Pulmonary Tuberculosis

• Tuberculosis (TB) is a communicable infectious disease caused by Mycobacterium tuberculosis, a slow-growing, obligate aerobic bacillus that is part of the Mycobacterium tuberculosis complex. 
• TB is primarily transmitted via airborne droplet nuclei and predominantly affects the lungs (pulmonary TB), although it can involve virtually any organ system, including the lymphatic, central nervous, gastrointestinal, genitourinary, skeletal, and hepatic systems.
• In its pulmonary form, TB is communicable and represents the most common manifestation of the disease. However, a significant proportion of individuals infected with M. tuberculosis do not initially develop active disease. Instead, the bacillus may remain dormant for years—this is referred to as latent TB infection (LTBI). 
• Latent infection carries a lifelong risk of reactivation, particularly in individuals with immunosuppressive conditions such as HIV, diabetes, or use of immunosuppressive therapies (e.g., corticosteroids, TNF-alpha antagonists).
• Pulmonary TB is characterised by caseating granulomatous inflammation, often with necrosis, and is responsible for the majority of TB-related morbidity and mortality. 
• It is the leading cause of death globally from a single infectious agent and remains a major public health concern, particularly in settings with high HIV prevalence or poor healthcare infrastructure.

Causative Agent

• Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb), a slow-growing, non-spore-forming, acid-fast bacillus that is an obligate aerobe and facultative intracellular parasite.
• Mtb organisms grow in serpentine cords and are characterised by lipid-rich cell walls composed of mycolic acids, glycolipids, and phosphoglycolipids. These structures provide resistance to lysosomal destruction and are responsible for acid-fast staining.
• Humans are the only known natural reservoir, although rare cases of transmission via organ transplantation and other routes have been documented.

Mechanism of Infection

• Infection occurs through inhalation of aerosolised droplet nuclei (1–5 μm) generated by individuals with active pulmonary (or laryngeal) TB during coughing, sneezing, or speaking.
• The likelihood of transmission is influenced by the bacillary burden (e.g., smear positivity, cavitation), duration and proximity of exposure, environmental ventilation, and the immune status of the exposed individual.

Latent vs Active Disease

• Following inhalation and alveolar deposition, Mtb is phagocytosed by alveolar macrophages but resists intracellular killing.
• In most immunocompetent hosts, the immune system controls but does not eradicate the infection, resulting in latent TB infection (LTBI).
• Approximately 10% of latently infected individuals progress to active disease during their lifetime, with the greatest risk within the first two years post-infection.
• Reactivation may occur due to immunosuppression, malnutrition, or other comorbidities.

Transmission Dynamics

• Transmission is predominantly airborne and enhanced in enclosed or poorly ventilated environments such as submarines, prisons, or shelters.
• Some TB strains appear to be more transmissible than others. For instance, isoniazid-resistant strains have been linked with lower secondary attack rates.
• Molecular epidemiology suggests that while a third of TB cases arise from recent transmission, the majority result from reactivation of latent infection.

Extrapulmonary Spread

• Mtb can disseminate haematogenously during primary infection or reactivation, particularly in immunocompromised individuals.
• Common extrapulmonary sites include lymph nodes, CNS, genitourinary system, bones, liver, spleen, peritoneum, and pericardium.
• Disseminated or miliary TB is more common in infants, elderly persons, and people living with HIV.

Host Risk Factors for Progression to Active TB

• Immunosuppression: HIV, malignancies, systemic corticosteroids, TNF-alpha inhibitors, and post-transplant immunosuppression.
• Nutritional and metabolic: Malnutrition, low body weight, diabetes mellitus, chronic renal failure, chronic malabsorption, and gastrectomy.
• Lifestyle and exposure: Cigarette smoking, alcohol use, injection drug use, homelessness, and residence in institutional settings.
• Pulmonary conditions: Silicosis, apical fibrosis, and prior untreated pulmonary TB.
• Recent TB exposure: Close contact with an infectious case, particularly within the last 18 months.

Immunomodulating Therapies and TB Risk

• TNF-alpha is crucial for maintaining granuloma integrity. Anti-TNF therapies, used in autoimmune conditions, disrupt this control and increase TB risk, including atypical and extrapulmonary presentations.
• Systemic corticosteroids (>15 mg/day for ≥4 weeks) and high-dose inhaled steroids are also associated with elevated TB risk.

Paediatric Considerations

• Children under 5 years are at higher risk of severe TB, including miliary and meningeal forms.
• Due to their limited cough and low bacillary load, children are less likely to transmit TB.
• Bone involvement, including the epiphyses, is more common in paediatric TB due to vascularity.

