Tuberculosis (TB): A Complete Clinical Guide to Pathogenesis, Diagnosis, Treatment and Prevention

Clinical Medicine Year 3 • Uganda-focused, student-doctor teaching chapter

Learning outcomes

• Define TB disease, latent TB infection, pulmonary TB, extrapulmonary TB and drug-resistant TB.
• Describe the microbiology of Mycobacterium tuberculosis, its transmission and its survival within macrophages.
• Explain the formation of the Ghon focus, primary complex, granuloma, caseation, cavitation, latency and reactivation.
• Recognise the clinical features of pulmonary, pleural, lymph-node, CNS, spinal, abdominal, genitourinary, pericardial, miliary and congenital/childhood TB.
• Take a complete TB history and perform a focused examination, including red-flag assessment.
• Select sputum, extrapulmonary and childhood specimens; interpret molecular tests, smear, culture, chest imaging, LF-LAM, TST/IGRA and susceptibility testing.
• Construct a safe management plan for drug-susceptible TB, TB/HIV, children, pregnancy, TB meningitis/pericarditis and drug-resistant TB.
• Recognise adverse effects, treatment failure, relapse, complications, post-TB lung disease and infection-control needs.
• Plan contact investigation, TB preventive treatment, vaccination, adherence support and public-health follow-up.

1. Definition and important distinctions

Tuberculosis disease is illness caused by active multiplication of organisms in a person’s tissues, with symptoms, signs, microbiological evidence, imaging abnormalities or a combination of these. It can affect any organ.

Latent TB infection (LTBI) means viable bacilli are contained by the immune system without clinical disease. The person has no symptoms caused by TB and does not ordinarily transmit infection, but can develop disease later if immune control weakens.

Infectious TB usually refers to untreated pulmonary or laryngeal disease in which bacilli are aerosolised. Most isolated extrapulmonary disease is not transmitted person-to-person, although pulmonary involvement must be excluded.

TB/HIV co-infection means both infections are present. HIV changes the probability of progression, the radiological pattern, the frequency of extrapulmonary disease, the interpretation of tests and the timing/choice of antiretroviral therapy.

2. Causative organism and microbiology

2.1 The tubercle bacillus

Mycobacterium tuberculosis is a slender, aerobic, non-motile, non-spore-forming bacillus. Its lipid-rich mycolic-acid cell wall makes it “acid-fast”: once stained, it resists decolourisation by acid-alcohol. The organism grows slowly, prefers oxygen-rich tissues and can survive for years in a dormant state inside granulomas.

• Acid-fastness: useful for smear microscopy, but a smear shows acid-fast bacilli and cannot by itself prove that every bacillus is M. tuberculosis.
• Slow growth: explains why culture and some susceptibility tests take longer than molecular tests.
• Intracellular survival: prevents easy killing by macrophages and permits persistence in a low-metabolic state.
• Lipid cell wall: contributes to resistance to environmental stress and affects drug penetration.
• Complex rather than single species: M. tuberculosis complex includes M. bovis and related organisms; this matters for zoonotic exposure and pyrazinamide susceptibility.

2.2 Why the organism is difficult to eradicate

Within one patient, bacilli may occupy different biological environments: rapidly multiplying organisms in cavities, slowly multiplying organisms in acidic necrotic tissue and dormant bacilli within granulomas. Combination therapy is required so that resistant mutants are suppressed and organisms in different compartments are treated. Poor adherence, inadequate absorption, drug interactions or an incorrect regimen can select drug resistance.

3. Epidemiology and determinants of disease

The linked Uganda teaching resource describes TB as a continuing public-health emergency and highlights the current national strategy’s emphasis on rapid molecular diagnosis, shorter regimens, decentralised care and digital adherence monitoring. It identifies a high burden of TB/HIV co-infection, childhood TB and drug-resistant TB. WHO updates burden estimates annually, so students should use the latest report rather than memorising an old global number. Read the Uganda TB teaching resource.

