Background Information

Definitions

Tuberculosis (TB): infectious disease caused by bacteria of the mycobacterium tuberculosis complex, predominantly Mycobacterium tuberculosis

By Clinical State

• Active TB: symptomatic form of TB
  • Pulmonary TB → active TB affecting the lungs; most common presentation (52.8% of UK cases in 2021)
  • Extrapulmonary TB → active TB involving other sites
  • Disseminated TB → TB affecting ≥2 organ systems
    • Miliary TB: subtype of disseminated TB caused by massive haematogenous spread of infection, producing numerous tiny nodules (1-2mm) throughout the lungs, which resemble millet seeds on imaging ^[Ref]

 

• Latent Tb: asymptomatic form of TB, but with a state of persistent immune response to M.tuberculosis antigens, but no clinical or radiographic evidence of active disease 

By Natural History

Primary TB: ^[Ref]

• Initial infection with mycobacterium tuberculosis in a previously unexposed invididual

Secondary (Post-primary OR Reactivation) TB: ^[Ref]

• Active TB that develops in a person with previous infection with mycobacterium tuberculosis, who either has latent infection (latent TB) OR prior history of primary tuberculosis
  • Most common cause → reactivation of latent TB, typically years after initial infection, often when host immunity is compromised
  • Less commonly → exogenous reinfection

By Drug Resistance

Multidrug-resistant TB (MDR-TB) 

• TB resistant to isoniazid and rifampicin 

Extensively drug-resistant TB (XDR-TB)

• MDR-TB that is also resistant to any fluoroquinolone and ≥1 Group A drug (bedaquiline or linezolid)

 

Epidemiology

Global 

• Considered an epidemic 
• Leading cause of death due to a single infectious agent (2nd only to COVID-19 in 2021)
  • Higher mortality burden in children
• Latent Tb is common (~1/4 of world’s population)

England/UK

• Low-incidence country
• Most cases → pulmonary TB (52.8%)
• Demographics
  • ~3/4 of cases = people born outside UK 
  • Much higher incidence in non-white ethnic groups
  • Men > women (60%)
• Geography: London = 35% of all cases
• Risk factors: strongly linked to deprivation 

Associated social characteristics → alcohol misuse, drug misuse, homelessness, imprisonment, mental health needs and asylum seeker status

Associated medical co-morbidities → diabetes, immunosuppression, cancer, steroid use, autoimmune disease

Aetiology

Species

Species	Primary Host	Transmission	Key Distinguishing Feature	Geography
M. tuberculosis	Humans	Airborne droplets	Principal cause of human TB; can persist in latent state	Global
M. bovis	Cattle (zoonotic)	Unpasteurised dairy; direct animal contact	Intrinsically pyrazinamide-resistant; requires treatment modification	Global (sporadic in humans, linked to bovine TB control)
M. africanum	Humans	Airborne (less transmissible)	Restricted to West Africa; slower progression	West Africa (rare outside except in immigrants)

Microbiological Features of Mycobacterium tuberculosis

Type

• Facultative  intracellular, rod-shaped bacillus 
• Aerobic, very slow-growing
• Mycobacterium species inc. Mycobacterium tuberculosis are examples Acid-fast bacilli (AFB)

Gram stain

• Does not stain well due to lipid-rich  cell wall

Special stains (for AFB)

• Ziehl-Neelsen (ZN): AFB appear red/pink against blue background OR
• Auramine-rhodamine fluorescent stain: AFB appear reddish-yellow on fluorescence microscopy

Risk Factors

Demographic and Geographic Factors

• Born in high-prevalence regions (>40 cases per 100,000/year).

• Non–UK-born individuals have ~18-fold higher incidence than UK-born (most commonly from India, Pakistan, Romania, Somalia, Eritrea).

• Male sex (≈60% of UK TB cases).

• Children under 5 years – higher risk and more severe (often extrapulmonary) disease.

Exposure History

• Close contact with individuals with active pulmonary or laryngeal TB

• History of untreated or inadequately treated TB → increasing risk of recurrence and drug resistance

Medical Comorbidities
Most comorbidities increase risk through immunosuppression (esp. impaired cell-mediated immunity)

• Immunodeficiency & haematological disorders → HIV infection (strongest risk factor for TB), haematological malignancies, post–solid organ transplantation (immunosuppressive therapy)
• Metabolic and Systemic conditions → diabetes mellitus, chronic kidney disease (particularly on dialysis), cirrhosis, malnutrition
• Drug-induced immunosuppression  → prolonged high-dose corticosteroids, cytotoxic chemotherapy, biologic agents (e.g. anti–TNF-α drugs)
• Local or structural predisposition → silicosis or other occupational lung diseases, previous gastrectomy or jejunoileal bypass surgery