Genetic Susceptibility

• NRAMP1/SLC11A1: Involved in intraphagosomal control of mycobacteria; polymorphisms are associated with increased TB risk.
• MBL2 and CD14: Encode proteins critical for mycobacterial recognition and opsonisation; variants are linked to altered susceptibility.
• SP110 and CISH: Regulate interferon signalling and cytokine suppression; certain polymorphisms are associated with TB vulnerability.
• IRGM: Important in autophagy and intracellular bacterial clearance; promoter variants can alter TB risk.
• IFNG and IFNGR1: Encode interferon-gamma and its receptor; key mediators in macrophage activation and granuloma maintenance.
• TIRAP/MAL: Adaptor in Toll-like receptor signalling; protective variants may influence TB risk.
• CD209 (DC-SIGN): Implicated in dendritic cell-mediated mycobacterial capture; associated polymorphisms affect disease susceptibility.
• HLA: Specific alleles such as HLA-DR2 and HLA-DQ1 have been associated with pulmonary TB susceptibility.

Entry and Initial Host Interaction

• Transmission of Mycobacterium tuberculosis (Mtb) occurs primarily through inhalation of aerosolised droplets, 1–5 μm in diameter, generated by coughing or speaking from individuals with active pulmonary or laryngeal TB.
• As few as 10 bacilli are sufficient to initiate infection. A single cough can release over 3,000 infectious droplets, and exposure to an infectious individual for as little as five minutes may suffice to transmit the bacilli.
• Once inhaled, Mtb bacilli are deposited in the alveoli and phagocytosed by resident alveolar macrophages. Despite internalisation, the bacilli avoid destruction through mechanisms including inhibition of phagosome-lysosome fusion and production of antioxidant enzymes (e.g., catalase, superoxide dismutase, thioredoxin).

Innate Immune Evasion and Antigen Presentation

• Mtb disrupts antigen presentation by impairing proteasomal function and downregulating MHC class II expression.
• The bacilli may escape into the cytosol or infect alveolar epithelial cells, while macrophages containing Mtb disseminate within lung tissue.
• Antigen-presenting dendritic cells carry Mtb antigens to lymph nodes, where they activate naïve CD4+ T cells via IL-12 signalling. These cells differentiate into Th1 cells and return to the lungs to mediate cellular immunity.

Granuloma Formation

• The hallmark of TB is granuloma formation—a structured aggregation of immune cells intended to contain the infection.
• Granulomas consist of infected and uninfected macrophages, Langhans giant cells, epithelioid cells, dendritic cells, lymphocytes, fibroblasts, and endothelial cells.
• Cytokines such as TNF-α and TGF-β regulate this process.
• The central region of the granuloma typically undergoes caseous necrosis, characterised by a hypoxic, acidic environment rich in fatty acids, which can suppress but not eliminate bacillary growth.

Granuloma Maturation and Heterogeneity

• Granulomas exhibit diverse phenotypes, including fibrotic, calcified, suppurative, or necrotic forms. A single host may harbour multiple types simultaneously.
• Mtb exploits granulomas as niches for persistence, surviving in a metabolically dormant state. Approximately 10% of individuals with latent TB will reactivate, often years later.
• ESX1-mediated pathways (e.g., via the RD1 region and ESAT-6) induce expression of MMP-9, which facilitates macrophage recruitment and matrix degradation, enabling granuloma expansion and dissemination.

Foamy Macrophages and Caseation

• Some infected macrophages differentiate into lipid-laden foamy macrophages, induced by ESX1 activity, which shift from glycolysis to ketogenesis.
• These cells are critical for maintaining the caseous centre and supplying Mtb with lipid nutrients.
• Apoptotic or necrotic macrophages release bacilli into the extracellular space, where cording morphology prevents re-phagocytosis and promotes dissemination.

Cavitation and Tissue Destruction

• Degradation of the extracellular matrix by enzymes such as MMP-1 leads to cavitation, particularly in the upper lobes.
• Cavities harbour high bacillary loads, enhancing infectiousness and complicating drug penetration, which fosters development of drug resistance.

Progression and Latency

• Three main outcomes follow Mtb exposure:
  • Immediate clearance by innate immunity—rare and typically seen in "resistors."
  • Latent infection—bacilli remain viable but contained within granulomas; patients are asymptomatic and non-infectious.
  • Primary active disease—occurs when containment fails, often within weeks of infection.
• Reactivation can occur in latently infected individuals, especially within two years post-exposure or during immunosuppressive states (e.g., HIV, corticosteroids, TNF-α inhibitors).

