Tuberculosis

Related Subjects: |Assessing Breathlessness |Fever - Pyrexia of unknown origin |Tuberculosis |TB Meningitis |Miliary Tuberculosis |Lady Windermere syndrome

🌍 Tuberculosis (TB) remains a major global infectious disease and an important UK public health diagnosis. 🧪 Offer HIV testing to people with suspected or confirmed TB, and consider other immunosuppression risks such as transplant medicines, biological therapy, corticosteroids, diabetes, CKD and malnutrition. 💉 BCG mainly protects children against severe disseminated TB, especially TB meningitis and miliary TB; it is much less reliable at preventing adult pulmonary TB. 📋 All suspected or confirmed active TB is notifiable in the UK, regardless of site of disease.

🔬 Microbiology

• Mycobacterium tuberculosis is an obligate aerobe, acid-fast bacillus. On Ziehl–Neelsen staining it appears as 🔴 red rods.
• Its lipid-rich cell wall contains mycolic acids, which explain acid-fastness, resistance to drying, slow growth and survival inside macrophages.
• ⏱️ It is slow-growing, with a generation time of roughly 12–18 hours, so culture may take weeks.
• 🧪 Cord factor is associated with virulence, granuloma formation and inhibition of normal macrophage killing.
• Classically, M. tuberculosis is niacin positive and nitrate reduction positive, although modern practice relies heavily on NAAT, culture and drug susceptibility testing.

🧠 Pathophysiology: why TB behaves like this

• After inhalation, bacilli reach the alveoli and are taken up by macrophages. The organism can survive intracellularly, so the immune system responds with a delayed type IV hypersensitivity reaction.
• Activated T cells and macrophages form granulomas, which attempt to wall off infection. This explains caseating granulomas, latent infection and later reactivation.
• Reactivation tends to affect the upper lobes because M. tuberculosis favours high oxygen tension.
• Severe immunosuppression may prevent good granuloma formation, so TB may be disseminated, smear-negative or radiologically atypical.

🌍 Epidemiology & Risk: UK focus

• UK risk is higher with recent close contact, birth or prolonged residence in a high-incidence country, homelessness, imprisonment, alcohol or drug misuse, previous untreated TB, and immunosuppression.
• 📈 HIV increases the risk of both reactivation and extrapulmonary TB. In advanced HIV, chest imaging may be non-classical or even deceptively normal.
• 💊 MDR-TB means resistance to at least isoniazid and rifampicin. RR-TB means rifampicin-resistant TB. These require specialist TB services.
• 🏥 Always consider TB in a patient with constitutional symptoms, prolonged cough, abnormal CXR, lymphadenopathy, sterile pyuria, meningitis of subacute onset, or unexplained pericardial/pleural effusion.

🫁 Clinical Types

• Primary TB: initial infection, often asymptomatic. A Ghon focus plus involved hilar lymph nodes forms a Ghon complex.
• Latent TB infection: immune containment of infection. The patient has no symptoms, no radiological evidence of active disease and is not infectious, but immunological tests may be positive.
• Post-primary / reactivation TB: classically apical pulmonary disease with cavitation, cough, haemoptysis, fever, night sweats and weight loss.
• Miliary TB: haematogenous dissemination causing diffuse “millet seed” lesions 🌾 and systemic illness.
• Extrapulmonary TB:
  • 🧠 CNS: TB meningitis, tuberculoma, spinal TB / Pott disease.
  • 🚻 Genitourinary: sterile pyuria, epididymo-orchitis, infertility.
  • 🍽️ Gastrointestinal: ileocaecal disease, abdominal pain, obstruction, ascites.
  • ❤️ Pericardial: pericarditis, effusion, later constrictive pericarditis.
  • 🧂 Adrenal: adrenal destruction causing primary adrenal insufficiency.
  • 🦴 Bone/joint: vertebral collapse, chronic monoarthritis, cold abscess.
  • 🧬 Lymph node TB: classically chronic painless cervical lymphadenopathy.

📋 Clinical Features

• 🗣️ Persistent cough, especially if lasting more than 3 weeks, with or without sputum or haemoptysis.
• 🌡️ Fever, night sweats, anorexia, weight loss and fatigue.
• 😮 Chest pain or breathlessness, especially with pleural or pericardial involvement.
• ⚠️ Extrapulmonary clues include meningism, confusion, back pain, spinal deformity, sterile pyuria, lymphadenopathy, ascites, monoarthritis or adrenal insufficiency.
• 👶 In children, TB can be non-specific: poor growth, fever, lethargy, cough, lymphadenopathy or contact with an infectious adult.

