Tuberculosis: Diagnosis and Management

Introduction

Tuberculosis (TB) is caused by Mycobacterium tuberculosis, an acid-fast, slow-growing bacillus spread person-to-person by inhaled droplet nuclei. It remains one of the world's leading infectious causes of death, and although UK incidence is low by global standards, it is concentrated in specific groups - people born outside the UK in high-incidence countries, those experiencing homelessness, people in prison, and people living with HIV - which makes a good social and travel history central to recognising it.¹

TB is a heavily examined topic precisely because it tests several skills at once: recognising a chronic, systemic presentation that mimics malignancy; understanding the difference between latent and active infection; interpreting a battery of different tests correctly; and remembering a multi-drug regimen with genuinely dangerous side effects.

Pathophysiology

Inhaled droplet nuclei reach the alveoli, where the bacilli are phagocytosed by macrophages. In most people, cell-mediated immunity contains the infection within a granuloma, forming a Ghon focus; the combination of this focus with the associated hilar lymph node is the Ghon (Ranke) complex, often visible incidentally on a chest X-ray years later as a healed, calcified nodule.

• Primary TB - infection at first exposure; usually contained, but can progress directly to active disease in young children or the significantly immunosuppressed, who lack the mature cell-mediated response needed to wall it off
• Latent TB - viable bacteria persist within the granuloma, contained but not eliminated; the person has no symptoms and is not infectious, but carries a lifelong risk of reactivation, highest in the first 2 years after infection
• Post-primary (reactivation) TB - the classic adult presentation, occurring when waning immunity allows contained bacteria to multiply again, typically in the apex of the upper lobe, where higher oxygen tension favours this obligate aerobe
• Miliary TB - haematogenous dissemination producing widespread, millet-seed-sized (1-2 mm) granulomas across multiple organs; a feature of primary progressive disease or reactivation in a severely immunosuppressed host

Risk factors for progression to active disease

Most infected people never develop active disease. The risk of progression, whether from primary infection or from reactivation of latent infection, is driven overwhelmingly by the state of the host's cell-mediated immunity.

• HIV infection - by far the single largest risk factor, and TB is an AIDS-defining illness
• Immunosuppressive treatment - long-term corticosteroids, and particularly anti-TNF-alpha biologic therapy, which is why latent TB screening is mandatory before starting these drugs
• Diabetes mellitus
• Chronic kidney disease, especially on dialysis
• Malnutrition and low body weight
• Silicosis and other chronic lung disease
• Malignancy, particularly haematological
• Young children and older adults
• Alcohol excess, smoking and IV drug use
• Close, prolonged contact with a person with active pulmonary TB

Clinical features

Pulmonary TB

• Chronic cough, classically for more than 2-3 weeks, sometimes productive
• Haemoptysis
• Weight loss and anorexia
• Night sweats
• Low-grade fever and malaise

The systemic, gradual, weeks-to-months tempo of these symptoms - rather than any single feature - is what should raise suspicion, especially alongside a relevant travel, migration or exposure history.

Extrapulmonary TB

Occurs in a significant minority of cases overall, and considerably more often in people with HIV. Recognising the range of presentations matters because extrapulmonary disease is easy to misattribute to something else entirely.

Investigations

Testing for latent infection

• Mantoux (tuberculin skin test) - intradermal injection with induration measured at 48-72 hours; simple and cheap, but cross-reacts with prior BCG vaccination, causing false positives
• Interferon-gamma release assay (IGRA), for example Quantiferon - a blood test unaffected by BCG status, so more specific; used for contact tracing, new-entrant screening, and before starting immunosuppressive or biologic therapy

Neither test distinguishes latent from active infection, nor confirms the diagnosis of active TB on its own - a positive result in a symptomatic patient prompts investigation for active disease, not treatment for latent infection.

Testing for active disease

• Chest X-ray - upper lobe cavitation, patchy or nodular consolidation, fibrosis, hilar lymphadenopathy, pleural effusion, or a diffuse miliary pattern
• Sputum samples (at least three, ideally including an early morning sample) for AFB smear microscopy, culture and nucleic acid amplification testing (NAAT)
• AFB smear (Ziehl-Neelsen stain) - rapid and cheap but only moderately sensitive; a positive smear indicates a higher bacterial load and greater infectiousness
• Culture - the gold standard, since it confirms viability and allows full drug sensitivity testing, but slow (typically 2-6 weeks on solid or liquid media)
• NAAT (e.g. GeneXpert MTB/RIF) - rapid (hours rather than weeks) and also detects rifampicin resistance, an important early flag for possible multidrug-resistant disease
• Bronchoscopy with bronchoalveolar lavage, or gastric aspirates in young children who cannot expectorate, if sputum cannot be obtained
• Biopsy and histology of an affected extrapulmonary site - caseating granulomas are characteristic, and tissue should also be sent for culture and NAAT
• HIV test, offered to everyone diagnosed with TB
• Baseline bloods before treatment - LFTs (all four first-line drugs can be hepatotoxic), U&Es and FBC, plus visual acuity and colour vision before starting ethambutol

