Tuberculosis: pulmonary and extrapulmonary

After this session, you should be able to describe the epidemiology, pathophysiology, and clinical features of pulmonary and extrapulmonary tuberculosis, and understand the diagnostic approaches. Always check drug doses and local protocols against the current Kenya MoH guidelines and your hospital formulary.

Definition

Tuberculosis (TB) is a chronic infectious disease caused primarily by Mycobacterium tuberculosis, a slow-growing, acid-fast bacillus. It typically affects the lungs (pulmonary TB) but can manifest in almost any organ system (extrapulmonary TB).

Anatomy and physiology you need

Understanding TB requires knowledge of:

• Respiratory system: Alveoli (site of initial infection), bronchi (cough, sputum production), lymphatic drainage (hilar lymph nodes).
• Immune system: Macrophages (phagocytosis, granuloma formation), T-lymphocytes (cell-mediated immunity, cytokine production), granuloma structure (caseous necrosis, fibrous cuff).
• Lymphatic system: Nodes throughout the body (common site for extrapulmonary TB).
• Central nervous system: Meninges (meningitis), brain parenchyma (tuberculoma).
• Skeletal system: Vertebrae (Pott's disease).
• Gastrointestinal system: Ileocecal region (common site for abdominal TB).
• Cardiovascular system: Pericardium (pericardial effusion, constrictive pericarditis).

Causes and risk factors

Cause:

• Mycobacterium tuberculosis complex (primarily M. tuberculosis, less commonly M. bovis, M. africanum).

Risk Factors:

• HIV infection: The strongest risk factor, leading to rapid progression from latent to active TB and increased risk of extrapulmonary and disseminated disease.
• Close contact with an infectious TB case: Especially in crowded living conditions.
• Immunosuppression:
  • Malnutrition (especially protein-energy malnutrition).
  • Diabetes mellitus.
  • Chronic kidney disease.
  • Malignancy (e.g., lymphomas, leukemias).
  • Immunosuppressive medications (e.g., corticosteroids, TNF-alpha inhibitors).
  • Silicosis.
• Age: Very young children and the elderly are more susceptible.
• Substance abuse: Alcoholism, intravenous drug use.
• Poverty and overcrowding: Facilitates transmission.
• Healthcare workers: Increased occupational exposure.

Pathophysiology

1. **Inhalation of droplet nuclei (containing M. tuberculosis)**

-> Deposited in alveolar spaces.

1. Alveolar macrophages phagocytose bacilli

-> Bacilli multiply within macrophages (initial replication).

1. Macrophages present antigens to T-lymphocytes

-> Cell-mediated immune response develops (2-8 weeks post-exposure).

1. Formation of granuloma (tubercle)

-> Macrophages, lymphocytes, epithelioid cells wall off bacilli. -> Central caseous necrosis (cheesy appearance) often develops. -> Contains infection, preventing further spread (latent TB).

1. Immune compromise / Granuloma breakdown

-> Bacilli reactivate and multiply. -> Tissue destruction, cavitation (in lungs).

1. Dissemination

-> Bacilli spread via airways (pulmonary TB). -> Bacilli spread via lymphatics or bloodstream (extrapulmonary TB, miliary TB).

Clinical features

History questions that matter

• Duration of cough: Persistent cough (>2 weeks) is the cardinal symptom, especially if productive.
• Sputum characteristics: Colour (mucoid, purulent, blood-stained), volume. Haemoptysis (streaks to frank blood) is highly suggestive.
• Constitutional symptoms: Fever (often low-grade, evening rise), night sweats (drenching), unexplained weight loss, fatigue, anorexia. These reflect systemic inflammation and catabolism.
• Chest pain: Pleuritic chest pain suggests pleural involvement.
• Dyspnoea: Can indicate extensive parenchymal disease, pleural effusion, or pericardial effusion.
• Contact history: Exposure to a known TB case increases suspicion.
• HIV status/risk factors: Crucial for assessing immune status and risk of atypical presentations or rapid progression.
• Past TB history/treatment: Important for assessing risk of relapse or drug resistance.
• Symptoms specific to extrapulmonary sites:
  • Lymph node: Painless swelling, often cervical.
  • Meningeal: Headache, neck stiffness, altered mental status, seizures.
  • Spinal (Pott's disease): Back pain, tenderness, neurological deficits (weakness, sensory loss).
  • Abdominal: Abdominal pain, distension, altered bowel habits, ascites.
  • Pericardial: Chest pain, dyspnoea, orthopnoea, signs of heart failure.
  • Miliary: Severe constitutional symptoms, dyspnoea, hepatosplenomegaly.

