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Tuberculosis

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Overview

Active and latent tuberculosis

Tuberculosis (TB) is an infection caused by Mycobacterium tuberculosis. It is spread through inhaling respiratory droplets. TB is a notifiable disease.

Active tuberculosis – when evidence of symptomatic/progressive disease of the lung and/or other organs. If untreated, one person with active pulmonary TB can spread the infection.

Latent TB – a persistent immune response to TB antigens without clinical evidence of active TB. The person is asymptomatic but not infectious. It may reactivate, and cause active TB.

Extrapulmonary and disseminated tuberculosis

Active extrapulmonary TB – symptoms that are seen in regions outside of the lungs, including the meninges, lymph nodes, bones and joints, heart, eyes, and gastrointestinal system etc.

Disseminated (miliary) TB – when ≥2 organ systems are affected which is more common in children and immunocompromised people, however, it can occur in the absence of immunodeficiency.

Multidrug-resistant TB – a strain of TB that is resistant to two first-line drugs. Taking the wrong dose or combination, or irregularly can increase the risk of this. Extensively drug-resistant TB may occur if further resistance occurs.

Pathophysiology

Primary tuberculosis

Upon entering the lungs, Mycobacterium tuberculosis infects the lungs and can proliferate within alveolar macrophages, resulting in tubercle-laden macrophages known as a Ghon focus. These combined with hilar lymph nodes form Ghon complexes. In immunocompetent people, the initial lesion heals by fibrosis. However, those who are immunocompromised may develop disseminated TB.

Secondary tuberculosis

If the person becomes immunocompromised (e.g. HIV), the infection can reactivate, which often happens in the lung apex and can spread. The most common area of secondary infection is the lungs. If bacteraemia occurs in primary/secondary infection, then deposits of bacteria can occur in different organs, which can also reactivate, resulting in disseminated infections. Sites that may be affected include spinal TB (osteomyelitis), TB meningitis, TB pericarditis, and abdominal TB.

Epidemiology

  • In 2021, the annual TB incidence in England was 7.8 per 100,000.

Risk Factors

Risk factors include:

  • Living in an endemic area (e.g. Asia, Africa, Eastern Europe, Latin America)
    • High prevalence areas are defined as >40 cases per 100,000 population per year
  • Exposure to a person infected with TB
  • HIV – the risk of developing active TB is 20-30 times more likely
  • Immunocompromised states – including immunosuppressive treatment and diabetes mellitus
  • Lung fibrosis – including silicosis and apical fibrosis
  • Young children – are more likely to develop severe disease
  • Poverty and deprivation – including hostels, shelters, prisons etc.
  • Alcohol
  • Intravenous drug use
  • Smoking

Presentation

Features of active tuberculosis include:

Features of extrapulmonary tuberculosis include:

  • Skin involvement – erythema nodosum (occurs due to a TB hypersensitivity reaction), lupus vulgaris (painful nodular lesions on the face)
  • Lymphadenopathy – often painless, rubbery, and in the supraclavicular and cervical regions
  • Neurological involvement – headache, vomiting, confusion, cranial nerve palsy
  • Skeletal/joint involvement – bone/joint pain, joint swelling, back pain
  • Abdominal involvement – abdominal/pelvic pain, constipation, bowel obstruction
  • Urinary involvement – dysuria, polyuria, haematuria

Investigations

Overview

Tests and their results include:

  • Chest X-ray: may show hilar lymphadenopathy, cavitation, and pleural effusion:
    • Upper lobe cavitation can suggest reactivated TB
    • Features tend to affect the upper lobes
  • Sputum smear – should be done with 3 specimens:
    • The sample is stained with the Ziehl-Neelsen stain for acid-fast bacilli
    • This is non-specific as it will stain positive for all Mycobacteria species
  • Nucleic acid amplification tests (NAAT):
    • Allows quicker diagnosis within 48 hours, but is less sensitive than culturing
  • Sputum culture – the gold-standard test:
    • This also can assess drug sensitivities, however, takes 1-3 weeks
  • HIV testing – should be offered to all people with TB:
    • HIV can alter the treatment of TB and may be the cause of its reactivation

Screening

Overview

Asymptomatic people at high risk should be screened for TB. This can include people in close contact with active TB, household members etc.