🚨 Infection Control & Public Health

• 📋 Notify suspected or confirmed active TB promptly through the local TB/public health pathway.
• 😷 Suspected infectious pulmonary or laryngeal TB should be managed with appropriate respiratory isolation while being assessed.
• 🏠 Contact tracing is coordinated by specialist TB services and public health teams. Household contacts, children and immunosuppressed contacts are particularly important.
• 🧪 Infectiousness is highest with smear-positive pulmonary or laryngeal TB, cavitating disease, cough and aerosol-generating exposures.

🔎 Investigations: UK/NICE-style approach

• 🩻 Chest X-ray is the usual initial imaging test for suspected pulmonary TB. CT may help define complex disease, lymph nodes, cavitation or alternative diagnoses.
• 🧪 Sputum testing: send sputum, induced sputum or BAL for AFB smear, culture and NAAT. NAAT can rapidly identify M. tuberculosis and may detect rifampicin resistance.
• 🧫 Culture remains the reference standard because it confirms the organism and enables full drug susceptibility testing.
• 🧬 IGRA/TST: mainly used for latent TB assessment and contact screening. IGRA is not affected by previous BCG, but neither IGRA nor TST reliably distinguishes active from latent TB.
• 🔬 Extrapulmonary TB: obtain tissue or fluid where possible for microscopy, culture, NAAT and histology. Histology may show caseating granulomas, but microbiological confirmation is preferred.
• 🧠 Suspected CNS TB: urgent neuroimaging if indicated, lumbar puncture where safe, CSF microscopy/culture/NAAT, and early specialist treatment because delay worsens outcome.
• 🧪 Baseline tests before treatment: LFTs, U&Es, FBC, HIV test, hepatitis B/C where relevant, pregnancy status where appropriate, and visual acuity/colour vision if ethambutol is used.

TB cavity

Miliary TB

💊 Management: Drug-Sensitive Active TB

• Standard 6-month regimen for most drug-sensitive pulmonary TB:
  • Initial phase, 2 months: isoniazid + rifampicin + pyrazinamide + ethambutol = HRZE.
  • Continuation phase, 4 months: isoniazid + rifampicin = HR.
• 💊 Give pyridoxine with isoniazid when there is increased neuropathy risk, such as pregnancy, diabetes, HIV, alcohol dependence, malnutrition, renal disease or existing neuropathy.
• 🧠 CNS TB usually requires longer treatment, commonly around 12 months, under specialist guidance.
• 🦴 Bone/joint TB, disseminated TB, drug-resistant TB or interruptions in treatment may also need longer or modified treatment.
• 🤝 Adherence support is essential. Use enhanced case management for people at risk of poor adherence. DOT is not for everyone, but is useful where adherence risk is high.
• 💉 Adjunct corticosteroids are important in TB meningitis and are often used in TB pericarditis, guided by specialists.

💊 High-Yield Drug Toxicities

• 💊 Isoniazid → hepatitis, peripheral neuropathy, seizures in overdose. Prevent neuropathy with pyridoxine when risk is increased.
• 🟠 Rifampicin → hepatitis, orange urine/tears, thrombocytopenia, and potent enzyme induction causing major drug interactions.
• 🔥 Pyrazinamide → hepatitis, hyperuricaemia and gout.
• 👁️ Ethambutol → optic neuritis with reduced visual acuity and red-green colour impairment.
• 👂 Aminoglycosides, now mainly in selected drug-resistant TB contexts, can cause ototoxicity and nephrotoxicity.
• 🧬 Linezolid, used in some drug-resistant TB regimens, can cause myelosuppression, peripheral neuropathy and optic neuropathy.

🤝 TB & HIV

• 🧪 Offer HIV testing to all people with suspected or confirmed TB.
• 📷 TB in advanced HIV may be extrapulmonary, disseminated, smear-negative or radiologically atypical.
• 💊 ART timing is specialist-led. In general, people with CD4 <50 cells/µL usually start ART within about 2 weeks of starting TB treatment once stable and tolerating therapy. Others often start within 8–12 weeks.
• 🧠 Avoid very early ART in CNS TB unless specialist advice supports it, because immune reconstitution may worsen intracranial inflammation.
• ⚠️ Rifampicin has major interactions with ART, anticoagulants, antiepileptics, steroids, contraception and many other drugs. Always check interactions and involve TB/HIV specialists.