4. Transmission and infection-control reasoning

4.1 How transmission occurs

When a person with infectious pulmonary or laryngeal TB coughs, speaks, sings or undergoes an aerosol-generating procedure, tiny droplet nuclei containing bacilli remain suspended in air. Transmission is more likely indoors, in crowded rooms, in poor ventilation and after prolonged exposure. A brief outdoor encounter is generally much less risky than sharing a poorly ventilated sleeping room.

Infection is not normally acquired from handshakes, sharing plates or touching intact skin. However, respiratory secretions and contaminated tissues still require standard infection-control precautions. M. bovis can be acquired through unpasteurised milk or direct contact with infected cattle and slaughter environments.

4.2 The infectiousness question

Infectiousness is influenced by cough, bacillary burden, cavitation, laryngeal involvement, treatment duration and adherence. A person who has started an effective regimen may become less infectious, but the exact decision to discontinue separation depends on clinical improvement, bacteriological response, local policy and the setting. Do not use one negative smear as the only basis for removing precautions.

5. Classification used in clinical practice

MDR-TB means resistance to at least isoniazid and rifampicin. RR-TB means rifampicin resistance, with or without resistance to other medicines, and is managed through the drug-resistant TB pathway. Modern definitions of pre-XDR/XDR depend on resistance to fluoroquinolones and other key drugs; always use the current WHO/NTLP definition.

6. Pathogenesis: from inhalation to organ damage

6.1 Entry and early alveolar infection

Inhaled bacilli bypass the upper airway and reach terminal bronchioles/alveoli. Alveolar macrophages ingest them, but the organism can inhibit phagosome–lysosome fusion and resist intracellular killing. Early multiplication is often clinically silent.

6.2 Lymphatic spread and primary complex

Infected macrophages migrate through lymphatics to hilar and mediastinal nodes. Around the time adaptive cell-mediated immunity develops, T lymphocytes activate macrophages and organise epithelioid cells, giant cells and lymphocytes into a granuloma. The initial lung lesion is the Ghon focus; the focus plus draining lymphangitis and hilar-node involvement is the primary complex.

6.3 Caseation and cavitation

Immune-mediated tissue injury produces caseous necrosis—soft, cheese-like material at the centre of a granuloma. If the lesion communicates with a bronchus, caseous material drains and a cavity forms. Cavities contain a high bacillary load and are especially important for cough transmission, haemoptysis and selection of resistant mutants.

6.4 Latency and reactivation

In most immunocompetent people, immune containment prevents active disease, but organisms remain viable. Years later, HIV, diabetes, malnutrition, renal failure, corticosteroids, anti-TNF treatment, ageing or another illness may weaken containment. Reactivation often favours oxygen-rich upper lobes, producing apical infiltrates and cavities, although HIV may produce atypical or lower-zone disease.

6.5 Haematogenous dissemination

When bacilli enter the bloodstream, they can seed marrow, liver, spleen, kidneys, meninges, choroid, bones and adrenal glands. Numerous tiny lesions produce miliary TB. In the CNS, rupture of a subependymal focus can cause basal meningitis, vasculitis, hydrocephalus and infarction. In the spine, infection of vertebral bodies can form a cold abscess and compress the cord.

7. Clinical presentation

7.1 Pulmonary TB

• Persistent cough, initially dry or later productive; duration of two weeks or more should trigger screening, but do not wait for a two-week threshold in high-risk or severely ill patients.
• Low-grade or evening fever, drenching night sweats, fatigue, anorexia and progressive weight loss.
• Haemoptysis from inflamed mucosa, cavity erosion or bronchiectatic/post-TB vessels; quantify blood and assess airway risk.
• Pleuritic chest pain from pleural involvement; dyspnoea or hypoxia from extensive disease, effusion, pneumothorax or coexisting lung disease.
• Examination may be deceptively normal. Possible findings include apical crackles, bronchial breathing, reduced air entry, pleural rub, lymphadenopathy, cachexia, clubbing or signs of respiratory failure.

7.2 Pleural TB

Fever, unilateral pleuritic pain and breathlessness are common. The effusion is usually an exudate with lymphocyte predominance, but early neutrophils or a negative smear do not exclude TB. A very large effusion may cause mediastinal shift and respiratory compromise.

