Introduction

Tuberculosis (TB) is a chronic infectious disease, caused by Mycobacterium tuberculosis (MTB) of which there are three types that infect humans:

  • M. tuberculosis – by far the most common type
  • M. bovis (bovine TB)
  • M. africanum

Tuberculosis is present in about 30% of the global population, but in developed countries it is rare since the advent of TB inoculation. Incidence in Australia is about 5-6 per 100 000 per year. Patients from developing countries, or remote indigenous communities within Australia are at much higher risk.

Infectious patients cough up large quantities of mycobacterium which can remain in the environment for a long period of time.

When MTB is encountered by the immune system, it is engulfed by macrophages, and these complexes form granulomas. These typically occur in the lungs, but the bacteria can also be carried to distant sites through the lymphatics, and granulomas can form at other sites. In most cases – up to about 80% – these granulomas heal and the infection is cured. In the majority of the remaining cases – about 90% –  the infection does not spread beyond the lungs, and becomes “latent” as it is kept under control within a granuloma by the host immune system. Latent TB is typically asymptomatic and may only present itself much later in life, and / or as a result of immunosuppression – thus becoming active TB. 

Testing for TB depends on the stage of the disease:

  • Latent TB – interferon gamma release assay (IGRA) or Tuberculin skin testing (TST)
  • Active TB – CXR and microbiology (usually sputum) for acid fast bacilli

Once identified, both latent and active TB should be treated. Multi-drug resistance (MDR TB) is common and treatment may often lasts for months or years on multiple antimicrobial agents, often with unpleasant side effects.

TB can cause a wide range of non-specific signs and symptoms, and as such, is often at the end of long lists of differentials!

Organism

Mycobacterium tuberculosis

Transmission

Via droplet spread – only the pulmonary form is infectious
Usually needs sustained close contact with an infectious case.

Epidemiology

  • Roughly one third of the world’s population has been infected with M. tuberculosis (2 billion people)
  • Nearly nine million new cases of TB, and 1.4 million deaths from TB per year (majority in developing countries)
  • Leading cause of death due to a curable infectious disease
  • Significant number cases occur in those co-infected with HIV
    • TB is though to be responsible for the deaths of 20% of patients with HIV
  • Approximately 9000 cases reported each year in the United Kingdom (mostly in large cities, especially in London), causing 350 deaths each year
    • About 1000 per year in Australia
    • Incidence is decreasing in developed countries but increasing in developing countries, due to increased drug resistance, HIV and an ageing population
  • Around 10% of cases are drug resistant

Risk factors

  • HIV (13% cases also have HIV)
  • Overcrowding/close contact with active case (1/3 chance of contracting from household member)
  • Ethnic minority groups
  • Malnutrition
  • IV drug use
  • Homelessness
  • Chronic lung disease
  • Immunosuppression

Transmission

  • Patients with active TB will infect on average 10-15 people per year
  • Household contacts have a 1 in 3 chance of contracting the infection
  • Healthcare workers and close social contacts are also at risk (e.g. at school or at work)
  • It is thought that most cases of active TB occurs many years after the initial infection was contracted

Pathogenesis

  • Mycobacteria reach the pulmonary alveoli
  • These are engulfed by alveolar macrophages and replicated within them.
    • In the vast majority of cases, the initial infection is contained in the lungs by the immune system, and does not spread, not cause an acute illness

Primary site of infection (in the lungs) = “Ghon focus” (generally in upper lobe)

  • Lymphocytes surround the infected macrophages along with fibrolasts and this causes granuloma formation
  • This prevents dissemination of bacteria (prevents extra-pulmonary TB)
  • Inside these lesions, the bacteria may develop abnormal cell death in the centre (caseous necrosis) and can eliminate the bacteria
  • This is sometimes referred to as LTBI – latent tuberculosis infection
  • In some instances infection can even be cleared
  • There is a 10% chance that LTBI can develop into active TB during a patient’s lifetime. The risk is greatest during the first two years of infection
    • Active TB typically presents with fever, night sweats, weight loss and cough, lasting usually more than 2-3 weeks

Alternatively, if there is a failure of the above mechanism…
The bacteria may gain entry to the bloodstream can spread throughout the body and set up many foci of infection (tubercles) (e.g. miliary TB).This is extra-pulmonary TB

  • Those with less effective immune systems progress to primary progressive tuberculosis
  • For less immunocompetent people, granulomas are formed but then the necrotic tissue undergoes liquefaction and the fibrous wall breaks down. Necrotic material then
    • Drains into bronchi and is coughed up and can infect others
    • Drains into nearby blood vessels and seeds to other areas leading to extrapulmonary TB

 

Clinical features

  • 90% of cases exhibit pulmonary features only
  • 10% exhibit extrapulmonary features

Differentials

TB is often associated with a wide range of differential diagnoses. Some oft he more likely include:

Complications

Multi-drug resistant TB (MDR-TB)- can develop of TB is not properly treated.