💤 Latent TB Infection

• Latent TB means the immune system has contained infection: the patient is asymptomatic, not infectious and has no evidence of active disease.
• 🧪 Testing is usually with IGRA and/or TST depending on age, risk and local pathway.
• 🚫 Before treating latent TB, exclude active TB clinically and radiologically; monotherapy or incomplete therapy in active disease risks resistance.
• 💊 Latent TB treatment options include rifampicin/isoniazid-based regimens depending on age, risk, interactions and specialist/local policy.
• 🧪 Check baseline risk factors for hepatotoxicity and relevant viral hepatitis testing before treatment where indicated.

💉 BCG Vaccination

• BCG is not routinely given to all children in the UK; it is targeted to babies, children or adults at higher risk of TB exposure.
• It is most useful for preventing severe childhood TB, particularly TB meningitis and miliary TB.
• BCG can affect TST results but does not affect IGRA results.

🆕 Newer TB drugs and MDR/RR-TB
Modern drug-resistant TB regimens are increasingly all-oral and specialist-led. They may include bedaquiline, delamanid, pretomanid, linezolid and fluoroquinolones such as moxifloxacin. Bedaquiline, delamanid and moxifloxacin can prolong the QT interval, so ECG monitoring is important. Linezolid can cause myelosuppression, peripheral neuropathy and optic neuropathy. These regimens can shorten treatment and avoid injectable toxicity, but they require TB specialist oversight, drug susceptibility results and careful monitoring.

🧠 Exam Pearls

• 🔴 Acid-fast bacillus + chronic cough/night sweats/weight loss = think TB.
• 🩻 Upper-lobe cavitation suggests reactivation TB.
• 🌾 Diffuse tiny nodules = miliary TB.
• 🧪 IGRA/TST support latent TB diagnosis but do not prove active TB.
• 🧫 Culture is slow but remains vital for confirmation and susceptibility testing.
• 👁️ Ethambutol = optic neuritis; 🟠 rifampicin = orange secretions and enzyme induction; 💊 isoniazid = neuropathy/hepatitis; 🔥 pyrazinamide = gout/hepatitis.
• 📋 Active TB is notifiable in the UK.

⚠️ Clinical safety point: suspected TB should not be managed in isolation by a non-specialist. Involve respiratory/infectious diseases/TB specialist teams early, notify public health pathways, assess infectiousness, and consider contact tracing, adherence support and drug interactions from the start.

Additional related clinical topics

Miliary (Disseminated) Tuberculosis

Key point: Miliary TB is haematogenous (blood-borne) dissemination of Mycobacterium tuberculosis, producing countless tiny granulomas across multiple organs (classically “millet seed” nodules in the lungs). It can be rapidly fatal if missed, and may present without a dramatic cough - think unexplained systemic illness, abnormal LFTs, cytopenias, or sepsis-like physiology.

📌 Why it matters (UK context)

• TB remains an important UK diagnosis; UKHSA provisional data for England reported 5,424 TB notifications in 2025 (broadly stable vs 2024).
• Miliary TB is less common than isolated pulmonary TB but is high-risk: higher rates of delayed diagnosis, multi-organ failure, and CNS involvement.
• In the UK, TB (including disseminated forms) requires specialist TB team involvement, notification, and contact tracing.

🧬 Pathophysiology (the “why”)

• Primary infection or reactivation can seed bacilli into the bloodstream → widespread micro-embolic spread to lungs, liver, spleen, bone marrow, adrenals, kidneys, meninges, and eye.
• Host response forms granulomas (macrophages, T-cells, caseation). The burden becomes “miliary” when dissemination is extensive.
• Risk rises with impaired cell-mediated immunity: HIV, steroids/biologics (anti-TNF), transplant, CKD, diabetes, malnutrition, pregnancy/post-partum, extremes of age.

