Tuberculosis (Adult)

1. Clinical Overview

Summary

Tuberculosis (TB) is a chronic granulomatous infectious disease caused by organisms of the Mycobacterium tuberculosis complex, primarily affecting the lungs but capable of disseminating to virtually any organ system. [1] Despite being preventable and curable, TB remains a leading cause of infectious disease mortality worldwide, with approximately 10.6 million new cases and 1.3 million deaths annually. [2] The pathogen is transmitted via respiratory droplets, and clinical disease develops in approximately 5-10% of immunocompetent individuals who become infected, with the remainder developing latent TB infection (LTBI). [3]

The classic clinical presentation includes chronic productive cough (greater than 2-3 weeks duration), constitutional symptoms (fever, night sweats, weight loss), and haemoptysis. [1] Diagnosis requires integration of clinical suspicion, chest radiography (typically showing upper lobe infiltrates with or without cavitation), microbiological confirmation through sputum smear microscopy, molecular testing (Xpert MTB/RIF), and mycobacterial culture. [4] Standard treatment comprises a 6-month regimen of four first-line drugs: Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol for the initial 2 months (intensive phase), followed by Rifampicin and Isoniazid for 4 months (continuation phase). [5]

Drug-resistant TB, particularly multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), represents a significant global health threat requiring prolonged treatment with second-line agents. [6] All TB cases require statutory notification and public health follow-up including contact tracing. The intersection of TB with HIV remains critical, as TB is the leading cause of death among people living with HIV. [2]

Key Facts

Clinical Pearls

Xpert MTB/RIF Pearl: GeneXpert MTB/RIF Ultra provides sensitivity of 88% (smear-negative, culture-positive) and detects rifampicin resistance mutations within 2 hours. It is the WHO-recommended initial diagnostic test for all patients with suspected TB. [4,8]

HIV Testing Pearl: HIV testing is mandatory in ALL patients diagnosed with TB. Globally, 12% of people with TB are co-infected with HIV, rising to over 50% in parts of sub-Saharan Africa. TB is the leading cause of death in people living with HIV. [2]

Pyridoxine Pearl: Co-administer pyridoxine (vitamin B6) 10-25 mg daily with isoniazid to prevent peripheral neuropathy. Essential in high-risk groups: HIV infection, diabetes, malnutrition, alcohol dependency, chronic renal failure, and pregnancy. [5]

Rifampicin Interactions Pearl: Rifampicin is a potent CYP450 inducer. Critical interactions include reduced efficacy of oral contraceptives, warfarin, antiretrovirals (particularly protease inhibitors and NNRTIs), and calcineurin inhibitors. Dose adjustments or alternative agents required. [9]

Contact Tracing Pearl: All household and close contacts require screening within 2 weeks of index case notification. Screen with symptom inquiry, chest radiograph, and IGRA (or TST). Treat LTBI if positive to break transmission chain. [10]

Smear-Negative TB Pearl: Up to 50% of culture-confirmed pulmonary TB cases are smear-negative. Clinical-radiological suspicion should prompt treatment initiation while awaiting culture, particularly in HIV-positive patients. [11]

Why This Matters Clinically

TB remains a re-emerging disease in high-income countries, driven by immigration from endemic regions, HIV co-infection, and increasing rates of drug resistance. [7] Delayed diagnosis leads to ongoing transmission, with each untreated case potentially infecting 10-15 contacts annually. [1] A high index of suspicion, particularly in at-risk populations, combined with rapid molecular diagnostics, is essential to reduce mortality and prevent transmission. Early appropriate treatment is cost-effective and prevents the development of resistance.