Lesion Types

• TB lesions are broadly categorised as:
  • Proliferative: form in individuals with robust immune responses; lesions are compact, fibrotic, and paucibacillary.
  • Exudative: predominate in high bacillary loads or weakened host defences; characterised by neutrophilic infiltration and caseous necrosis.
• Primary lesions often localise in subpleural lung zones and extend via lymphatics to hilar nodes, forming the Ghon complex. Calcified complexes may be radiographically detectable as Ranke complexes.

Dissemination and Extrapulmonary Disease

• Mtb may disseminate via blood or lymphatics, particularly in immunocompromised hosts, causing extrapulmonary or miliary TB.
• Common extrapulmonary sites include cervical lymph nodes (scrofula), vertebrae (Pott disease), adrenal glands, meninges, and the genitourinary tract.
• These lesions mirror the granulomatous pathology of pulmonary TB.

Subclinical and Asymptomatic Disease

• Subclinical TB is increasingly recognised; patients exhibit intermittent culture positivity despite absence of overt symptoms.
• Such individuals may still transmit infection and benefit from multi-drug treatment akin to active TB cases.

Global Overview

• Tuberculosis (TB) remains one of the leading causes of death from a single infectious agent globally. In 2023, TB caused approximately 1.25 million deaths, including 161,000 among individuals co-infected with HIV.
• The World Health Organization (WHO) reported an estimated 10.8 million new TB cases in 2023, affecting 6.0 million men, 3.6 million women, and 1.3 million children. TB affects people across all regions and age groups.
• TB is particularly devastating in areas with high HIV prevalence and limited healthcare infrastructure. In 2022, 1.3 million TB-related deaths were reported globally, including 167,000 among HIV-positive individuals. Approximately 81% of global TB deaths (both HIV-negative and HIV-positive) occurred in the WHO African Region and South-East Asia Region.
• Disruptions caused by the COVID-19 pandemic led to underdiagnosis and underreporting of TB in 2020. However, reported case numbers began to increase again in subsequent years as public health systems resumed normal operations.

United States Trends

• TB incidence in the United States has followed a long-term downward trend since the mid-20th century due to improved living conditions and the introduction of effective treatments like streptomycin. Cases declined from 126,000 in 1944 to 14,000 in 2004.
• The COVID-19 pandemic caused a temporary artificial decline in reported TB cases in 2020, primarily due to reduced healthcare access, social distancing, and masking. This was followed by a rebound in 2021 and 2022.
• In 2022, 8,300 TB cases were reported (2.5 per 100,000 persons), rising to 9,615 in 2023 (2.9 per 100,000). This marked a return to pre-pandemic incidence levels. The total estimated population with latent TB infection in the US is approximately 13 million.

Demographic Patterns in the US

• In 2021 and 2023, non–US-born individuals accounted for the majority of TB cases in the US:
  • In 2021, 71.4% of TB cases occurred in non–US-born persons, with an incidence rate of 12.5 per 100,000 compared to 0.8 per 100,000 among US-born persons.
  • In 2023, 76% of TB cases occurred in non–US-born persons.
• The most common countries of birth for non–US-born TB cases included Mexico, the Philippines, India, Vietnam, and China. Countries with the highest incidence rates in the US population included the Republic of the Marshall Islands, Congo, Mongolia, Bhutan, Myanmar, and Somalia.
• Racial and ethnic distribution of TB cases in 2021 was as follows: 36% non-Hispanic Asian, 30.6% Hispanic or Latino, 18.0% non-Hispanic Black or African American, and 11.2% non-Hispanic White.
• TB incidence increases with age, with individuals aged 65 years or older exhibiting the highest rates (4.0 per 100,000 in 2021).
• Males consistently account for a higher proportion of cases—61.3% overall in 2021 (62.6% among US-born and 60.7% among non–US-born persons).

Presence of Risk Factors

• Key risk factors include exposure to infection, immunosuppression, silicosis, malignancy, birth in an endemic country, and HIV in appropriate areas.

Cough

• Duration over 2 to 3 weeks.
• Initially dry, later productive.
• Only 50% of patients in outpatient studies had cough exceeding two weeks.

Fever

• Usually low-grade and intermittent.
• May be absent in up to 20% of cases, especially in older adults.
• Chills may be associated.

Anorexia

• Frequently accompanies systemic illness.
• Often presents with weight loss or fatigue.