7.3 Lymph-node TB

Cervical nodes are often painless, firm or matted and may soften and form a sinus. Axillary, mediastinal or abdominal nodes can compress airways, vessels, bowel or ureters. In HIV, nodes may be generalized and necrotic.

7.4 TB meningitis and CNS TB

Symptoms may develop gradually: headache, fever, vomiting, lethargy, personality change, photophobia or neck stiffness. Cranial-nerve palsy, reduced consciousness, seizures, focal weakness, papilloedema or hydrocephalus indicate advanced disease. Children may present with irritability, poor feeding, bulging fontanelle or failure to thrive.

7.5 Spinal and osteoarticular TB

Persistent back pain, night pain, restricted movement, kyphosis, paravertebral swelling, a cold abscess, limb weakness, sensory change, sphincter dysfunction or a non-healing sinus suggests vertebral TB. Neurological deficit means cord compression until proved otherwise.

7.6 Abdominal and genitourinary TB

Abdominal TB can cause chronic pain, fever, ascites, altered bowel habit, obstruction, peritonitis, ileocaecal thickening or a mass. Genitourinary TB may cause sterile pyuria, haematuria, flank pain, infertility, epididymal swelling or menstrual disturbance. Adrenal destruction can cause hypotension, hyperpigmentation and electrolyte abnormalities.

7.7 Pericardial TB

Fever, chest discomfort, dyspnoea, tachycardia, raised JVP, muffled heart sounds, pulsus paradoxus or hypotension suggest pericardial effusion/tamponade. Constrictive pericarditis may present later with oedema, hepatomegaly and ascites.

7.8 Miliary TB

Prolonged fever, severe wasting, cough or dyspnoea, hepatosplenomegaly, lymphadenopathy, cytopenias, jaundice, confusion, choroidal lesions or adrenal failure can occur. The chest radiograph may show diffuse tiny nodules, but early imaging can be normal.

7.9 TB in HIV

With advanced immunosuppression, the patient may have a dry cough, little haemoptysis, diffuse infiltrates, intrathoracic lymphadenopathy, pleural effusion or extrapulmonary disease without classic upper-lobe cavities. A normal radiograph does not safely exclude TB in advanced HIV.

7.10 Childhood and adolescent TB

Children may have persistent fever, cough, weight loss or failure to thrive, reduced play, night sweats, lymph-node enlargement, recurrent pneumonia or contact with an adult TB case. Severe forms include TB meningitis, miliary disease and disseminated bone involvement. Adolescents may resemble adults and can transmit pulmonary disease.

8. Focused TB history and examination

8.1 History checklist

• Symptoms: cough duration, sputum, blood volume, fever pattern, night sweats, weight change, appetite, chest pain, breathlessness and fatigue.
• Site symptoms: headache, vomiting, confusion, weakness, back pain, joint swelling, abdominal pain, ascites, urinary symptoms, infertility, visual symptoms and pericardial symptoms.
• Exposure: household case, workplace/prison/school exposure, shared bedroom, ventilation, prior contact investigation and BCG history.
• Previous TB: dates, regimen, doses missed, treatment outcome, laboratory results, drug resistance, adverse reactions and reasons for stopping.
• Host factors: HIV test/ART, diabetes, kidney/liver disease, pregnancy, breastfeeding, malnutrition, smoking, alcohol, steroids/biologics and cancer treatment.
• Social and access factors: transport, food insecurity, stigma, privacy, ability to attend refills, literacy, phone access and treatment supporter.

8.2 Examination checklist

Record temperature, pulse, respiratory rate, oxygen saturation, blood pressure, mental state, weight/BMI and performance status. Look for pallor, jaundice, lymph nodes, clubbing, oral thrush, wasting, skin lesions and injection marks. Examine the respiratory system, heart/JVP, abdomen, spine and joints. Perform a complete neurological examination when headache, confusion, focal symptoms or HIV is present. Document visual acuity/colour vision before ethambutol when feasible.