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2. Epidemiology

Global Burden

Tuberculosis is the second leading infectious cause of death globally after COVID-19 and disproportionately affects low- and middle-income countries. [2]

Regional Distribution:

• 44% of cases occur in South-East Asia Region
• 23% occur in African Region
• 8 countries account for two-thirds of global burden: India (28%), Indonesia (9.2%), China (7.4%), Philippines (7.0%), Pakistan (5.7%), Nigeria (4.5%), Bangladesh (3.6%), Democratic Republic of Congo (2.9%) [2]

UK Epidemiology

The UK is classified as a low-incidence country (less than 10 cases per 100,000 population) with marked geographic and demographic heterogeneity. [7]

High-Risk Groups in UK:

• Born in high-incidence country (India, Pakistan, Bangladesh, sub-Saharan Africa)
• Recent arrival from endemic area (within 5 years)
• Homeless individuals
• Prison population
• People who inject drugs
• HIV-positive individuals
• Close contacts of known TB cases
• Healthcare workers in high-risk settings
• Immunocompromised (biologics, transplant, chemotherapy)

Risk Factors for TB Disease

Latent TB Infection vs Active TB Disease

Understanding this distinction is fundamental to TB management:

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3. Aetiology & Pathophysiology

Causative Organisms

The Mycobacterium tuberculosis complex comprises several closely related species:

Microbiological Characteristics:

• Aerobic, non-spore-forming bacillus
• Slow-growing (doubling time 12-24 hours; visible colonies 3-8 weeks)
• Acid-fast on Ziehl-Neelsen staining (mycolic acid cell wall)
• Obligate intracellular pathogen (survives within macrophages)
• Optimal growth at 37°C with 5-10% CO₂
• Resistant to desiccation, weak acids, and many disinfectants

Transmission

TB is transmitted via the airborne route through droplet nuclei:

Step 1: Generation of Infectious Aerosols

• Produced by coughing, sneezing, speaking, singing
• Each cough generates 3,000 droplet nuclei
• Droplet nuclei are 1-5 μm diameter (optimal for alveolar deposition)
• Remain suspended in air for hours in enclosed spaces

Step 2: Inhalation and Deposition

• Particles > 5 μm trapped in upper airway mucosa
• Particles 1-5 μm reach terminal alveoli
• Bacilli engulfed by alveolar macrophages

Factors Affecting Transmission:

Pathogenesis of Primary TB Infection

Stage 1: Initial Infection (Day 0-21)

1. Inhaled bacilli reach terminal alveoli (usually lower/middle lobes)
2. Alveolar macrophages engulf bacilli via complement and surfactant receptors
3. Bacilli survive and replicate within phagosomes by preventing phagosome-lysosome fusion
4. Infected macrophages release chemokines, recruiting additional innate immune cells
5. Bacilli spread via lymphatics to hilar lymph nodes

Stage 2: Adaptive Immune Response (Week 2-8)

1. Dendritic cells present mycobacterial antigens to T cells in lymph nodes
2. CD4+ Th1 lymphocytes activated; produce IFN-γ and TNF-α
3. IFN-γ activates macrophages to kill intracellular bacilli
4. TNF-α essential for granuloma formation and maintenance
5. TST/IGRA becomes positive (indicates immune sensitisation)

Stage 3: Granuloma Formation

The hallmark of TB is the granuloma - an organised structure designed to contain infection:

Primary Complex (Ghon Complex):

• Ghon focus: Primary pulmonary lesion (usually subpleural, lower/middle lobes)
• Ghon complex: Ghon focus + draining hilar lymphadenopathy
• Ranke complex: Healed, calcified Ghon complex

Stage 4: Outcomes of Primary Infection

Pathogenesis of Reactivation (Post-Primary) TB

Reactivation occurs when immune control fails, typically years to decades after primary infection:

Risk Factors for Reactivation:

• HIV infection (10% per year vs 10% lifetime)
• TNF-α inhibitor therapy
• Immunosuppressive medications
• Malnutrition
• Diabetes mellitus
• Advanced age
• Malignancy

Characteristics of Reactivation TB:

• Location: Upper lobes preferred (higher oxygen tension, reduced lymphatic drainage)
• Cavitation: Common (tissue destruction by immune response)
• Infectivity: High (large numbers of bacilli in cavities)
• Spread: Via bronchi (bronchogenic spread) or blood (miliary TB)

Virulence Factors

Extrapulmonary TB - Pathogenesis

Extrapulmonary TB results from haematogenous or lymphatic dissemination:

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4. Clinical Presentation

Pulmonary Tuberculosis

Constitutional Symptoms:

Respiratory Symptoms:

Physical Signs:

Atypical Presentations

Extrapulmonary Tuberculosis

Extrapulmonary TB accounts for 15-20% of all TB cases and up to 50% in HIV-positive individuals. [16]

Lymph Node TB (Scrofula)

Most common form of EPTB:

Pleural TB

Central Nervous System TB

CNS TB carries high mortality (25-30%) and morbidity if untreated. [17]

TB Meningitis:

Tuberculoma:

• Space-occupying lesion(s); seizures; focal deficits
• May occur during treatment (paradoxical reaction)
• Ring-enhancing lesion(s) on MRI

Bone and Joint TB (Pott's Disease)

Miliary TB

Disseminated haematogenous TB representing failure of containment:

Genitourinary TB

Pericardial TB

Abdominal TB

Red Flags and Emergency Presentations

[!CAUTION] Immediate Action Required:

• Massive haemoptysis (> 200 mL): Risk of asphyxiation; lateral decubitus (affected side down); urgent bronchial artery embolisation
• Respiratory failure: ICU; mechanical ventilation; high mortality
• TB meningitis: Immediate treatment; do not await confirmation; adjunctive steroids
• Spinal TB with neurological deficit: Urgent MRI; neurosurgical review; decompression
• Pericardial tamponade: Emergency pericardiocentesis
• Miliary TB with multiorgan failure: ICU; consider MDR-TB

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5. Investigations

Diagnostic Algorithm

                SUSPECTED TUBERCULOSIS
                         ↓
    ┌────────────────────────────────────────────────┐
    │           INITIAL ASSESSMENT                   │
    │  • Symptoms: cough > 2 weeks, fever,            │
    │    night sweats, weight loss, haemoptysis      │
    │  • Risk factors: endemic country, HIV,          │
    │    contact, immunosuppression                  │
    │  • Examination: signs of disease/complications │
    └────────────────────────────────────────────────┘
                         ↓
    ┌────────────────────────────────────────────────┐
    │           RESPIRATORY ISOLATION                │
    │  • Single room, negative pressure if available │
    │  • N95/FFP2 for staff; surgical mask for patient│
    └────────────────────────────────────────────────┘
                         ↓
    ┌────────────────────────────────────────────────┐
    │           IMMEDIATE INVESTIGATIONS             │
    │  • Sputum × 3 (spot, early morning, spot)      │
    │    - Smear microscopy (ZN/auramine)            │
    │    - Xpert MTB/RIF (first-line molecular)      │
    │    - Mycobacterial culture + DST               │
    │  • Chest X-ray (PA)                            │
    │  • HIV test (MANDATORY in all patients)        │
    │  • Baseline bloods: FBC, LFTs, U&E, HbA1c      │
    │  • Hepatitis B/C serology                      │
    └────────────────────────────────────────────────┘
                         ↓
           Xpert MTB/RIF or Smear positive?
            ↓ Yes                    ↓ No
    ┌───────────────┐      ┌─────────────────────────┐
    │ START         │      │ High clinical suspicion?│
    │ TREATMENT     │      │ Consider:               │
    │ IMMEDIATELY   │      │ • Induced sputum        │
    │               │      │ • Bronchoscopy + BAL    │
    │ • Notify      │      │ • Empirical treatment   │
    │   public      │      │   while awaiting culture│
    │   health      │      │                         │
    └───────────────┘      └─────────────────────────┘

Microbiological Investigations

Sputum Testing

Sample Collection:

• Collect 3 sputum specimens (spot → early morning → spot) on consecutive days
• Minimum 5 mL volume per specimen
• If unable to expectorate: induced sputum (3% hypertonic saline nebulisation)
• If still unsuccessful: bronchoscopy with BAL

Specimen Handling:

• Transport to laboratory within 24 hours
• Refrigerate at 4°C if delayed
• Decontamination (NaOH-NALC) before culture

Drug Susceptibility Testing (DST)

Essential for all culture-positive cases:

Chest Radiography

Classic CXR Findings in Pulmonary TB:

Atypical CXR Findings (HIV-positive):