Weight Loss

• Common and may be unintentional.
• Indicative of systemic disease progression.

Malaise

• Non-specific and often recognised in retrospect after diagnosis.
• May present as generalised fatigue or reduced activity levels.

Night Sweats

• Typically drenching and more common in advanced disease.

Pleuritic Chest Pain

• Suggests pleural involvement.
• May be localised and worsens with breathing or coughing.

Haemoptysis

• Occurs in <10% of cases.
• May result from cavitary disease or underlying bronchiectasis.

Psychological Symptoms

• Includes depression or mood disturbances.
• Often underrecognised in chronic illness.

Asymptomatic

• Especially in subclinical TB or latent infection.
• Often discovered incidentally during screening or imaging.

Dyspnoea

• Occurs in late-stage disease.
• Associated with effusions, extensive fibrosis, or cavitary lesions.

Clubbing

• Seen in long-standing disease.
• Often reflects chronic hypoxia.

Erythema Nodosum and Erythema Induratum

• Painful, erythematous nodules typically on the shins.
• Represents immunological response to TB antigens.

History of TB or TB Exposure

• Includes known contact with active TB cases.
• Recent TST or IGRA conversion increases suspicion.
• May be linked to household, occupational, or healthcare exposures.

Birth in an Endemic Region

• High-risk areas include Asia, Latin America, and sub-Saharan Africa.

HIV Infection

• Greatly increases the risk of both primary progression and reactivation.
• May lead to atypical or extrapulmonary TB.
• TB co-infection can elevate HIV viral load.

Immunosuppressive Medications

• Includes systemic corticosteroids, TNF-alpha inhibitors, and post-transplant immunosuppression.
• Risk increases with higher doses and longer durations.

Silicosis

• Associated with impaired macrophage function.
• Increases TB risk by up to 30-fold.

Apical Fibrosis

• Identified on chest x-ray as fibrotic upper lobe changes.
• Indicates prior untreated TB and potential reactivation site.

Malignancy

• Particularly haematological and head & neck cancers.
• May contribute to immune suppression.

End-Stage Renal Diseas

• Associated with reduced cellular immunity.
• Risk further increased by haemodialysis.

Intravenous Drug Use

• Independent risk factor.
• Often coexists with HIV and other comorbidities.

Malnutrition

• Includes low BMI, coeliac disease, and history of gastrectomy or jejunoileal bypass.

Alcoholism

• Often overlaps with other socioeconomic risk factors.
• Impairs immune function.

Diabetes Mellitus

• Affects macrophage and T-cell responses.
• Globally, 13–14% of TB patients have concurrent diabetes.

High-Risk Congregate Settings

• Includes prisons, homeless shelters, and long-term care facilities.
• Close contact and poor ventilation enhance transmission.

Low Socioeconomic Status or Ethnic Minority Background

• Associated with increased TB incidence.
• Likely related to healthcare access, housing conditions, and comorbidities.

Age Extremes

• Children <5 years and adults >65 years are more vulnerable.
• Older adults may present atypically, often with non-resolving pneumonia.

Tobacco Smoking

• Increases risk of both latent and active TB.
• Associated with worse treatment outcomes.

Abnormal Chest Auscultation

• May reveal bronchial breath sounds, especially over affected upper lobes.
• Crackles (rales) may be present, commonly inspiratory and sometimes post-tussive.
• Amphoric breath sounds—distant, hollow quality—may be audible over cavitary lesions
• Examination may be entirely normal in early or mild pulmonary TB.

Clubbing

• Seen in long-standing disease with chronic hypoxia.
• More likely in patients with extensive cavitary or fibrotic changes.

Lymphadenopathy

• Classically painless and firm; typically involves anterior/posterior cervical or supraclavicular chains.
• May be bilateral and may suppurate or form sinus tracts in advanced cases.

Cutaneous Lesions

• May include erythema nodosum or erythema induratum on the shins.
• Represent hypersensitivity responses to mycobacterial antigens.

Chorioretinitis

• Rare but may be seen in miliary or disseminated TB.
• Requires fundoscopic examination.

Neurological Findings

• May present in meningeal or cerebral TB.
• Includes confusion, altered consciousness, or focal deficits.
• Coma may be present in TB meningitis or TB-related encephalopathy.

Dyspnoea

• May be evident during examination in patients with large effusions, cavitary disease, or extensive consolidation.
• Usually a late manifestation.

Erythema Nodosum and Erythema Induratum

• Erythema nodosum: painful, raised, red nodules on the anterior shins.
• Erythema induratum: lobular panniculitis on the calves; often ulcerates.