9. Investigations and interpretation

9.1 The diagnostic pathway

1. Identify presumptive disease: symptoms, examination, contact or screening risk.
2. Choose the best specimen: sputum for pulmonary disease; tissue/fluid from the affected site for extrapulmonary disease; age-appropriate respiratory or stool samples in children.
3. Perform a molecular WHO-recommended rapid diagnostic: Xpert MTB/RIF Ultra, TrueNat or the currently approved platform. It detects TB DNA and rifampicin resistance quickly.
4. Assess severity and site: chest radiograph, ultrasound, CT/MRI, lumbar puncture or biopsy according to the syndrome.
5. Send culture and susceptibility testing: especially if molecular resistance is detected, treatment history is complex, disease is severe or the result is discordant.
6. Test for HIV and comorbidities: glucose/HbA1c, pregnancy, FBC, renal and liver function, hepatitis risk and baseline ECG/vision/hearing when the regimen requires it.

9.2 Specimen quality is part of the test

A negative result from saliva, a tiny sample or a specimen taken after several days of antibiotics is not equivalent to a negative result from a good early-morning deep-cough sputum. Explain the procedure, supervise collection privately, use the correct container, label the site and send promptly. Induced sputum or gastric aspirate may be needed when a child or debilitated adult cannot expectorate.

9.3 When tests disagree

Use the entire evidence set: pre-test probability, symptoms, examination, contact, HIV status, imaging, microbiology, response and alternative diagnoses. Do not treat a non-specific radiograph as proof, and do not dismiss a high-risk patient solely because smear or one molecular sample is negative. Obtain a second specimen, sample the affected site, consult the TB team and investigate a dangerous alternative.

10. Differential diagnosis

11. Treatment: principles before prescriptions

The aims are to cure the individual, prevent death and disability, stop transmission, prevent acquired resistance and protect the household. Use weight-band fixed-dose combinations where supplied, prescribe every component of the regimen, explain the purpose of each drug and document the bacteriological baseline.

• Never add one drug to a failing regimen without specialist advice.
• Never stop rifampicin or isoniazid abruptly because symptoms improved.
• Review all medicines for rifampicin interactions, including contraceptives, anticoagulants, anticonvulsants, antiretrovirals and some antifungals.
• Give pyridoxine with isoniazid when indicated, especially in pregnancy, HIV, diabetes, malnutrition, alcohol use, renal disease and neuropathy risk.
• Base dose changes on the current weight and reassess after major weight change.

12. Drug-susceptible TB regimens

13. Drug-resistant TB (RR/MDR/pre-XDR/XDR)

Any rifampicin-resistance result, previous treatment with poor outcome, contact with DR-TB or persistent positive cultures requires rapid referral to the DR-TB service. Current all-oral shorter regimens may include combinations built around bedaquiline, pretomanid, linezolid and moxifloxacin (for example BPaLM/BPaL) when the patient meets eligibility and susceptibility criteria. Other regimens are used when resistance, pregnancy, age, toxicity or comorbidity excludes the shorter option.

Supportive DR-TB care

• Explain the reason for a longer or more complex course and involve a treatment supporter.
• Screen for depression, stigma, hearing/vision problems, neuropathy and food insecurity.
• Use community-based differentiated service delivery when clinically stable.
• Document culture conversion, adverse events, missed doses, contacts and final outcome.

14. TB/HIV co-infection

Offer HIV testing to every person with TB and TB testing to people living with HIV who have symptoms or risk. HIV may produce smear-negative, non-cavitary, disseminated or extrapulmonary disease. Use urine LF-LAM for eligible seriously ill patients with advanced HIV according to current guidance.

• Start TB treatment promptly once TB is diagnosed or strongly suspected.
• Start ART during TB treatment according to current national timing, generally earlier in people with very low CD4 counts and after stabilising TB meningitis when CNS inflammation makes timing more complex.
• Check rifampicin interactions with the ART regimen; do not assume the usual dose is safe with every antiretroviral.
• Provide cotrimoxazole preventive therapy and other HIV care as indicated.
• Warn about immune reconstitution inflammatory syndrome (IRIS): paradoxical fever, enlarging nodes, worsening inflammation or new lesions after ART. Exclude treatment failure, resistance and another infection before attributing symptoms to IRIS.