• Normal CXR (up to 10-15%)
• Mediastinal lymphadenopathy without parenchymal disease
• Lower/middle lobe disease
• Minimal cavitation
• Miliary pattern more common

Additional Investigations

Baseline Blood Tests

HIV Testing

MANDATORY in all TB patients:

• Offer rapid HIV test at diagnosis
• 12% global co-infection rate; higher in endemic areas
• Co-infection affects treatment timing, regimen, prognosis
• If HIV-positive: CD4 count, viral load, start ART

Tuberculin Skin Test (TST) and Interferon-Gamma Release Assays (IGRA)

Investigations for Extrapulmonary TB

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6. Management

Management Algorithm

          CONFIRMED/PROBABLE PULMONARY TB
                     ↓
┌──────────────────────────────────────────────────┐
│         INITIAL STEPS (Day 1)                    │
│  • Respiratory isolation (airborne precautions)  │
│  • HIV test (MANDATORY)                          │
│  • Baseline bloods (FBC, LFT, U&E, HbA1c)        │
│  • Notify public health (statutory)              │
│  • Assess for drug resistance risk               │
│  • Assess drug interactions                      │
│  • Initiate contact tracing                      │
└──────────────────────────────────────────────────┘
                     ↓
┌──────────────────────────────────────────────────┐
│      STANDARD TREATMENT (2HRZE/4HR)              │
│                                                  │
│  INTENSIVE PHASE (2 months):                     │
│  • Rifampicin 10 mg/kg (max 600 mg) daily        │
│  • Isoniazid 5 mg/kg (max 300 mg) daily          │
│  • Pyrazinamide 25 mg/kg (max 2 g) daily         │
│  • Ethambutol 15 mg/kg daily                     │
│  + Pyridoxine 10-25 mg daily                     │
│                                                  │
│  CONTINUATION PHASE (4 months):                  │
│  • Rifampicin 10 mg/kg (max 600 mg) daily        │
│  • Isoniazid 5 mg/kg (max 300 mg) daily          │
│  + Pyridoxine 10-25 mg daily                     │
│                                                  │
│  TOTAL DURATION: 6 months                        │
└──────────────────────────────────────────────────┘
                     ↓
┌──────────────────────────────────────────────────┐
│           MONITORING                             │
│  • Clinical: symptoms, weight, adherence         │
│  • Sputum at 2 months (should be culture-negative)│
│  • LFTs: baseline, 2 weeks, then monthly         │
│  • Visual acuity: baseline, monthly (ethambutol) │
│  • Drug levels: if poor response/toxicity        │
│  • CXR: at completion                            │
└──────────────────────────────────────────────────┘
                     ↓
                End of treatment
                     ↓
┌──────────────────────────────────────────────────┐
│           TREATMENT OUTCOMES                     │
│  • Cured: culture-negative at end of treatment   │
│  • Completed: finished treatment, no culture     │
│  • Failed: culture-positive at 5 months          │
│  • Died: during treatment                        │
│  • Lost to follow-up: interrupted > 2 months      │
└──────────────────────────────────────────────────┘

First-Line Anti-Tuberculosis Drugs

Pyridoxine Supplementation:

• Prevents isoniazid-induced peripheral neuropathy
• Dose: 10-25 mg daily
• Essential for high-risk groups: HIV, diabetes, alcohol excess, malnutrition, pregnancy, chronic renal failure

Fixed-Dose Combinations (FDCs)

WHO recommends FDCs to improve adherence:

• Intensive phase: RHZE tablet (e.g., Rimstar)
• Continuation phase: RH tablet
• Dose by weight bands

Treatment of Specific Situations

Extrapulmonary TB

TB in HIV Co-infection

Drug-Resistant TB

WHO Drug Groups for MDR-TB:

• Group A (preferred): Levofloxacin/moxifloxacin, bedaquiline, linezolid
• Group B (add to A): Clofazimine, cycloserine/terizidone
• Group C (if A/B cannot be used): Ethambutol, delamanid, pyrazinamide, imipenem, amikacin, ethionamide

Key Points:

• Bedaquiline-based shorter regimens (BPaLM/BPaL): 6 months total; high efficacy [20]
• All MDR-TB patients should be managed by specialist MDR-TB services
• DOT mandatory
• Monthly monitoring for adverse effects

Directly Observed Therapy (DOT)

Drug Interactions

Hepatotoxicity Management

Definition: ALT > 3× ULN with symptoms OR ALT > 5× ULN without symptoms

Management Algorithm:

1. Stop all hepatotoxic drugs (RIF, INH, PZA)
2. Exclude other causes (viral hepatitis, alcohol)
3. Wait for LFTs to normalise
4. Reintroduce one drug at a time (RIF first, then INH, then PZA)
5. If PZA implicated, may omit and extend treatment to 9 months (2HRE/7HR)
6. If severe/recurrent hepatotoxicity, use non-hepatotoxic regimen (fluoroquinolone, aminoglycoside, ethambutol, cycloserine)

Infection Control

Public Health Measures

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7. Latent TB Infection (LTBI)

Definition and Significance

LTBI represents a state of persistent immune response to TB antigens without clinical, radiological, or microbiological evidence of active disease. [21]

Who to Screen for LTBI

Diagnosis of LTBI

NICE Recommendation (UK):

• Use IGRA as first-line for LTBI screening
• TST acceptable if IGRA unavailable
• Single positive test sufficient to diagnose LTBI (if active TB excluded)

LTBI Treatment Regimens

Key Considerations:

• Exclude active TB before starting LTBI treatment
• Check for drug interactions
• Monitor LFTs (baseline, monthly)
• Counsel on hepatotoxicity symptoms

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8. BCG Vaccination

BCG Vaccine Overview

UK BCG Policy (Since 2005)

Universal neonatal BCG was discontinued; targeted vaccination:

BCG Complications

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9. Complications of Tuberculosis

Pulmonary Complications

Drug-Related Complications

Paradoxical Reactions

Worsening or new TB symptoms/lesions despite appropriate treatment:

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10. Prognosis and Outcomes

Treatment Outcomes (Drug-Sensitive TB)

Prognostic Factors

Poor Prognostic Factors:

Long-Term Sequelae

Follow-Up

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11. Prevention and Control

Hierarchy of TB Prevention

1. Primary prevention: BCG vaccination (protects against severe childhood TB)
2. Secondary prevention: Early case detection; contact tracing; LTBI treatment
3. Tertiary prevention: Effective treatment of active disease; infection control

Contact Tracing Protocol

New Entrant Screening

UK policy for migrants from high-incidence countries (≥40/100,000):

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12. Key Guidelines

Major Guidelines Referenced

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13. Examination Focus

Common Exam Questions

1. "What are the risk factors for tuberculosis?"
2. "How would you investigate a patient with suspected pulmonary TB?"
3. "Describe the first-line treatment regimen for TB and the mechanism of each drug."
4. "What are the side effects of anti-TB medications and how would you monitor for them?"
5. "How do you differentiate latent TB infection from active TB disease?"
6. "What are the features of drug-resistant TB and how would you manage it?"
7. "Describe the pathogenesis of TB from primary infection to reactivation."
8. "What are the indications for and options for LTBI treatment?"
9. "How would you manage a patient with TB meningitis?"
10. "What public health measures are required for a patient diagnosed with TB?"

Viva Points

Opening Statement: "Tuberculosis is a chronic granulomatous infection caused by Mycobacterium tuberculosis, primarily affecting the lungs but capable of extrapulmonary dissemination. It affects 10.6 million people annually and causes 1.3 million deaths globally. Diagnosis relies on clinical suspicion, chest radiography, and microbiological confirmation including molecular testing (Xpert MTB/RIF) and culture. Standard treatment is a 6-month regimen: 2 months of RIPE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol) followed by 4 months of Rifampicin and Isoniazid."

