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 sitesCNS (typically meninges), lymph nodes, bones/joints, pericardium, skin, eyes, gastrointestinal or genitourinary systems
- Disseminated TBCommoner in children or immunosuppressed → 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 children10% of cases but 14% of deaths
- 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
- FacultativeFacultative intracellular pathogens like MTB can live and multuply inside host cells (e.g., macrophages) or outside in extracellular environments; this flexibility aids persistence and immune evasion intracellular, rod-shaped bacillus
- Aerobic, very slow-growing
- Mycobacterium species inc. Mycobacterium tuberculosis are examples Acid-fast bacilliAcid-fast bacilli are bacteria with mycolic acid–rich cell walls (e.g. Mycobacteria) that retain carbol fuchsin despite acid–alcohol decolorisation. (AFB)
Gram stain
- Does not stain well due to lipid-richcomprised of mycolid acid 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).
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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 immunitymediated by T cells & macrophages)
- 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 damageincluding inflammatory damage and necrosis of the lung parenchyma and airways [Ref]
- Lung cavitationdestruction of parenchyma with cavity formation
- 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)
- Infection predisposition
- Bronchiectasis
- Lung fibrosis & scarring (restrictive lung disease)
- COPDChronic obstructive pulmonary disease
Vascular and haemorrhagic complications
- Rasmussen aneurysminflammatory pseudoaneurysm of a pulmonary artery branch adjacent to a tuberculous cavity; may rupture, causing life-threatening hemorrhage
Other
- Pneumothoraxdue to rupture of subpleural cavity or bullae into the pleural space
- Fibrosing mediastinitisfibrotic reaction involving mediastinal structures, leading to airway or vascular compression
- Cor pulmonale (secondary to chronic hypoxia / scarring)
Extrapulmonary Manifestations / Complications
| System / Site | Complication | |
|---|---|---|
| Pleural | Pleural effusion, chronic empyema | |
| Cardiac | Pericarditis → constrictive pericarditisTB pericarditis is the most common cause of constrictive pericarditis worldwide or tamponade | |
| Lymphatic (commonest form of extra-pulmonary TB) | Tuberculous lymphadenitis (scrofula), mediastinal lymphadenopathy | |
| Skeletal | Osteomyelitis, Pott’s disease typically presents with chronic back pain, constitutional symptoms (fever, night sweats, weight loss), and may cause gibbus deformity (kyphotic deformity) from vertebral collapse or neurological deficits due to spinal cord compression, often accompanied by a paravertebral “cold” abscess (e.g. psoas abscess).(spinal TB) | |
| Genitourinary | Renal scarring, ureteric strictures, infertility | |
| Gastrointestinal | Intestinal obstruction, perforation, malabsorption | |
| Cutaneous | Lupus vulgarispresents as slowly enlarging reddish-brown plaques on the face with apple-jelly nodules on diascopy (most common form of cutaneous TB), scrofulodermaScrofuloderma is a cutaneous manifestation of tuberculosis that occurs by direct extension of infection from an underlying focus, such as tuberculous lymphadenitis, bone, or joint disease, into the overlying skin. It starts as a firm subcutaneous nodule that progresses into ulcers with draining sinus tracts | |
| Adrenal | Tuberculous adrenalitisTB is a leading cause of Addison's disease in developing countries. It results from adrenal destruction by granulomas. → Addison’s disease |
Central Nervous System
- Tuberculous meningitis → most common and severe manifetsation of CNSCentral nervous system TB
- Tuberculoma (granulomatous intracranial mass lesion)
- Hyponatraemia (SIADHSyndrome of inappropriate ADH secretion )
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-TBExtensively drug-resistant TBworse prognosis than MDR-TBMultidrug-resistant 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 focusThe primary lesion (granuloma), typically subpleural in location, formed in the lung parenchyma following infection with MTB (hallmark of primary tuberculosis) ± spread to hilar nodes (Ghon complexcombination of a primary parenchymal lesion (Ghon focus) and ipsilateral regional lymph node involvement, typically hilar or mediastinal lymphadenopathy)
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 findingsThese findings are considered sequelae of previous infection and are not specific for active disease. The presence of such abnormalities, especially if stable for at least 6 months and without clinical symptoms, supports the diagnosis of latent rather than active tuberculosis
|
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 |
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Specific situations:
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| Close contact |
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| Occupational risk | Unvaccinated <35 y/o healthcare workers are typically offered vaccination during occupational health screening
Healthcare workers:
|
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:
|
Test for T cell-mediated immunity against M. tuberculosis-specific antigens via:
|
| Procedure | 2 step-procedure:
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1 step procedure:
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| Advantages |
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| Limitations |
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Management
Offer the following testing before starting treatment for latent TB:
- HIV
HIV testing is recommended before starting LTBI treatment because HIV greatly increases the risk of progression to active TB and can influence the choice and duration of therapy.
- Hepatitis B and C
Hepatitis B and C testing is advised, especially in patients with risk factors, because underlying viral hepatitis increases the risk of hepatotoxicity from isoniazid and rifamycins. Identifying hepatitis allows for closer liver monitoring and possible regimen adjustment.
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
Symptoms
- Systemic symptoms (gradual onset, reflecting chronic infection)
- B symptomsB symptoms are caused by chronic systemic inflammation. Pulmonary TB is the leading cause. Other causes include: chronic infections such as HIV/AIDs, subacute bacterial endocarditis, lymphoma (classic cause) and acute leukemia.: 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)
- Persistent cough (often >2-3 weeks)
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
- Variable findings depending on disease stage and lung site affected:
- 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 NAATNucleic acid amplification tests for M. tuberculosis complex if:
- HIV +ve patient, or
- Rapid information about species would affect managementExamples include risk factors for multidrug-resistant TB: - Contact with known case of multidrug-resistant TB - History of previous TB treatment, esp. if there was poor adherence to treatment - Birth or residence in a country that the WHO reports a high proportion (≥5%) of multidrug-resistant TB new cases, or
- Large contact-tracing initiative
Children
1st line: NAATNucleic acid amplification tests 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
|
Typically affects upper lobes
|
Microbiological tests:
| Test | Description | Advantages | Disadvantages |
|---|---|---|---|
| Acid-fast bacilli smear microscopy |
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| Culture | Gold standard diagnostic test
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| NAATNucleic acid amplification test | Use as initial testing |
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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 clinicallyExamples include risk factors for multidrug-resistant TB: - Contact with known case of multidrug-resistant TB - History of previous TB treatment, esp. if there was poor adherence to treatment - Birth or residence in a country that the WHO reports a high proportion (≥5%) of multidrug-resistant TB new cases, perform NAAT for rifampicin resistance
Choice of drug:
| Drug resistance | Recommended treatment |
|---|---|
| Rifampicin |
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| Isoniazid |
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| Pyrazinamide |
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| Ethambutol |
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Detailed management of drug-resistant tuberculosis (MDR/XDR-TB) is beyond the expected knowledge level for the UKMLA.
This information is included for completeness and to provide clinical context. In practice, all cases of suspected or confirmed MDR-TB are managed by specialist infectious disease or respiratory teams in consultation with UKHSA.
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 contactsPeople who have had prolonged, frequent or intense contact with a person with infectious TB. Examples include household contacts and boyfriends or girlfriends (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)