Asymptomatic Presentation

• Up to 20% of patients with active TB may have no physical signs.
• Particularly common in elderly or immunosuppressed individuals.

Haemoptysis

• Although typically historical, frank haemoptysis may be observed on examination or reported during sputum production.
• Suggests advanced or cavitary disease.

Pleural Findings

• Decreased breath sounds and dullness to percussion may indicate pleural effusion.
• Pleural rub may occur with adjacent pleuritis.

General Examination Clues

• Cachexia or significant weight loss may be visible.
• Fever, if present, is typically low-grade.
• Tachypnoea and mild hypoxia may be noted in advanced disease.
• Hepatosplenomegaly in disseminated or miliary TB.

Initial Imaging

Chest Radiography

• First-line test for pulmonary TB in symptomatic individuals or those with positive screening tests.
• Common findings in immunocompetent patients include fibronodular opacities, cavitary lesions in the upper lobes, and hilar or paratracheal lymphadenopathy.
• Atypical findings, such as middle or lower lobe infiltrates or pleural effusions, are more common in immunocompromised individuals (e.g., advanced HIV).
• May show miliary patterns in disseminated disease or calcified nodules in latent or healed TB.
• A normal chest x-ray does not exclude active TB, especially in immunosuppressed patients.

Computed Tomography (CT)

• Used when chest radiography is inconclusive or more detailed imaging is needed.
• Can reveal cavitary lesions, tree-in-bud opacities (suggesting endobronchial spread), bronchiectasis, or nodular infiltrates.
• Valuable in evaluating mediastinal lymphadenopathy and for ruling out other pathologies.
• CT is also helpful in detecting extrapulmonary manifestations (e.g., tuberculomas, vertebral lesions).

Microbiological Diagnosis

Sputum Acid-Fast Bacilli (AFB) Smear

• Three sputum samples (ideally including an early morning specimen) should be collected for smear microscopy.
• Positive smears suggest infectious pulmonary TB but lack species specificity (e.g., may detect non-tuberculous mycobacteria).
• Sensitivity is around 50–60% in high-burden settings.
• Graded from 1+ to 3+/4+ based on organism burden.

Sputum Culture

• Gold standard for diagnosis.
• Enables species identification and drug susceptibility testing.
• Grown on solid media (e.g., Lowenstein-Jensen) takes 4–8 weeks; liquid culture systems (e.g., BACTEC) yield results in 1–3 weeks.
• Monthly cultures are recommended during treatment until two consecutive negatives are achieved.

Nucleic Acid Amplification Tests (NAATs)

• Detect M. tuberculosis DNA and can identify rifampicin resistance.
• Xpert MTB/RIF and Xpert Ultra are widely used, with the latter offering higher sensitivity.
• Particularly useful in smear-negative TB and for ruling out disease rapidly.
• Recommended by the CDC for at least one respiratory specimen when TB is considered clinically.
• Cannot distinguish between viable and non-viable organisms—culture still required for full evaluation.

ELISpot (Interferon-Gamma Release Assay on BAL Fluid)

• May be used in smear-negative, culture-negative suspected TB.
• High sensitivity and specificity in diagnosing active pulmonary TB from bronchoalveolar lavage fluid.

Drug Susceptibility Testing

• Performed on all positive cultures to assess resistance, especially to isoniazid and rifampicin.
• Indications for testing include previous TB treatment, origin from high MDR-TB prevalence countries, exposure to resistant TB, or clinical non-response.
• Techniques include conventional culture-based methods, PCR, and DNA sequencing.
• Genotype MTBDRplus and MTBDRsl assays allow detection of MDR-TB and XDR-TB respectively.

Other Microbiological Tests

• Gastric Aspirate: Used in children or those unable to expectorate.
• Stool Testing: Detects swallowed bacilli; useful in children when sputum is not obtainable.
• Bronchoalveolar Lavage: Considered when non-invasive methods fail; may reveal granulomas on biopsy.
• Urine Culture: Indicated in genitourinary TB; pyuria with sterile cultures should prompt TB testing.
• Blood Culture: Especially useful in HIV-positive patients; requires special mycobacterial growth media.

Immunological Tests for Latent TB

Tuberculin Skin Test (TST)

• Involves intradermal injection of PPD; measured at 48–72 hours.
• Cut-offs for positivity vary by risk group: ≥5 mm for high-risk groups (e.g., HIV, recent contacts), ≥10 mm for moderate risk, ≥15 mm for low risk.
• BCG vaccination does not alter interpretation under CDC guidelines.
• Limitations include false negatives in immunosuppression and false positives from non-tuberculous mycobacteria.