⚠️ When to suspect miliary TB (clinical clues)

• Constitutional: fever, night sweats 🌙, weight loss, anorexia, profound fatigue.
• Respiratory: dry cough, dyspnoea, tachypnoea; may be mild or absent early.
• Sepsis-like picture: hypotension, high lactate, multi-organ dysfunction.
• Organ hints:
  • Liver: cholestatic/raised ALP, hepatosplenomegaly, jaundice.
  • Bone marrow: pancytopenia, unexplained anaemia.
  • CNS: headache, confusion, meningism, cranial nerve palsies (think TB meningitis / tuberculomas).
  • Adrenal: hyponatraemia, hyperkalaemia, hypotension → possible adrenal TB/Addisonian crisis.
  • Eye: choroidal tubercles (important clue; urgent ophthalmology if visual symptoms).

🩻 Imaging

• CXR: classic diffuse, fine nodular (“miliary”) mottling - but can be normal early.
• HRCT chest: more sensitive; shows innumerable 1–3 mm nodules with random distribution.
• CT/MRI brain if neuro symptoms/signs: meningitis features, hydrocephalus, tuberculomas.
• Abdominal imaging (USS/CT) if hepatosplenomegaly, abnormal LFTs, lymphadenopathy, ascites.

🧪 Investigations (practical, high-yield)

1) Baseline bloods

• FBC (anaemia, leukopenia, thrombocytopenia), CRP/ESR.
• U&E (hyponatraemia; renal impairment impacts dosing), LFTs (common derangement), glucose.
• HIV test (offer routinely in suspected/confirmed TB), hepatitis B/C baseline before treatment where relevant.

2) Microbiology (send early, send widely)

• Respiratory samples (even if cough minimal): sputum (induced if needed), BAL if intubated/bronchoscopy.
• NAAT/PCR (e.g., Xpert MTB/RIF-style assays) where available for rapid detection ± rifampicin resistance signal.
• Culture from multiple sites (slow but essential) + full drug susceptibility testing.
• Blood cultures for mycobacteria (especially in HIV/advanced disease) and urine AFB/culture if GU involvement suspected.
• Bone marrow aspirate/trephine if pancytopenia/PUO - can yield TB on culture/histology.

3) Histology

• Biopsy accessible sites: lymph node, liver, pleura, bone marrow. Look for granulomas; send tissue for AFB stain + TB PCR + culture.

4) Lumbar puncture (LP) - do not miss CNS TB

• LP if any CNS symptoms/signs or unexplained delirium.
• Typical TB meningitis CSF: lymphocytic predominance, high protein, low glucose (but can be mixed early).

🔎 Differential diagnosis (things that mimic “miliary”)

Condition	Clues	How to distinguish
🦠 Disseminated fungal infection (e.g., histoplasmosis)	Immunosuppression, travel/exposure	Fungal cultures/antigen tests, biopsy
🎗️ Miliary metastases	Known malignancy, weight loss, bone pain	CT pattern + tumour markers/biopsy
🫁 Sarcoidosis / hypersensitivity pneumonitis	Non-infective systemic features	ACE (non-specific), BAL profile, biopsy (non-caseating)
🦠 Pneumocystis jirovecii (HIV)	Severe hypoxia, diffuse ground-glass	CT pattern + PCR/BAL; LDH raised
🧫 Sepsis with DIC / HLH	Shock, cytopenias, ferritin very high	Bone marrow + HLH workup; TB can trigger HLH

🚑 Immediate management (what you do first)

• Escalate early: involve the TB specialist team urgently; miliary TB is “severe TB” until proven otherwise.
• Assess severity: oxygenation, ABG/VBG, lactate, organ dysfunction; consider ITU if respiratory failure/ARDS.
• Infection control: treat as potentially infectious pulmonary TB until assessed - use airborne precautions if pulmonary involvement suspected (local IPC policy + TB team advice).
• Start treatment promptly if high clinical suspicion, especially if critically unwell, after obtaining urgent samples (do not delay lifesaving therapy waiting for culture).

💊 Treatment (drug-susceptible TB, typical UK approach)

In the UK, standard initial therapy for active TB is 4-drug therapy while awaiting drug susceptibilities:

Phase	Regimen	Typical duration	Notes
Intensive 🔥	Rifampicin + Isoniazid + Pyrazinamide + Ethambutol (RIPE)	2 months	Use ethambutol until sensitivities known
Continuation ✅	Rifampicin + Isoniazid	4 months	Total 6 months for many non-CNS cases

Important: Duration often needs extension in disseminated disease depending on site (e.g., CNS TB, bone/joint TB). Always follow the TB specialist plan and local protocol. NICE NG33 is the core UK reference for TB services and management principles.

