Introduction

Tuberculosis (TB) is caused by bacteria of the Mycobacterium tuberculosis complex. It is a notifiable disease with important public health and management implications which may include isolation and contact tracing.

If untreated, tuberculosis has a high mortality, 33% of untreated patients die within one year.

Mycobacterium tuberculosis is transmitted from person-to-person almost exclusively via droplet nuclei while speaking, sneezing or coughing.  The infection does not necessarily produce active tubercular disease. The infection can heal spontaneously, or more often, be contained by the immune system in a ‘dormant’ or ‘latent’ stage which may last for many years, only reactivating later in life if the person becomes debilitated or immunocompromised.

In HIV-positive individuals the risk of development of tuberculosis is dependent upon the CD4+ cell count. TB often appears when the cell count is still fairly high (250–500/microL) therefore TB can be an early AIDS-defining disease.  HIV testing may be required when a diagnosis of TB is made, consult your local guidelines.

Aetiology of tuberculosis

Mycobacterium tuberculosis is an intracellular pathogen. On inoculation (usually inhalation into the lungs), it is phagocytosed by monocytes. There are then three possible outcomes:

• Active disease
• Complete resolution with no signs of disease
• Latent disease
  

Diagnosis of tuberculosis

Rapid diagnosis of TB is important for the treatment of the individual patient and to implement appropriate public health precautions. 

Clinical

The clinical presentation depends on the organs involved. The majority of infections present with pulmonary TB.

Extrapulmonary manifestations and disseminated tuberculosis are more common in patients with AIDS.

Laboratory diagnosis

The laboratory has a critical role in the early diagnosis and management of TB, determining infectiousness and assessing drug susceptibility, as well as in the longer-term management, especially if multi-drug resistant TB (MDR-TB) is involved.

Pulmonary TB. Sputum samples taken first thing in the morning on three consecutive days should be obtained and sent to the laboratory for microscopy and culture.

Extrapulmonary TB. Specimens from the appropriate sites, such as a draining sinus should be obtained and sent to the laboratory for microscopy and culture.

• Microscopy. A presumptive diagnosis of tuberculosis can be made on the presence of acid-fast bacilli under microscopic examination of direct smears. Although less sensitive than culture, microscopy is a key test in both diagnosis and establishing infectiousness. If sputum samples from a previously positive patients are negative on three consecutive occasions over 14 days, (or a duration proportionate to the effectiveness of the drug treatment), the patient can be assumed to be non-infectious by the respiratory route. 
• Culture. A definitive diagnosis of TB requires identification of Mycobacterium tuberculosis from a specimen (eg. sputum or tissue such as lymph node biopsy).  Mycobacteria are slow-growing (3–6 weeks on solid media and 1–4 weeks in liquid media) but a provisional identification can be made by PCR or the colony appearance and growth characteristics. Susceptibility to chemo-therapeutic agents ought to be established. Sensitivity testing is normally performed at a reference laboratory.
• Rapid diagnostic tests. Several technologies have been utilised in an attempt to create a rapid test for TB including PCR. Some of these rapid amplification tests can give a result in 24 h but are expensive, are no more sensitive than an acid-fast bacilli film and are not a substitute for culture, but may be useful in certain patients (eg. if MDR-TB is suspected). Discuss with your microbiologist.

Due to the time required for culturing Mycobacterium tuberculosis, a presumptive diagnosis can be made on clinical grounds supported by Heaf test or other tuberculin tests.

Imaging

• In a patient with respiratory symptoms, tuberculosis may be suspected based on x-ray evidence.

Other diagnostic tests

Management of tuberculosis

The treatment should be supervised by a physician with full training in the management of TB with direct access to a TB nurse or health visitor especially if MDR-TB is suspected or confirmed. Seek specialist advice.

Decisions on the type of isolation required should be made at consultant level, in discussion with the Infection Control Doctor considering the infectiousness of the patient, the type of facilities available, local policies and the possibility of multi-drug resistant strains of TB.

Treatment will generally depend on whether the infection is active or latent. It is usually only necessary to treat latent infection in certain individuals eg.

• HIV +ve
• Close contacts of patients with active infection
• Other high-risk groups such as IV drug users.

Patients with smear positive pulmonary TB should be kept in suitable isolation facilities until non-infectious.

Antibiotic rationale

There are four main problems in the antibiotic treatment of TB. 

• Mycobacterium tuberculosis is an intracellular pathogen. In addition, the organism is slow growing and often metabolically inactive, giving fewer biochemical targets for chemotherapy. There are a limited number of effective agents.
• A very few remaining organisms can produce recurrent disease, which is more likely to be drug-resistant.  Therefore, treatment regimens must be sufficiently long to eradicate the infection, typically 6–12 months. 
• Resistance to monotherapy is reasonably widespread.  Treatment is normally initiated with multiple drugs to cover the possibility of a resistant strain. The regimen can be ‘stepped down’ when sensitivity results are available.
• Compliance is a major problem and poor compliance can lead to relapse and the emergence of drug-resistant disease.  Several factors contribute to poor compliance:
• The duration of treatment (6–12 months)
• The multiple combination regimens
• The toxicity or interactions of the drugs used (eg. rifampicin potentiates the metabolism of opiate drugs so addicts may find it difficult to comply)
• The type of patients at risk (many patients have little stability in their lives eg. the homeless and IV drug users).

Directly observed therapy can help improve compliance in specific vulnerable groups.

TB and HIV drug interactions

Rifampicin induces cytochrome 3A P450 which metabolises protease inhibitors. This may lead to variable or undetectable levels of the protease inhibitor. The risk-benefit of alternative treatments needs to be considered on an individual patient basis. 

Antibiotic regimens

The British Thoracic Society guidelines recommend that patients with pulmonary tuberculosis should be treated as follows.

Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998.

Recommended doses of standard antituberculosis drugs for adults