Examination findings and why each occurs

• General appearance: Cachexia (weight loss), pallor (anaemia of chronic disease), signs of chronic illness.
• Vital signs: Tachycardia (fever, anaemia), tachypnoea (lung involvement), low-grade fever.
• Respiratory system:
  • Inspection: Reduced chest expansion on affected side (pleural effusion, fibrosis).
  • Palpation: Tracheal deviation (large effusion, fibrosis), reduced tactile fremitus (effusion), increased tactile fremitus (consolidation).
  • Percussion: Dullness (consolidation, effusion), hyper-resonance (rare, compensatory emphysema).
  • Auscultation: Crackles (post-tussive apical crackles are classic, indicate active inflammation/cavitation), bronchial breath sounds (consolidation), diminished breath sounds (effusion, severe destruction). Pleural rub (pleurisy).
• Lymph nodes: Palpable, often firm, non-tender, matted lymphadenopathy (especially cervical, supraclavicular) in lymph node TB. May be fluctuant if abscessed.
• Abdomen: Tenderness, distension, ascites (peritoneal TB), hepatosplenomegaly (miliary TB).
• Cardiovascular: Distant heart sounds, raised JVP, pulsus paradoxus (pericardial effusion/constriction).
• Neurological: Neck stiffness, altered mental status, focal neurological deficits (meningeal TB, spinal cord compression).
• Musculoskeletal: Spinal tenderness, gibbus deformity (Pott's disease), cold abscesses.

Differential diagnosis

Investigations

Diagnosis and severity

Diagnosis of TB requires a high index of suspicion, especially in endemic areas and among high-risk groups.

• Pulmonary TB:
  • Definitive: Isolation of M. tuberculosis from sputum or other respiratory samples by culture, or detection by Xpert MTB/RIF.
  • Presumptive: Clinical symptoms, suggestive CXR findings, and positive sputum smear microscopy (AFB). Treatment often initiated based on presumptive diagnosis while awaiting culture/Xpert.
• Extrapulmonary TB:
  • Definitive: Histopathological evidence of caseating granulomas with or without AFB, or isolation of M. tuberculosis from the affected site (e.g., lymph node biopsy, pleural fluid, CSF, ascetic fluid).
  • Presumptive: Clinical features, imaging suggestive of TB, and exclusion of other common causes, especially in a patient with pulmonary TB or known exposure.
• Severity: Assessed by:
  • Extent of disease: Unilateral vs. bilateral, cavitary vs. non-cavitary, single vs. multiple sites of extrapulmonary involvement.
  • Presence of complications: Massive haemoptysis, respiratory failure, spinal cord compression, neurological deficits, cardiac tamponade.
  • Immune status: HIV co-infection, severe immunosuppression.
  • Drug resistance: Presence of drug-resistant TB significantly increases severity and complexity of management.
  • Systemic symptoms: Degree of weight loss, fever, and functional impairment.

Management

Immediate Stabilisation:

• Respiratory distress: Oxygen therapy, bronchodilators if wheezing, consider intubation and ventilation in severe cases.
• Haemoptysis: Position patient to prevent aspiration, identify source if massive, consider tranexamic acid, interventional radiology (bronchial artery embolisation) or surgery in life-threatening cases.
• Shock: IV fluids, vasopressors as needed.
• Meningitis: Dexamethasone (adjunctive therapy) to reduce inflammation and neurological sequelae.
• Pericardial effusion/tamponade: Pericardiocentesis.

Definitive Treatment: Standard First-Line Regimen (Kenya) The standard regimen for drug-susceptible TB is a 6-month course:

• Intensive Phase (2 months): Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Ethambutol (E) – often referred to as 2HRZE.
• Continuation Phase (4 months): Isoniazid (H), Rifampicin (R) – often referred to as 4HR.