🧠 If CNS involvement (TB meningitis / tuberculoma)

• Requires urgent specialist management, neuroimaging, LP (where safe), and typically longer treatment than 6 months.
• Corticosteroids are standard adjunctive therapy for TB meningitis and reduce inflammatory damage (oedema, vasculitis, infarction risk).

❤️ If TB pericarditis

• Also typically treated with adjunctive steroids (specialist-led) due to risk of constriction and intense inflammation.

🌡️ Steroids in “severe” miliary TB

• Not routine for all miliary TB, but may be considered in selected severe inflammatory complications (e.g., ARDS, adrenal involvement) - this should be TB specialist/ICU-led because immunosuppression can worsen uncontrolled infection if misapplied.

🧯 Monitoring & safety (don’t get caught out)

• Baseline: LFTs, U&E, FBC; consider visual acuity/colour vision if ethambutol is used (especially prolonged therapy).
• Drug interactions (very common): rifampicin is a strong enzyme inducer → affects warfarin, DOACs, many antiepileptics, methadone, contraceptives, steroids, and antiretrovirals. Liaise with pharmacy/HIV team early.
• Hepatotoxicity: isoniazid/rifampicin/pyrazinamide can all contribute - interpret LFT rises with symptoms, bilirubin, and clinical trajectory.
• Paradoxical reactions / IRIS: clinical worsening after starting therapy (esp. HIV) due to immune rebound; distinguish from resistance, non-adherence, or alternative diagnosis.
• Adherence support: TB teams may use DOT/VOT (direct/video observed therapy) for complex cases or adherence risk.

🧑‍🧑‍🧒 Public health duties (UK)

• TB is notifiable and managed through specialist TB services with contact tracing.
• Assess close household contacts for symptoms and TB testing; consider latent TB screening/treatment according to risk.
• Consider social factors: housing insecurity, substance use, barriers to follow-up - addressing these reduces transmission and relapse risk.

🚨 Complications (what kills patients)

• Acute respiratory failure / ARDS
• TB meningitis → infarction, hydrocephalus, long-term disability
• Bone marrow failure and severe anaemia/cytopenias
• Adrenal insufficiency
• HLH (rare but critical; TB can be a trigger)

🌍 Advice for patients and clinicians in low- and middle-income settings: In resource-limited settings, early recognition of miliary TB is critical because delayed diagnosis is a major driver of mortality. Any patient with prolonged fever, weight loss, night sweats, unexplained anaemia, or multi-organ symptoms should prompt strong clinical suspicion, even if chest X-ray findings are subtle or absent. Where advanced imaging and cultures are unavailable, treatment should be started on strong clinical grounds after basic microbiological sampling, as untreated dissemination rapidly leads to respiratory failure, CNS disease, and adrenal insufficiency. Ensuring reliable access to full-course combination therapy, supporting adherence through community health workers, and addressing malnutrition and HIV co-infection are as important as prescribing drugs. From a systems perspective, strengthening contact tracing, reducing stigma, and integrating TB care into primary health services remain the most effective long-term strategies for reducing transmission and late presentations.

✅ “Makindo exam pearls”

• Think miliary TB in PUO + weight loss + abnormal LFTs/cytopenias, especially with immunosuppression or epidemiological risk.
• A normal early CXR does not exclude it - HRCT is more sensitive.
• Always ask: “Could there be CNS TB?” - because it changes urgency, imaging, LP decisions, steroid use, and duration.

🖼️ Suggested Makindo images/figures to add

• Figure: “Miliary pattern on CXR vs HRCT (random micronodules)”
• Diagram: “Haematogenous dissemination pathway (lungs → bloodstream → organs)”
• Flowchart: “Suspected miliary TB: samples first → start RIPE → assess CNS → TB team + IPC”

📚 References (UK & international)

• NICE Guideline NG33: Tuberculosis (last reviewed Feb 2024; NICE PDF copyright 2025).
• UKHSA (England): National quarterly report of TB - Quarter 4, 2025 (provisional).
• WHO consolidated guidelines on TB, Module 4: Treatment and care (updated evidence-based recommendations).
• Ray S et al. Review: Diagnosis and management of miliary tuberculosis. :