Interferon-Gamma Release Assays (IGRAs)

• Include QuantiFERON-TB Gold and T-SPOT.TB.
• Detect M. tuberculosis-specific T-cell responses to ESAT-6 and CFP-10.
• More specific than TST in BCG-vaccinated populations and do not require return visits.
• Indeterminate results may occur in immunocompromised patients.
• Do not distinguish latent from active TB.

Advanced Testing in Special Populations

HIV-Positive Individuals

• Should be screened for TB at baseline and regularly thereafter.
• More likely to have extrapulmonary TB and atypical or normal chest radiographs.
• ART reduces TB incidence, though risk remains high in the first 3 months.
• ELISpot assays and routine sputum cultures should be considered even when asymptomatic.

Pregnancy

• TST and IGRAs are safe during pregnancy.
• Chest x-ray can be performed with shielding when TB is suspected.
• Empirical treatment may be initiated in high-risk cases without radiographic delay.

Paediatric TB

• Gastric aspirates and nasopharyngeal samples may be useful for microbiological diagnosis.
• Diagnosis often clinical due to paucibacillary nature.
• Chest radiograph may show hilar lymphadenopathy or infiltrates; radiographs may be normal in disseminated disease.
• Placental biopsy and cultures may assist in diagnosing congenital TB.

Extrapulmonary TB Evaluation

Histopathology

• Caseating granulomas are pathognomonic; seen in lymph node, bone marrow, liver, and CNS biopsies.
• TB bacilli are rarely visualised directly on histology.

CSF Analysis and Neuroimaging

• Indicated in suspected TB meningitis or tuberculomas.
• CSF may show lymphocytosis, elevated protein, and low glucose.
• CT/MRI may show hydrocephalus, basal meningeal enhancement, or ring-enhancing lesions.

Molecular and Resistance Typing

Genotyping

• Includes RFLP, spoligotyping, MIRU-VNTR, and whole genome sequencing.
• Used for epidemiological tracing, outbreak investigation, and identifying virulent strains.

Rapid Resistance Detection

• GeneXpert and line-probe assays (e.g., MTBDRplus) detect resistance mutations in katG, inhA, and rpoB genes.
• Important for early detection of MDR-TB and XDR-TB.

Lung Malignancy (including Non-Small Cell Lung Cancer)

• Clinical Similarity: Symptoms such as haemoptysis, weight loss, chronic cough, and chest pain overlap with TB. Both conditions may coexist, particularly in older patients.
• Diagnostic Considerations: Persistent or enlarging lesions on imaging despite TB treatment should raise suspicion. Confirmation requires CT chest, sputum cytology, or tissue biopsy.

Fungal Lung Infections

• Clinical Similarity: Histoplasmosis, blastomycosis, and coccidioidomycosis can present with chronic cough, fever, weight loss, and pulmonary infiltrates.
• Distinguishing Features: Geographical exposure is critical. Diagnosis is confirmed by fungal culture or serology and negative TB cultures.

Community-Acquired Pneumonia (CAP)

• Clinical Similarity: Presents acutely with fever, dyspnoea, and productive cough.
• Diagnostic Strategy: Typically resolves with antibiotics; bacterial pathogens are isolated on sputum culture. Important to avoid fluoroquinolones initially to prevent partial TB treatment.

COVID-19 (SARS-CoV-2 Infection)

• Clinical Similarity: Overlaps in symptoms including fever, dry cough, and breathlessness.
• Distinguishing Test: Confirmed by RT-PCR detecting viral RNA. TB should be considered in patients with persistent symptoms post-COVID or in endemic areas.

Sarcoidosis

• Clinical Similarity: May present with lymphadenopathy, cough, and systemic symptoms.
• Diagnostic Hallmark: Non-caseating granulomas on biopsy. Sputum AFB cultures are negative.

Nocardiosis

• Clinical Similarity: Causes cavitary pulmonary lesions that resemble TB, especially in immunocompromised patients.
• Laboratory Clues: Nocardia is weakly acid-fast and identifiable by its branching filamentous morphology. Gram stain and modified AFB stain aid differentiation.

Actinomycosis

• Clinical Similarity: Chronic infection with sinus tract formation and mass-like lesions that may mimic TB or malignancy.
• Diagnostic Confirmation: Anaerobic cultures and histological presence of sulphur granules.