 

Social and Environmental Determinants

• Deprivation: those in the most deprived 10% of areas have >6× higher TB incidence
• Crowded living conditions (e.g., hostel/shelter residency, prison/detention centres)
• Homelesness

 

Lifestyle Factors

• Excessive alcohol use
• Injecting drug use (IVDU)
• Smoking

Complications

Pulmonary

Complications due to structural parenchymal damage ^[Ref]

• Lung cavitation
  • Infection predisposition
    • Aspergilloma → fungal ball developing in residual Tb cavities
    • Secondary bacterial infections (of cavities or damaged lung tissue)
  • Massive haemoptysis (erosion of blood vessels overlying a lung cavity)
• Bronchiectasis
• Lung fibrosis & scarring (restrictive lung disease)
• COPD

Vascular and haemorrhagic complications 

• Rasmussen aneurysm

Other 

• Pneumothorax
• Fibrosing mediastinitis
• Cor pulmonale (secondary to chronic hypoxia / scarring)

 

Extrapulmonary Manifestations / Complications

System / Site	Complication
Pleural	Pleural effusion, chronic empyema
Cardiac	Pericarditis → constrictive pericarditis or tamponade
Lymphatic (commonest form of extra-pulmonary TB)	Tuberculous lymphadenitis (scrofula), mediastinal lymphadenopathy
Skeletal	Osteomyelitis, Pott’s disease (spinal TB)
Genitourinary	Renal scarring, ureteric strictures, infertility
Gastrointestinal	Intestinal obstruction, perforation, malabsorption
Cutaneous	Lupus vulgaris (most common form of cutaneous TB), scrofuloderma
Adrenal	Tuberculous adrenalitis → Addison’s disease

 

Central Nervous System

• Tuberculous meningitis → most common and severe manifetsation of CNS TB
• Tuberculoma (granulomatous intracranial mass lesion)
• Hyponatraemia (SIADH)

Prognosis

Prognosis depends on: drug susceptibility, HIV status, comorbidities, and treatment completion

Untreated active TB is slowly progressive and potentially fatal

Poor prognostic factors 

• HIV co-infection → 2× higher mortality than HIV-negative individuals
• Increasing age
• Extensive or disseminated disease
• Delayed diagnosis or incomplete treatment
• Other immunosuppressive states: malnutrition, diabetes, CKD
• Drug-resistance → worse outcomes, prolonged therapy, lower cure rates
  • XDR-TB worse prognosis than MDR-TB 

Overview

 

Characteristics	Latent TB	Primary TB	Secondary TB
Definition	Persistent immune response to M. tuberculosis antigens, no clinical/radiographic evidence of active disease	Initial infection following first exposure	Active TB that develops in a person with previous infection with mycobacterium tuberculosis
Epidemiology	~1/4 of world’s population	Minority of active TB cases (mainly occuring in children and immunologically naive individuals)	majority of active TB cases
Pathogenesis	Host immunity contains bacilli → dormant/persistent state inside granulomas	Infection begins with a Ghon focus (hallmark of primary tuberculosis) ± spread to hilar nodes  (Ghon complex) Typically affects the middle and lower lung zones Immune response determines outcome: clearance, latency, or progression to active disease	Dormant bacilli resume replication when immunity wanes or risk factors are present Typically affects the upper lung zones
Progression notes	5–10% lifetime risk of progression; greatest in the first 2 years. Risk ↑ in HIV, immunosuppression, children <5y, comorbidities	~92% develop latency or self-clear infection ~8% progress to active disease within 10 years (most within first 2 years)	Characterised by higher infectious burden & disease severity
Infectivity	Not infectious	Modestly infectious	Highly infectious, especially cavitary pulmonary TB
Clinical features	Asymptomatic	Often asymptomatic OR mild pnuemonic illness → fever, cough, malaise, lymphadenopathy	Pronounced/Typical TB symptoms →  Chronic cough, haemoptysis, fever, night sweats, weight loss
Radiographic features	Normal CXR Potential findings calcified granulomas fibronodular opacities pleural thickening	middle/lower zone consolidation (or Ghon focus) ± ipsilateral hilar/mediastinal lymphadenopathy; pleural effusion possible; cavitation uncommon	Upper lobe infiltrates, cavitation and/or fibrosis

BCG Vaccination

Indications

BCG vaccine is NOT part of the routine immunisation schedule in the UK, but is selectively offered to those at higher risk of TB exposure.