15. Monitoring during treatment

Common adverse effects students must recognise

• Isoniazid: peripheral neuropathy, hepatitis and drug interactions; pyridoxine reduces neuropathy risk.
• Rifampicin: orange-red body fluids, hepatitis, thrombocytopenia and many enzyme-inducing interactions.
• Pyrazinamide: hepatotoxicity, hyperuricaemia and arthralgia.
• Ethambutol: optic neuritis, reduced visual acuity and red-green colour discrimination.
• Second-line agents: QT prolongation, cytopenias, neuropathy, renal injury, hearing loss, psychiatric effects and tendon or musculoskeletal toxicity depending on the combination.

Severe jaundice, confusion, persistent vomiting, visual loss, severe rash with mucosal involvement, angio-oedema, profound weakness, reduced urine, syncope or a new severe psychiatric symptom requires urgent assessment and the national adverse-event protocol.

16. Complications of TB

17. Post-TB lung disease and survivorship

Cure does not always mean normal lungs. Patients may remain breathless or have chronic sputum, recurrent infection, haemoptysis, fatigue, reduced exercise tolerance, bronchiectasis, fibrosis, aspergilloma, pulmonary hypertension or anxiety/depression. At the end of therapy, ask about symptoms, smoking, work capacity, nutrition and recurrent exposure; examine oxygen saturation and consider chest imaging, spirometry, sputum evaluation and referral for pulmonary rehabilitation.

18. Prevention and public-health management

18.1 Contact investigation

For every bacteriologically confirmed pulmonary/laryngeal case, list household members and other close contacts. Screen for symptoms, examine children and vulnerable adults, test for HIV and investigate active disease before giving preventive therapy. Children under five and people living with HIV deserve particular urgency.

18.2 TB preventive treatment (TPT)

After active TB is excluded, eligible contacts and other high-risk groups may receive a national preventive option such as 1HP, 3HP or 3HR. Review liver disease, pregnancy, interactions, adherence and symptoms at each visit. TPT is not a substitute for evaluating new cough or fever.

18.3 Vaccination and environmental control

• Give BCG according to Uganda’s immunisation schedule; it protects children particularly against severe disseminated TB and meningitis.
• Improve ventilation, sunlight/air flow, cough hygiene and spacing in clinics, homes, schools, prisons, taxis and workplaces.
• Use respirators and negative-pressure/aerosol precautions where indicated in health facilities.
• Pasteurise milk and address zoonotic exposure to cattle and abattoir products.

18.4 Adherence and social protection

Adherence is a clinical intervention, not a moral judgement. Ask why doses are missed: transport, food, side effects, stigma, work, forgetfulness, disclosure concerns or stock-outs. Use treatment supporters, community refills, reminder systems, video DOT or smart pill boxes where available. Link families to nutrition, transport and social-protection support when catastrophic costs threaten completion.

19. Three clinical reasoning examples

20. Examination and ward-round pearls

• TB can be present without fever, haemoptysis, crackles or an abnormal first chest radiograph.
• Always ask “What is the best specimen from the diseased site?” rather than ordering sputum for every form of TB.
• A negative smear is common in children, HIV and extrapulmonary disease; it is not a rule-out test.
• Rifampicin resistance changes the pathway immediately; do not continue routine first-line treatment blindly.
• Before calling persistent fever “treatment failure,” check adherence, absorption, resistance, IRIS, a complication and an alternative diagnosis.
• TB meningitis, spinal cord compression, tamponade, respiratory failure and massive haemoptysis are emergencies.
• At every review, assess both microbiology and the patient’s ability to complete treatment.
• Preventive therapy is given only after active disease has been reasonably excluded.

21. References and further reading

• Midwives Revision Uganda: Tuberculosis and New National Management Guidelines — used for Uganda-focused classification, diagnostics, TB/HIV, prevention and current strategy themes.
• WHO Global Tuberculosis Reports — current burden data and technical resources.
• Uganda Ministry of Health, Uganda National TB and Leprosy Programme: current national manual, treatment cards and drug-resistant TB protocols.
• WHO consolidated guidelines on tuberculosis: module on diagnosis, treatment, prevention and care; always check the latest edition.
• Uganda Clinical Guidelines and current national HIV/TB co-management guidance.