Non-Tuberculous Mycobacteria (NTM)

• Clinical Similarity: Can cause nodular, cavitary, or bronchiectatic lung disease resembling TB.
• Diagnostic Tools: AFB smear positive but NAAT negative for M. tuberculosis. Culture and DNA probe differentiate species.

Chronic Pulmonary Aspergillosis

• Clinical Similarity: Develops in pre-existing lung cavities, often due to past TB.
• Diagnostic Features: Aspergillus IgG serology; CT imaging shows intracavitary fungal balls or crescent signs.

Bronchiectasis

• Clinical Similarity: Persistent productive cough and recurrent infections mimic chronic TB symptoms.
• Radiographic Differentiation: High-resolution CT reveals dilated bronchi with thickened walls and mucus impaction.

Lung Abscess

• Clinical Similarity: Cavitary lesion with foul-smelling sputum, weight loss, and fever.
• Differentiation: CT or chest x-ray reveals cavitation with air-fluid levels; responds to antibiotic therapy.

Constrictive Pericarditis

• Clinical Similarity: Can be a late complication of TB pericarditis, presenting with dyspnoea, ascites, and elevated JVP.
• Investigations: Echocardiogram or CT/MRI shows pericardial thickening and calcification.

Pott Disease (Spinal Tuberculosis)

• Clinical Similarity: Presents with chronic back pain, vertebral deformity, and neurologic deficits.
• Diagnostic Approach: MRI reveals vertebral destruction and paraspinal abscess; confirmed by biopsy showing caseating granulomas.

Overall Principles and Objectives

• The dual goals of TB management are to achieve microbiological cure and interrupt disease transmission.
• Treatment initiation should not be delayed in cases with high clinical suspicion, even before microbiological confirmation.
• A complete course of therapy requires strict adherence; failure to do so may result in relapse, ongoing transmission, and drug resistance.
• Isolation is necessary during the infectious phase, typically until the patient has three consecutive negative sputum smears.
• Collaboration with public health authorities is essential for contact tracing, adherence monitoring, and epidemiological surveillance.

Latent Tuberculosis Infection (LTBI)

Indications for Screening and Retesting

• Close contacts of infectious TB cases within the previous 2 years should be screened using tuberculin skin test (TST) or interferon-gamma release assay (IGRA).
• If initial testing occurs within 8 weeks of exposure and is negative, repeat testing is necessary after this window period.

Standard Treatment Regimens

• 6 or 9 months of daily isoniazid (INH): Effective in reducing lifetime TB risk by ~60–90%.
• 3 months of weekly rifapentine + isoniazid (3HP): Well-tolerated and now widely endorsed for adults and children ≥2 years.
• 3 months of daily isoniazid + rifampicin (3HR): Commonly used for broader age groups.
• 1 month of daily rifapentine + isoniazid (1HP): Short-course regimen suitable for those ≥13 years.
• 4 months of daily rifampicin (4R): An alternative regimen, particularly where isoniazid resistance is suspected or tolerance is poor.

Special Considerations

• Rifamycin-based regimens are preferred where drug interactions (e.g., with antiretrovirals) can be managed.
• Isoniazid should always be co-prescribed with pyridoxine (vitamin B6) to prevent neuropathy, especially in malnourished individuals, pregnant women, diabetics, or those with HIV.
• In patients exposed to isoniazid- or rifampicin-resistant TB, tailored regimens are required; expert consultation is essential.
• Fluoroquinolone-based regimens (e.g., levofloxacin for 6–12 months) are recommended in selected high-risk contacts of MDR-TB patients.

Active Drug-Susceptible TB

Standard 6-Month Regimen

• Intensive Phase (2 months): Daily isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE).
• Continuation Phase (4 months): Daily isoniazid and rifampicin (HR).
• Ethambutol may be omitted in areas with documented low isoniazid resistance.
• Pyridoxine should be administered with isoniazid to prevent peripheral neuropathy.
• Corticosteroids are generally not indicated in pulmonary TB, unless there is severe hypersensitivity or concurrent pericarditis or meningitis.

Shortened Regimen (4 months)

• For adolescents ≥12 years with non-severe, drug-susceptible TB:
  • Drugs: Isoniazid, rifapentine, moxifloxacin, pyrazinamide (BHMZ).
  • Limitations: Not currently approved for use in children <12, pregnant women, or patients with CD4 <100 cells/µL.

Paediatric Considerations

• Children 3 months to 16 years with non-severe TB (e.g., hilar lymphadenopathy, isolated pleural effusion, or single-lobe non-cavitary disease) may complete therapy in 4 months.
• Infants and those with extensive or disseminated disease require the full 6-month regimen.