Mantoux -ve is the main requirement for ALL people before offering BCG vaccination:

• +ve Mantoux test (induration ≥5 mm) are NOT given BCG as they are sensitised and vaccination is unnecessary

Main indications for BCG vaccine:

Category	Specific Group
Neonates / children	Living in UK areas with TB incidence ≥40/100,000
	With a parent / grandparent born in a country with TB incidence ≥40/100,000
	Specific situations: HIV +ve mother Immunosuppressed mother Family history of TB in the last 5 years
Close contact	Unvaccinated (no prior BCG), and Mantoux -ve, and Close contact with a patient with sputum smear-positive pulmonary / laryngeal TB
Occupational risk	Unvaccinated <35 y/o healthcare workers are typically offered vaccination during occupational health screening Healthcare workers: Direct contact with TB patients or potentially infectious materials Works in high-risk settings (e.g. TB clinics, infectious disease wards, pulmonary units, microbiology, pathology department, autopsy room) Involved in care of high TB risk populations (e.g. prisoners, homeless people, asylum seekers, refugees, drug / alcohol misuse)

Latent TB Guidelines

Investigation and Diagnosis

1st line: Mantoux test (tuberculin skin testing) (+ve test defined by induration ≥5mm regardless of BCG history)

• +ve Mantoux test → assess for active TB (see below)

 

• If no signs of active TB
  • Offer treatment for latent TB
  • However, if more evidence of infection is needed to decide on treatment (e.g. requiring enhanced case management, or adverse events from treatment) → offer interferon-γ release assay

If testing in immunocompromised patients: offer Mantoux test and interferon-γ release assay

• Immunocompromised individuals have a higher chance of false negatives on both tests; combining them increases the detection rate ^[Ref]
   

Diagnostic Tests Information

	Mantoux test (tuberculin skin testing)	Interferon–γ release assay
Mechanism	Test for T cell-mediated immunity against M. tuberculosis via: Type IV hypersensitivity	Test for T cell-mediated immunity against M. tuberculosis-specific antigens via: Measure amount of interferon-γ released by T cells using ELISA
Procedure	2 step-procedure: Step 1: purified protein derivative injected intradermally Step 2: measure the diameter of the induration (not the erythema) 48-72 hours later	1 step procedure: Blood is drawn into test tubes QuantiFERON-TB Gold In-Tube assay used
Advantages	Inexpensive	Only requires a single visit to clinic Preferred test in those with prior BCG vaccination Results available within 24 hours
Limitations	Does not differentiate between latent and active TB Requires 2 visits to clinic False +ve from previous BCG vaccination or exposure to non-tuberculosis mycobacteria False -ve in Sarcoidosis Immunosupressed Recent live attenuated vaccination <6 months old Recent (8-10 weeks) or very old TB infection Disseminated TB disease	Cannot differentiate between live and dead mycobacteria Expensive

 

Management

Offer the following testing before starting treatment for latent TB:

• HIV 
• Hepatitis B and C 

NICE recommends either of the following regimens, depending on clinical circumstances:

Drugs	Duation	Indication
Rifampicin + isoniazid (+ pyridoxine)	3 months	Shorter duration is preferred in <35 y/o if hepatotoxicity is a concern
Isonidazid (+ pyridoxine)	6 months	To avoid rifampicin which is a potent liver enzyme inducer Can be problematic in those with HIV and post-transplant due to the medications they need to take

 

Active TB Guidelines

Investigation and Diagnosis

Clinical Features

Note

• Latent TB is asymptomatic
• Primary TB is commonly asymptomatic/minimally symptomatic
• Typical features of active pulmonary tuberculosis are mainly seen in secondary TB

Pulmonary TB: ^{[Ref 1] [Ref 2]}

Symptoms 

• Systemic symptoms (gradual onset, reflecting chronic infection)
  • B symptoms: Low-grade fever, night sweats, weight loss (often significant)
  • Anorexia
  • Malaise & weakness

 

• Pulmonary symptoms
  • Persistent cough (often >2-3 weeks)
    • Progressive nature: initially dry, later productive / haemoptysis with disease progression
  • Sputum production (may become purulent)
  • Haemoptysis (blood-streaked or frank) → classic but less frequent finding
  • Dyspnoea
  • Pleuritic chest pain (suggests pleural involvement)

Physical Examination Findings

Often nonspecific and may be normal in early disease

• General 
  • Pallor (anaemia of chronic disease)
  • Clubbing (advanced or chronic cases)
  • Cachexia / generaliesd wasting
  • Tuberculous lymphadenitis → lymphadenopathy (esp. supraclavicular/cervical)

 