Screening tests may identify latent TB, however, their results depend on the person’s immune status, history of TB exposure, and whether they have had the Bacillus Calmette-Guérin (BCG) vaccination. They can include:

  • Mantoux test – tuberculin is injected intradermally:
    • Skin induration >5 mm represents a positive result
  • Interferon-gamma release assay (IGRA) – testing white blood cells’ response to TB antigens:
    • This is faster and less likely to give a false positive result

If a test for latent TB infection is positive, the person should be assessed for TB. If there is no evidence of active infection, then the person should be treated for latent TB to prevent progression to active disease.

If a test for latent TB infection is positive:

Management

Referral

If a person has suspected/active TB, arrange admission or referral depending on clinical judgement:

  • Hospital admission – if highly symptomatic, systemically unwell, or has complex needs (e.g. homelessness)
  • Urgent referral to local multidisciplinary TB team – for all other cases to confirm diagnosis and start management

Active tuberculosis

The management of active tuberculosis can be remembered with the acronym RIPE:

  • Rifampicin for 6 months
  • Isoniazid for 6 months
  • Pyrazinamide for 2 months
  • Ethambutol for 2 months

Latent tuberculosis

The management of latent tuberculosis may be one of the following:

  • 3 months isoniazid + pyridoxine + 6 months rifampicin or
  • 6 months isoniazid + pyridoxine

Tuberculosis Drugs

Rifampicin

Mechanism of action

Rifampicin works by inhibiting bacterial DNA-dependent RNA polymerase, resulting in reduced RNA synthesis and cell death.

Adverse effects

Adverse effects of rifampicin include:

  • Orange secretions
  • Hepatitis
  • Nausea and vomiting
  • Interactions with other medications due to P450 enzyme induction

Isoniazid

Mechanism of action

Isoniazid works by inhibiting mycolic acid synthesis, disrupting cell wall synthesis.

Adverse effects

  • Peripheral neuropathy – pyridoxine (vitamin B6) is co-prescribed to prevent this
  • Hepatitis
  • Interactions with other medications due to P450 enzyme inhibition

Pyrazinamide

Mechanism of action

The mechanism of action of pyrazinamide is unknown, however, its activity requires its conversion to pyrazinoic acid which inhibits mycobacterial pyrazinamidase.

Adverse effects

  • Hepatitis
  • Hyperuricaemia and gout – due to inhibiting uric acid excretion
  • Photosensitivity
  • Arthralgia

Ethambutol

Mechanism of action

Ethambutol’s mechanism of action is not completely known, however, it works by inhibiting arabinosyl transferase, reducing the polymerisation of arabinose into arabinan, which gives it bacteriostatic effects.

Adverse effects

  • Optic neuritis – visual acuity is checked before and during treatment
  • Nephrotoxicity

Complications

Respiratory complications – haemoptysis, bronchiectasis, pneumothorax, lung parenchymal destruction, empyema, and aspergillosis.

Immune reconstitution disease – a transient worsening in symptoms seen 3-6 weeks after starting treatment and can present with enlarging lymphadenopathy, fever, and worsening chest X-ray findings.

Drug resistance – the risk is higher if treatment is not taken properly (e.g. incorrect dose, timing, duration etc.)

Obstetric complications – including vertical transmission, miscarriage, restricted foetal growth, preterm labour, pre-eclampsia, and postpartum haemorrhage.

Prognosis

  • If untreated, TB slowly progresses and can lead to death
  • The proportion of deaths is around twice as high in people with HIV and TB versus TB alone

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