TST). The test has remained more or less unmodified for the last 60 years. The T-SPOT.TB blood test offers a 21st century alternative to the TST providing greater accuracy, convenience and logistical advantages.

Diagnostic Tests for Detecting Active Tuberculosis

People who are suspected of having active TB may be given a number of different tests to confirm the damage caused by the infection or to identify the organisms responsible for the infection.

Skin test
The tuberculin skin test described previously is sometimes used for the diagnosis of active tuberculosis, with the same limitations. The skin test can only identify if a person has or does not have TB infection, it doesn’t differentiate between latent and active TB.

Radiological examinations – Chest X-ray and CT scan
Chest X-ray is used to check for lung abnormalities in people who have symptoms of TB disease. The results of a chest X-ray may be suggestive of TB; however the technique is not specific as many other diseases produce similar features. Even experienced radiologists have difficulty in determining the cause of some abnormalities. Therefore the results from a chest X-ray cannot confirm that a person has TB disease (i.e. the test is imperfect as a ‘rule in’ test). Using chest X-ray, it is difficult to distinguish past, cured TB from current active disease since scarring in the lungs remains after a previous TB infection (even if the patient is completely cured).

TB chest x-ray (left) and CT scan (right)
TB chest x-ray (left) and CT scan (right)

The chest X-ray also has poor sensitivity; in the early stages of disease, the damage to the lungs may not yet have become sufficiently marked to be detectable so people who have active TB are missed. It is therefore an imperfect ‘rule out’ test. Clearly the chest X-ray is completely useless as either a rule in or a rule out test if the TB is not in the lungs. So in the 40% of all cases of active TB where the disease is not found in the lungs (extra or non-pulmonary TB) the chest X-ray is of no use.

In some hospitals Computerised Tomography (CT Scan) and Magnetic Resonance Imaging (MRI) have proved useful for imaging tuberculosis lesions, particularly those in the brain and spine. CT scans are therefore often used to identify non-pulmonary TB.

Smear Microscopy
The simplest laboratory test is the examination of sputum for the detection of acid-fast bacilli (AFB). This diagnostic test reagents are cheap and the test is performed in minutes. However, the WHO estimates that it only identifies 35% of patients with active TB. As the test identifies Mycobacterium tuberculosis cells suspended in liquid samples it has particular difficulty in detecting many forms of non-pulmonary TB which occur in a variety of organs in the body. This test will also identify acid fast bacilli other than Mycobacterium tuberculosis so its specificity is less than 100%.

Despite these shortcomings it remains the front line tool for active TB diagnosis, partly because the more definitive culture techniques take longer and because it can also determine if a person is infectious. It is argued that while AFB bacilli are found in the sputum the patient can continue to pass on the disease to other people.

In some countries patients are kept in hospital until there are no AFB visible in the sputum as they are then considered not to be infectious. Sputum smear is thus one method that can be used to monitor an active TB patient’s response to therapy.

Ziehl-Neelsen acid fast stain
Ziehl-Neelsen acid fast stain

The MTB are the small red rod shaped organisms. Auramine fluorescence stains are a newer adaptation of this test. It requires fluorescence microscopy but is a little more sensitive as the fluorescence is easier to see than the coloured stain.

Culture
Culture techniques are still seen as the gold standard for active TB as they can be extremely sensitive, so long as live mycobacteria can be obtained in the sample. It is therefore the “gold standard” test since a positive result means that the person is infected with Mycobacterium tuberculosis. It is therefore used for comparison with other methods when calculating sensitivity in active disease. Mycobacterium tuberculosis can be cultured from a variety of specimens including sputum, central spinal fluid (CSF), pleural effusion, bronchoalveolar lavage (BAL), gastric aspirate etc and can thus be used to detect pulmonary as well as non-pulmonary disease. By assessing the effect of antibiotics on the cultured bacilli, this technique can also identify the antibiotic susceptibility of the particular strain of TB infecting the patient. It is therefore the main method for identifying if a person has multi-drug resistant (MDR) TB.

However, it is not always possible to obtain Mycobacteria in the sample, especially in non-pulmonary TB, so culture techniques do not have high sensitivity.

If performed correctly, culture should have very high specificity and can distinguish Mycobacterium tuberculosis from other Mycobacteria. A drawback of this test is the time to result which can be anything from 2 to 6 weeks.

NAAT
Nucleic acid amplification tests (NAATs), such as polymerase chain reaction (PCR), are a relatively new development in active TB testing. Even though NAAT techniques can magnify even the smallest amounts of genetic material, the sample used still has to contain a certain number of TB bacilli and this is not always possible, particularly with non-pulmonary TB where sensitivity can be as low as 60%. To increase the number of bacilli in the sample, and hence improve the sensitivity of the test, the laboratory will often culture the sample, to allow the bacilli to multiply, before carrying out the PCR test. This can take several days or weeks. The main use of NAAT is not to diagnose TB per se, but to rule out infections caused by atypical mycobacteria in a sputum smear positive patient, before culture results are known. This helps treatment to be initiated quickly, with the therapy then being modified later based on the culture results obtained a few weeks later.

More recently NAATs have been used to identify MDR TB as mutations in the DNA of MTB which confer drug resistance have been discovered. These methods are quicker than culture but generally only identify resistance to rifampicin and isoniazid.