Key Statistics to Quote:

• Global burden: 10.6 million cases, 1.3 million deaths/year
• UK incidence: 6.6 per 100,000 (4,425 cases in 2022)
• HIV co-infection: 12% globally
• LTBI → active TB: 5-10% lifetime risk
• Xpert MTB/RIF sensitivity: 89% (smear+), 67% (smear−)
• Treatment success rate: > 95% for drug-sensitive TB

Classification to Know: Drug resistance categories (monoresistant, RR-TB, MDR-TB, pre-XDR, XDR-TB)

Evidence to Cite:

• Xpert MTB/RIF landmark study (NEJM 2010) [4]
• Theron et al. Xpert Ultra (Lancet ID 2018) [8]
• Prasad et al. steroids in TB meningitis Cochrane review [18]

Common Mistakes

❌ Mistakes that fail candidates:

• Not testing for HIV in every TB patient
• Forgetting pyridoxine supplementation with isoniazid
• Not monitoring LFTs during treatment
• Failing to notify public health
• Not recognising that TST/IGRA cannot distinguish LTBI from active TB
• Missing the need for 12-month treatment in TB meningitis
• Not adjusting for drug interactions with rifampicin
• Treating XDR-TB without specialist input
• Forgetting to ask about prior TB treatment (resistance risk)
• Not considering extrapulmonary TB in HIV-positive patients with fever

Model Answers

Q: A 35-year-old man from India presents with 4 weeks of productive cough, fever, night sweats, and 5 kg weight loss. How would you investigate and manage him?

A: "This presentation raises high clinical suspicion for pulmonary tuberculosis given the chronic cough, constitutional symptoms, and epidemiological risk factor of birth in a high-incidence country.

My immediate management would be:

1. Respiratory isolation with airborne precautions
2. Sputum samples × 3 for AFB smear, Xpert MTB/RIF, and mycobacterial culture
3. Chest X-ray looking for upper lobe infiltrates, cavitation, or effusion
4. HIV test - this is mandatory in all TB patients
5. Baseline blood tests: FBC, LFTs, U&E, HbA1c, hepatitis serology

If Xpert is positive or there is high clinical suspicion, I would start standard treatment: 2 months of Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol, followed by 4 months of Rifampicin and Isoniazid. I would add Pyridoxine to prevent isoniazid-induced neuropathy.

I would notify public health within 3 days and initiate contact tracing for household contacts.

Monitoring would include clinical review, sputum culture at 2 months (expecting culture conversion), monthly LFTs, and visual acuity testing for ethambutol toxicity."

Differentials to Consider

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14. Patient Communication

What is Tuberculosis?

"TB is a bacterial infection that mainly affects your lungs. It's caused by a germ called Mycobacterium tuberculosis that spreads through the air when someone with TB coughs or sneezes. TB has been around for thousands of years, and while it's a serious infection, it's completely curable with the right treatment."

Is It Curable?

"Yes, TB is curable with a course of antibiotics taken for 6 months. With proper treatment, over 95% of people with TB are cured. The key is taking all your medications exactly as prescribed, even when you start feeling better."

The Treatment

"Your treatment involves taking several tablets every day for 6 months:

• For the first 2 months, you'll take 4 different medications
• For the remaining 4 months, you'll take 2 medications
• You'll also take vitamin B6 to protect your nerves

It's very important to:

• Take your medications at the same time every day
• Never miss doses - this can cause the bacteria to become resistant
• Complete the full course even when you feel well"

Side Effects to Report

"Please tell us immediately if you experience:

• Feeling sick, vomiting, or losing your appetite
• Yellow skin or eyes (jaundice)
• Dark urine or pale stools
• Numbness or tingling in your hands or feet
• Visual problems - any change in your vision or colour perception
• Unusual bruising or bleeding
• Skin rash or itching

Your urine, sweat, and tears may turn orange-red from the medication - this is normal and harmless."

Am I Infectious?

"If you have TB in your lungs, you can spread it to others through coughing. However, after 2 weeks of treatment, you're usually no longer infectious to others. We'll test your sputum to confirm. Until then:

• Cover your mouth when coughing
• Open windows for ventilation
• Wear a mask around others
• Avoid close contact with babies or people with weak immune systems"

What About My Family and Contacts?

"We need to check people you've been in close contact with, especially those living with you. They'll be offered screening which may include:

• Questions about symptoms
• A chest X-ray
• A blood test

This is to protect them and prevent spread. If they've been infected but aren't sick, we can offer treatment to prevent them developing TB."