Diagnosis

Active TB

  • CXR. Signs may include:
    • Patchy nodal shadows in the upper zones
    • Cavitating lesions
    • Fibrous contractions
    • Air space consolidation
    • Typically apical lesions
    • Milliary TB – multiple 1-10mm nodules throughout the lungs
    • It may be difficult to distinguish active from latent TB on CXR alone
  • Samples e.g. sputumpus, or a tissue biopsy:
    • 3 separate sputum samples in pulmonary TB (including one early morning sample)
    • Can do broncoscopy and lavage or gastric washings (rarely required)
    • Ziehl-Neelsen (ZN) stain – rapid direct microscopy for acid-fast bacilli
      • Detects about 50% of cases of TB on a single sample
      • TB bacteria stain in a characteristic way due to the waxy nature of their walls
      • Culture used to confirm the diagnosis
    • Löwenstein-Jensen culture (takes 4-8 weeks due to slow bacterial growth and sensitivities take a 3-4 weeks more)
      • Samples also tests for drug sensitivities
      • Multi-resistant strains may require up to 20 months of treatment
  • Molecular assays
    • Detect MTB DNA
    • Also detects if rifampicin resistant

*treatment should be started before culture results are back, and continued even if cultures are negative*

Latent tuberculosis

Mantoux tuberculin skin test aka Tuberculin skin test (TST) – used to screen people at high risk for TB

  • Tuberculin protein is injected into the dermis
  • Patient re-presents after 48-72 hours and the level of inflammation at the inject site is assessed – by measuring the size of the induration
    • The diameter of the induration (inflammation) gives an indication of the likelihood of TB infection
  • “Positive” (i.e. TB present) results require correlation with a patient’s risk factors
    • >5mm induration – positive result for patients with HIV or other immunosuppression, recent contact with known TB
    • >10mm induration – positive result for patients in high risk areas, or moved from high risk area <5 years ago, IV drug users, residential care / hospital patients
    • >15mm induration – positive result for patients with no underlying risk factors
  • False positives in those previously immunised
  • False negatives in certain conditions such asarcoidosisHodgkin’s lymphoma

Interferon gamma release assays (IGRA) – aka quantiferon gold test

  • Results not affected by previous TB vaccination
  • Positive test indicates that the patient’s immune system has prior recognition of TB antigens (not due to vaccination) and thus indicates previous, latent or active TB. Further testing is required (as above) to assess if test indicates latent or active disease

Positive result with either TS or IGRA indicates the need to investigate for active TB

There are no agreed guidelines on whether TST or IGRA is the preferred method. Australian guidelines recommend the use of TST first line and IGRA if TST is not conclusive (or if previously vaccinated).

Contact screening

  • Offer latent TB testing to household contacts to close work and school contacts to patients who have been diagnosed with active TB

Treatment

Local guidelines are variable and depend on the strains present in the local community. Treatment is recommended for most cases of latent TB and obviously all cases of active TB.

Antibiotics

For more infor see ‘extra info’ section below

  • Multidrug regimen for prolonged period in active disease (isoniazid and rifampicinpyrazinamide and ethambutol)
    • All 4 for 2 months, then,
  • Single antibiotic for latent TB for 3-6 months
  • MDR-TB should be treated with at least four effective antibiotics for 18 to 24 months is recommended.

 

Prevention

  • Vaccination (BCG)
  • Public health measures: treatment/prophylaxis of contacts etc
  • Notifiable disease in UK

Extra Info

Drugs used in TB

Rifamycins
Inhibits DNA transcription
Rifamycin, rifabutin
Cidal
Nausea, anorexia, pseudomembranous colitis, hepatotoxicity, orange colouration of excreted bodily fluids, toxicity syndromes, drug interactions
Also used in mycobacterial infections – these most commonly occur in those with HIV. Resistance prevents more widespread use
Widespread – develops rapidly
Y
?
?
?
Isoniazid
Inhibits synthesis of cell wall
Isoniazid
Cidal / static
Nausea, vomiting, constipation, peripheral neuropathy, hepatitis, SLE-like-symptoms
Bactericidal on dividing organisms, static on resting. Only effective against myobacteria
Occurs rapidly if used alone
N
N
N
?
Pyrazinamide
Lowers intracellular pH, disrupting synthesis of fatty acids
pyrazinamide
Cidal
Hepatotoxicity, nausea, vomiting, arthralgia, sideroblastic anaemia
Only effective against myobacteria
Occurs rapidly if used alone
N
N
N
?
Ethambutol
Interferes with cell wall synthesis
Ethambutol
Static
Optic neuritis – resulting in red/green colourblindness. neuritis
Only effective against myobacteria
Uncommon
N
N
N

Mycobacteria

This is its own genus of bacteria (like G+ or G-). The group include TB and leprosy. They are acid fast. They are also aerobic.
 
Acid fast
This basically means the organisms are difficult to stain using normal staining techniques. The name refers to the fact they can’t be stained by normal acid (ethanol) staining techniques. These bacteria are often particularly difficult to culture and identify; e.g. TB takes around 6-8 weeks

 

References

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