Monitoring and Follow-up:

• Clinical: Regular assessment for symptom resolution and adverse drug reactions.
• Sputum Smear Microscopy: Monthly during the intensive phase, then at the end of treatment to confirm cure.
• Liver function tests (LFTs): Baseline, then as clinically indicated, especially if hepatotoxicity is suspected.
• Renal function: Baseline.
• Visual acuity/colour vision: Baseline and regularly for patients on Ethambutol.
• Audiometry: If aminoglycosides are used for MDR-TB.

Contraindications and Safety:

• Severe liver disease: Adjust regimen or use alternative drugs.
• Pregnancy: All first-line drugs are generally safe, but streptomycin (if used for MDR-TB) is contraindicated due to ototoxicity.
• Renal impairment: Adjust doses of Ethambutol and Pyrazinamide.
• Drug interactions: Rifampicin is a potent enzyme inducer, interacting with antiretrovirals, oral contraceptives, warfarin, etc.

Adverse Effects and Management:

• Hepatotoxicity: Nausea, vomiting, dark urine, jaundice. Stop all drugs, reintroduce one by one once LFTs normalise.
• Peripheral neuropathy: Tingling/numbness. Give pyridoxine (Vitamin B6) with isoniazid.
• Optic neuritis: Blurred vision, red-green colour blindness. Stop ethambutol immediately.
• Hyperuricemia: Joint pain. Manage with NSAIDs, consider stopping pyrazinamide if severe.
• Red-orange body fluids: Harmless, counsel patient.
• Rash: Antihistamines, consider drug withdrawal if severe.

Drug-Resistant TB (DR-TB):

• Suspect DR-TB: Previous TB treatment, contact with DR-TB case, failure to respond to first-line drugs, persistent positive smears.
• Diagnosis: Xpert MTB/RIF (detects rifampicin resistance), Line Probe Assay (LPA), phenotypic Drug Susceptibility Testing (DST).
• Management: Requires longer, more complex regimens with second-line drugs (e.g., fluoroquinolones, injectables like amikacin/kanamycin, bedaquiline, delamanid). Managed by specialists.

TB in HIV and IRIS:

• Co-infection: High prevalence in Kenya. Start ART within 2-8 weeks of starting TB treatment (except TB meningitis, where ART is delayed to 4-8 weeks).
• Drug interactions: Rifampicin interacts with many ARVs (e.g., protease inhibitors, non-nucleoside reverse transcriptase inhibitors). Adjust ARV regimen.
• Immune Reconstitution Inflammatory Syndrome (IRIS): Paradoxical worsening of TB symptoms or new manifestations after starting ART, due to recovering immune system. Manage symptomatically, sometimes with corticosteroids.

Prevention:

• BCG vaccination: For infants, protects against severe forms (miliary, meningitis).
• Isoniazid Preventive Therapy (IPT): For HIV-positive individuals, children <5 years in contact with active TB, and other high-risk groups.
• Infection control: Isolation of smear-positive patients, good ventilation, masks.
• Early diagnosis and treatment: To break the chain of transmission.

Complications and Prognosis

Complications:

• Respiratory: Cavitation, bronchiectasis, fibrosis, pleural effusion/empyema, pneumothorax, massive haemoptysis, chronic respiratory failure.
• Cardiac: Constrictive pericarditis.
• Neurological: Hydrocephalus, cranial nerve palsies, stroke (TB meningitis).
• Skeletal: Spinal deformity (Pott's disease), joint destruction.
• Renal: Amyloidosis, renal failure.
• Gastrointestinal: Strictures, malabsorption.
• Endocrine: Adrenal insufficiency (Addison's disease).
• Disseminated: Miliary TB, multi-organ failure.
• Drug-related: Severe adverse drug reactions, drug-resistant TB.

Prognosis:

• Generally good with prompt and appropriate treatment for drug-susceptible TB (cure rates >85%).
• Worse for drug-resistant TB, HIV co-infection, severe extrapulmonary forms (e.g., meningitis, miliary TB), and delayed diagnosis/treatment.
• Mortality is highest in patients with TB meningitis and miliary TB, especially if untreated or treatment is delayed.

