18th June 2024

Tuberculosis

Background

Tuberculosis (TB) is caused by the Mycobacterium tuberculosis complex, a group of “mycobacteria”; slow-growing obligate aerobic bacteria, so-called for the unique properties of their cell wall. TB ranks as a leading infectious cause of morbidity and mortality worldwide, with approximately one third of the world’s population estimated to be infected and 10 million cases of active disease being estimated in 2020, causing over 1.4 million deaths.

TB is spread mainly via inhalation of aerosolised particles of those with pulmonary tuberculosis, though it may affect any organ system. Inhaled bacilli undergo phagocytosis by tissue macrophages, forming a microscopic structure called a granuloma, mediated chiefly by IFN-γ. Latent TB reactivates (causing “secondary” or “reactivation” TB) in 5-10% of patients on average, with risk factors for reactivation including malnutrition, alcohol excess, diabetes mellitus, immunomodulatory drugs (most notably IFN-γ-targeting monoclonal antibodies) and immunocompromised states (i.e.  HIV infection).

Clinical Characteristics

Given that any organ system is potentially affected by TB, clinical presentation can be varied. The broader symptoms associated with TB include weight loss and drenching night sweats. In the case of pulmonary TB (which accounts for >70% of TB cases, productive cough with haemoptysis is typical. Crucially, TB generally takes a less acute or fulminant path than most serious bacterial infections, with symptoms frequently present for weeks to months before diagnosis. Other symptoms or signs specific to other organ sites may alternatively be present; i.e. abdominal distension, intestinal obstruction with ascites or a palpable mass (peritoneal or gastrointestinal TB); reduced air entry to auscultation (pleural TB); drowsiness, focal neurology, headache and signs of raised intracranial pressure (TB meningitis); back pain with long tract signs (spinal TB, or “Pott’s” disease) or painful, red eyes (granulomatous uveitis) – to name but a few. Erythema nodosum is another important manifestation of TB.

Diagnosis

Imaging

It is not possible here to describe TB’s radiological appearance in every organ system it affects. A plain film chest radiograph, however, is the first investigation in investigating TB. Fibrotic changes can be seen in the lung apices in prior secondary TB, while consolidation with or without cavitation, mediastinal adenopathy or pleural effusion can be seen in secondary or reactivation TB. Primary TB can affect any part of the lung and typically does not feature cavitation.

Microbiological diagnosis

TB is a microbiological diagnosis ultimately; however, obtaining microbiological proof is not always possible. While the gold standard for TB diagnosis is culture (performed on the specialised Löwenstein-Jensen medium), this can take up to 7 weeks. Samples can undergo Ziehl Neelsen staining for “acid fast bacilli”, or auramine staining of samples (i.e. sputum, bronchial washings urine, tissue, CSF, etc.) for quicker results, however yield is lower than culture. In “paucibacillary” sputum samples negative for staining, nucleic acid amplification technique (NAAT) can be used to give a rapid result, as well as detecting genes associated with rifampicin or isoniazid resistance. These tests have the best evidence and best performance in respiratory samples rather than extrapulmonary sites.

Latent TB is diagnosed using a combination of history and immunological testing. Mantoux testing uses an intradermal injection of purified proteins from M.tuberculosis to generate a localised skin reaction, the diameter of the induration of which is measured. Prior BCG vaccination can lead to false positives however, and more-modern tests such as the Interferon-λ-Release Assay (IGRA), which tests blood T-cell responses to several M. tuberculosis-specific proteins for evidence of prior exposure, can be more informative.

Treatment

Treatment duration for TB depends on bacterial susceptibilities and the affected body site. For pulmonary TB with a “pan-sensitive” organism, treatment is 6 months with a combination of the first-line anti-tuberculous agents; rifampicin, isoniazid, pyrazinamide and ethambutol. Treatment in this case consists usually of a 2-month “intensive phase” of all 4 drugs, followed by a consolidation phase of typically 4 months. Other second-line anti-tuberculous agents used in the case of resistance or contraindications to components of the first-line therapy include fluoroquinolones, bedaquiline and aminoglycosides. All TB medications require regular monitoring for side effects and complications.

References

• Ryan KJ. Sherris Medical Microbiology, 7e. USA: McGraw-Hill Education; 2017
• National Institute for Health Care Excellence. Tuberculosis. London: NICE; 2021.(NICE Guideline No. 33). Available from: https://www.nice.org.uk/guidance/ng33
• Thwaites G, Fisher M, Hemingway C, Scott G, Solomon T, Innes J; British Infection Society. British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. J Infect. 2009 Sep;59(3):167-87. doi: 10.1016/j.jinf.2009.06.011. Epub 2009 Jul 4. PMID: 19643501
• American Thoracic Society. The tuberculin skin test statement of American Thoracic Society, Medical Section of the American Lung Association. Am Rev Respir Dis. 1981;124:356–63
• European Centre for Disease Prevention and Control, WHO Regional Office for Europe. Tuberculosis surveillance and monitoring in Europe 2021 – 2019 data. Copenhagen: WHO Regional Office for Europe; 2021
• Guidelines for the prevention and management of Mycobacterium tuberculosis infection and disease in adult patients with chronic kidney disease. Thorax. 2010;65(6):558-558