• Chest examination
  • Variable findings depending on disease stage and lung site affected:
    • Consolidation → dullness to percussion, coarse crackles, diminished breath sounds
    • Cavitation → hyperresonance on percussion
    • Bronchial obstruction → wheeze
    • Pleural effusion / Empyema → stony dull percussion, reduced/absent breath sounds

• Other
  • Erythema nodosum (uncommon, but classic cause)

 

Diagnostic Guidelines

Adults

1st line test: chest X-ray

If X-ray appearance suggests TB → perform microbiology sample testing (definitive testing):

• Obtain 3 deep cough sputum respiratory samples (preferably 1 early morning sample)
  • If patient unable to produce sputum → induce sputum or bronchoscopy and lavage

 

• Send for microscopy, culture and histology
• Ideally, before starting treatment (otherwise within 7 days of starting treatment)

Request NAAT for M. tuberculosis complex if:

• HIV +ve patient, or
• Rapid information about species would affect management, or
• Large contact-tracing initiative

Children

1st line: NAAT for M. tuberculosis complex (M. tuberculosis, M. bovis, M. africanum)

Diagnostic Tests Information

Chest X-ray findings:

Primary TB	Post-primary (reactivation) TB
Typically affects middle / lower lobes Ghon complex (Ghon focus + involved regional lymph node, usually hilar lymph node) Hilar lymphadenopathy (usually unilateral) Consolidation (homogenous with ill-defined borders)	Typically affects upper lobes Patchy consolidation with cavitary lesions (common) Fibrosis

Microbiological tests:

Test	Description	Advantages	Disadvantages
Acid-fast bacilli smear microscopy	Ziehl Neelsen / auramine stain applied Sample visualised under the microscope	Rapid detection	Low sensitivity Cannot differentiate between M. tuberculosis and other non-tuberculosis mycobacteria Cannot differentiate between live and dead mycobacteria (both will stain)
Culture	Gold standard diagnostic test Provides information on drug susceptibility	High sensitivity Identify exact species Identify drug resistance	Takes 2-6 weeks for positive culture to develop
NAAT	Use as initial testing	High sensitivity and specificity Rapid detection Detection of drug-resistant strains Low cross-reactivity with non-tuberculosis mycobacteria	Cannot differentiate between live and dead mycobacteria (both will be detected) Requires laboratory equipment and trained staff

 

Management

If there are clinical features consistent with a diagnosis of TB, start treatment without waiting for culture results.

Standard TB Treatment (Drug-Susceptible TB)

Refer to TB specialist once diagnosis is made.

Standard Treatment (No CNS Involvement)

• Initial phase: 2 months of RIPE – rifampicin + isoniazid (+ pyridoxine) + pyrazinamide + ethambutol, then
• Continuation phase: 4 months of rifampicin + isoniazid (+ pyridoxine)

Active TB with CNS Involvement

• Initial phase: 2 months of RIPE – rifampicin + isoniazid (+ pyridoxine) + pyrazinamide + ethambutol, then
• Continuation phase: 10 months of rifampicin + isoniazid (+ pyridoxine)

Also offer adjunctive corticosteroid (dexamethasone or prednisolone) at the start of anti-TB treatment regimen

• Start with high dose initially, then gradually withdraw it over 4-8 weeks

Drug-Resistant TB Treatment

If multidrug-resistant TB is suspected clinically, perform NAAT for rifampicin resistance

Choice of drug:

Drug resistance	Recommended treatment
Rifampicin	Treat with at least 6 drugs Test for resistance to 2nd line drugs
Isoniazid	Initial phase (first 2 months): rifampicin + pyrazinamide + ethambutol Continuation phase (for 7 months): rifampicin + ethambutol
Pyrazinamide	Initial phase (first 2 months): rifampicin + isoniazid (+ pyridoxine) + ethambutol Continuation phase (for 7 months): rifampicin + isoniazid (with pyridoxine)
Ethambutol	Initial phase (first 2 months): rifampicin + isoniazid (+ pyridoxine) + pyrazinamide Continuation phase (for 4 months): rifampicin + isoniazid (with pyridoxine)

Infection Control

If suspected or confirmed pulmonary / laryngeal TB → place patient in single room

If suspected or confirmed multidrug-resistant TB → place patient in single room (if low risk) or negative pressure room (if high risk)

Contact Tracing

If pulmonary or laryngeal TB is diagnosed → offer screening to close contacts (social contacts are not necessary)

• If symptomatic → test for active TB (i.e. chest X-ray first line)
• If asymptomatic
  • >65 y/o → consider chest X-ray (if abnormal → testing for active TB)
  • ≤65 y/o → Mantoux test to test for latent TB and consider BCG vaccination (if no prior vaccination and Mantoux -ve)

References