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15. References

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2. World Health Organization. Global Tuberculosis Report 2023. Geneva: WHO; 2023. Available at: https://www.who.int/publications/i/item/9789240083851

3. Houben RM, Dodd PJ. The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling. PLoS Med. 2016;13(10):e1002152. doi:10.1371/journal.pmed.1002152

4. Boehme CC, Nabeta P, Hillemann D, et al. Rapid Molecular Detection of Tuberculosis and Rifampin Resistance. N Engl J Med. 2010;363(11):1005-1015. doi:10.1056/NEJMoa0907847

5. World Health Organization. WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-susceptible tuberculosis treatment. Geneva: WHO; 2022. Available at: https://www.who.int/publications/i/item/9789240048126

6. World Health Organization. WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment, 2022 update. Geneva: WHO; 2022. doi:10.2139/ssrn.4074549

7. UK Health Security Agency. Tuberculosis in England: 2023 report. London: UKHSA; 2023. Available at: https://www.gov.uk/government/publications/tuberculosis-in-england-2023-report

8. Dorman SE, Schumacher SG, Alland D, et al. Xpert MTB/RIF Ultra for detection of Mycobacterium tuberculosis and rifampicin resistance: a prospective multicentre diagnostic accuracy study. Lancet Infect Dis. 2018;18(1):76-84. doi:10.1016/S1473-3099(17)30691-6

9. Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivistö KT. Pharmacokinetic interactions with rifampicin: clinical relevance. Clin Pharmacokinet. 2003;42(9):819-850. doi:10.2165/00003088-200342090-00003

10. National Institute for Health and Care Excellence. Tuberculosis (NG33). London: NICE; 2016 (updated 2023). Available at: https://www.nice.org.uk/guidance/ng33

11. Getahun H, Harrington M, O'Brien R, Nunn P. Diagnosis of smear-negative pulmonary tuberculosis in people with HIV infection or AIDS in resource-constrained settings: informing urgent policy changes. Lancet. 2007;369(9578):2042-2049. doi:10.1016/S0140-6736(07)60284-0

12. Lawn SD, Churchyard G. Epidemiology of HIV-associated tuberculosis. Curr Opin HIV AIDS. 2009;4(4):325-333. doi:10.1097/COH.0b013e32832c7d61

13. Baddley JW, Cantini F, Goletti D, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [I]: anti-tumor necrosis factor-α agents). Clin Microbiol Infect. 2018;24 Suppl 2:S10-S20. doi:10.1016/j.cmi.2017.12.025

14. Jeon CY, Murray MB. Diabetes mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies. PLoS Med. 2008;5(7):e152. doi:10.1371/journal.pmed.0050152

15. Lin HH, Ezzati M, Murray M. Tobacco smoke, indoor air pollution and tuberculosis: a systematic review and meta-analysis. PLoS Med. 2007;4(1):e20. doi:10.1371/journal.pmed.0040020

16. Peto HM, Pratt RH, Harrington TA, LoBue PA, Armstrong LR. Epidemiology of extrapulmonary tuberculosis in the United States, 1993-2006. Clin Infect Dis. 2009;49(9):1350-1357. doi:10.1086/605559

17. Thwaites GE, van Toorn R, Schoeman J. Tuberculous meningitis: more questions, still too few answers. Lancet Neurol. 2013;12(10):999-1010. doi:10.1016/S1474-4422(13)70168-6

18. Prasad K, Singh MB, Ryan H. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev. 2016;4(4):CD002244. doi:10.1002/14651858.CD002244.pub4

19. Gopalan N, Andrade BB, Swaminathan S. Tuberculosis-immune reconstitution inflammatory syndrome in HIV: from pathogenesis to prediction. Expert Rev Clin Immunol. 2014;10(5):631-645. doi:10.1586/1744666X.2014.892828

20. Conradie F, Bagdasaryan TR, Borisov S, et al. Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis. N Engl J Med. 2022;387(9):810-823. doi:10.1056/NEJMoa2119430

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