Differential diagnosis

• Lung cancer - shares weight loss, haemoptysis and a chronic cough, and the two can coexist
• Lymphoma - lymphadenopathy and B symptoms overlap closely with TB lymphadenitis
• Sarcoidosis - also produces non-caseating granulomas and hilar lymphadenopathy, but without the caseation, systemic infectious features or acid-fast organisms of TB
• Non-tuberculous mycobacterial infection - can produce a similar clinical and radiological picture, distinguished on culture speciation
• Fungal infection (histoplasmosis, coccidioidomycosis) in the relevant geographic and travel context
• Community-acquired pneumonia and lung abscess - usually more acute in onset than TB

Management

Standard treatment: the RIPE regimen

Standard treatment for fully sensitive pulmonary (and most extrapulmonary) TB is six months in total, in two phases.²

TB meningitis and bone/joint TB are treated for longer - typically 12 months - reflecting poorer drug penetration and the consequences of under-treatment in these sites. Corticosteroids are added in TB meningitis and TB pericarditis, to reduce the inflammatory damage caused by the immune response as much as the organism itself.

Adherence and infection control

Directly observed therapy (DOT) - a health worker witnessing each dose - is used for patients at higher risk of non-adherence, given the consequences of an incomplete course: relapse and the development of drug resistance. Patients with smear-positive pulmonary or laryngeal TB are considered infectious and are isolated (in a negative-pressure side room if admitted) until they have completed at least 2 weeks of effective treatment and are showing clinical improvement, with a lower threshold and longer isolation for suspected multidrug-resistant disease.

Drug-resistant TB

Multidrug-resistant TB (MDR-TB) is resistant to at least rifampicin and isoniazid; extensively drug-resistant TB (XDR-TB) adds resistance to key second-line agents. Both need longer, more complex and more toxic regimens under specialist infectious diseases and microbiology input, which is why rapid NAAT-based detection of rifampicin resistance at diagnosis matters so much.

Latent TB treatment

Treating latent infection substantially reduces the lifetime risk of reactivation, and is offered to those at higher risk of progression - including new HIV diagnoses, people about to start biologic or other significant immunosuppression, and close child contacts. Options include isoniazid and rifampicin for 3 months, isoniazid alone for 6 months, or rifampicin alone for 4 months, chosen according to interactions, hepatotoxicity risk and adherence.

BCG vaccination

The BCG is a live attenuated vaccine, no longer given universally in the UK (targeted at higher-risk neonates and infants since 2005). It reduces the risk of severe, disseminated childhood disease (miliary TB, TB meningitis) more reliably than it prevents pulmonary TB in adults, and it causes false-positive Mantoux results, which is why IGRA testing is preferred where BCG history is uncertain.

Public health duties

• TB is a notifiable disease - notify UKHSA on clinical suspicion, without waiting for microbiological confirmation
• Contact tracing - close contacts are screened with Mantoux and/or IGRA, with a chest X-ray where indicated, and offered treatment for latent or active disease as appropriate
• Isolation for infectious pulmonary or laryngeal disease, as above
• Directly observed therapy for patients at risk of poor adherence, given the public health as well as individual consequences of an incomplete course

Complications

• Massive haemoptysis from cavitary disease eroding into a vessel
• Bronchiectasis and post-TB lung fibrosis, causing long-term respiratory impairment
• Aspergilloma forming within an old, healed TB cavity
• Pneumothorax
• Constrictive pericarditis after TB pericarditis
• Spinal deformity and cord compression in Pott's disease
• Infertility from genitourinary TB
• Historically, adrenal (Addisonian) failure from TB destruction of the adrenal glands
• Death, particularly with delayed diagnosis, drug resistance or HIV coinfection

Prognosis

Fully sensitive TB treated with a complete course has an excellent cure rate. Outcomes worsen significantly with delayed diagnosis, drug resistance, poor adherence, and HIV coinfection or other significant immunosuppression, and CNS and disseminated disease carry a materially higher mortality and rate of long-term disability than uncomplicated pulmonary disease. Completion of treatment, not simply starting it, is what determines cure and prevents the emergence of resistance - which is the underlying rationale for directly observed therapy and close public health follow-up.