High-yield exam points

• ADA in pleural fluid: Adenosine Deaminase >40 U/L is highly suggestive of TB pleurisy, especially in high prevalence areas.
• TB meningitis CSF: High protein, low glucose, lymphocytosis. Culture is often negative, so diagnosis relies on clinical suspicion, CSF findings, and sometimes Xpert MTB/RIF.
• Why rifampicin interacts: It's a potent inducer of cytochrome P450 enzymes, leading to accelerated metabolism of many drugs (e.g., ARVs, oral contraceptives, warfarin).
• Hepatotoxicity: Most common with Isoniazid, Rifampicin, and Pyrazinamide. All three can cause it.
• When to suspect MDR: History of previous TB treatment, contact with a known MDR-TB case, failure to convert sputum smear after 2 months of first-line treatment, or persistent positive smears at 5 months.

Clinical case

A 28-year-old male, known HIV-positive on ART for 3 years, presents with a 3-week history of worsening cough, fever, night sweats, and significant weight loss. He also complains of a painful, swollen neck lump that has been present for 2 months. On examination, he is cachectic, febrile (38.5°C), and has bilateral cervical lymphadenopathy, with one node in the right posterior triangle that is matted, firm, and non-tender, measuring 4x3 cm. His chest examination reveals decreased breath sounds and dullness to percussion at the right lung base. Sputum smear microscopy is positive for Acid-Fast Bacilli (AFB).

Questions:

1. What is the most likely diagnosis for his neck lump?
2. What is the most appropriate initial investigation for his lung findings, given the sputum smear result?
3. Considering his HIV status, what specific management consideration is crucial regarding his ART?

Model Answers:

1. Tuberculous lymphadenitis (Scrofula).
2. Chest X-ray to assess the extent of pulmonary involvement and look for typical TB patterns (e.g., infiltrates, cavitation, pleural effusion).
3. Continue his current ART regimen, but be mindful of potential drug interactions between rifampicin and certain antiretrovirals, and monitor for Immune Reconstitution Inflammatory Syndrome (IRIS).

Practice questions

Question 1

A 35-year-old male presents with a persistent cough, fever, and weight loss. Sputum smear is positive for AFB. He is started on standard first-line anti-TB treatment. Two weeks later, he complains of tingling and numbness in his feet. Which drug is most likely responsible for this symptom?

A. Rifampicin B. Pyrazinamide C. Ethambutol D. Isoniazid

Answer: D. Isoniazid Explanation: Isoniazid commonly causes peripheral neuropathy, which can be prevented or treated with pyridoxine (Vitamin B6).

Question 2

A 40-year-old female on anti-TB treatment develops yellowing of her eyes, dark urine, and nausea. Her liver function tests show significantly elevated transaminases. What is the immediate next step in her management?

A. Continue all drugs and monitor LFTs daily. B. Stop all anti-TB drugs immediately. C. Reduce the dose of Pyrazinamide only. D. Add pyridoxine to her regimen.

Answer: B. Stop all anti-TB drugs immediately. Explanation: Symptoms and signs of hepatotoxicity warrant immediate cessation of all anti-TB drugs to prevent further liver damage.

Question 3

Which of the following CSF findings is most characteristic of Tuberculous Meningitis?

A. High glucose, low protein, neutrophilic pleocytosis. B. Low glucose, high protein, lymphocytic pleocytosis. C. Normal glucose, normal protein, no cells. D. High glucose, high protein, eosinophilic pleocytosis.

Answer: B. Low glucose, high protein, lymphocytic pleocytosis. Explanation: Tuberculous meningitis typically presents with low CSF glucose, elevated protein, and a predominance of lymphocytes.

Question 4

A 25-year-old HIV-positive patient is diagnosed with pulmonary TB and started on anti-TB treatment. He is also on a protease inhibitor-based ART regimen. Which anti-TB drug requires careful consideration due to significant drug interactions with his ART?

A. Isoniazid B. Ethambutol C. Rifampicin D. Pyrazinamide

Answer: C. Rifampicin Explanation: Rifampicin is a potent inducer of cytochrome P450 enzymes, leading to significant interactions with many ARVs, including protease inhibitors.

Question 5

Which of the following is a key adverse effect of Ethambutol that requires regular monitoring?

A. Peripheral neuropathy B. Red-orange discoloration of body fluids C. Optic neuritis D. Hyperuricemia

Answer: C. Optic neuritis Explanation: Ethambutol can cause optic neuritis, leading to blurred vision and red-green colour blindness, necessitating baseline and regular visual acuity and colour vision testing.

Drafted with AI assistance from standard references and reviewed for structure. Check details against your lecture notes and the Kenya MoH guideline.