Directly Observed Therapy (DOT) and Adherence Strategies

• DOT is preferred in patients at risk of non-adherence (e.g., HIV-positive, MDR-TB, psychiatric comorbidities).
• vDOT (video DOT): Now endorsed as equivalent to in-person DOT in many settings.
• WHO “Treatment Support”: Encompasses observed therapy by a family member or trained individual.
• Intermittent Regimens: Require supervision; daily dosing is mandated for unsupervised (self-administered) regimens.

Management in Special Populations

HIV Co-Infection

• TB therapy is identical to HIV-negative patients, with daily dosing recommended.
• ART Initiation: Begin within 2 weeks of TB treatment in those with CD4 <50, and within 8 weeks in others.
• Drug Interactions: Rifampicin induces CYP450 enzymes, reducing levels of many antiretrovirals. Rifabutin, with less potent induction, is preferred for patients on protease inhibitors.

Renal Impairment

• Standard dosing applies if creatinine clearance >30 mL/min.
• If CrCl <30 mL/min or patient is on dialysis:
  • Ethambutol and pyrazinamide should be dosed thrice weekly after haemodialysis.
  • Serum drug level monitoring may be necessary in advanced cases.

Hepatic Dysfunction

• ALT rise <5× ULN without symptoms: continue therapy with close monitoring.
• ALT >5× ULN or >3× ULN with symptoms: halt hepatotoxic drugs and start a non-hepatotoxic regimen (e.g., ethambutol, levofloxacin, linezolid).
• Once ALT <2× ULN, reintroduce isoniazid or rifampicin sequentially, checking LFTs every 4–7 days.
• Rifabutin may be substituted for rifampicin due to its lower hepatotoxicity risk.

Pregnancy and Breastfeeding

• Recommended regimen: Isoniazid, rifampicin, ethambutol (±pyrazinamide).
• Pyrazinamide is generally considered safe and allows for a shorter 6-month regimen.
• Breastfeeding is permitted; however, breast milk concentrations are subtherapeutic for the infant and do not substitute for prophylaxis if needed.

Isoniazid-Resistant TB

• Definition: Resistance to isoniazid with retained rifampicin susceptibility.
• Treatment:
  • Rifampicin, ethambutol, pyrazinamide, and levofloxacin for 6 months.
  • If fluoroquinolones are contraindicated, omit levofloxacin and continue the rest for 6 months.
• No distinction between intensive and continuation phases is needed.

Multidrug-Resistant TB (MDR-TB)

• Definition: Resistance to at least isoniazid and rifampicin.
• Pre-XDR TB: Additional resistance to a fluoroquinolone.
• XDR-TB: Further resistance to bedaquiline or linezolid.

Short-Course Regimens

• 6-Month BPaLM Regimen: Bedaquiline, pretomanid, linezolid, moxifloxacin.
  • For patients ≥14 years with limited prior exposure to second-line agents.
  • BPaL (without moxifloxacin) can be used in fluoroquinolone-resistant cases.
• 9-Month All-Oral Regimen: Includes high-dose isoniazid, levofloxacin, pyrazinamide, clofazimine, ethambutol, ethionamide, and bedaquiline.
  • Followed by 5 months of levofloxacin, clofazimine, ethambutol, and pyrazinamide.

Longer Regimens (≥18 Months)

• Include at least 4 effective agents based on drug susceptibility and history.
• Group A: Bedaquiline, linezolid, levofloxacin/moxifloxacin
• Group B: Clofazimine, cycloserine
• Group C: Ethambutol, delamanid, pyrazinamide, amikacin, carbapenems, PAS, ethionamide
• Surgical intervention (e.g., lobectomy) may be considered in highly localised disease.

Fluoroquinolone Safety Considerations

• Potential for serious adverse effects: tendon rupture, neuropathy, aortic dissection, CNS effects.
• Regulatory agencies recommend restricted use to life-threatening infections or confirmed resistance.
• Careful benefit-risk assessment is necessary, especially in the elderly and those with cardiovascular disease.

Treatment Failure and Recurrence

Treatment Failure

• Defined as persistent positive sputum smear or culture at 5 months or later during therapy.
• Common causes: non-adherence, drug resistance, malabsorption.

Recurrence

• Relapse (same strain) vs. Reinfection (different strain).
• Recurrences mostly occur within 6–12 months post-treatment.
• In prior DOT patients, the same regimen may be reused if the organism remains susceptible.
• SAT patients are at higher risk of MDR-TB and may require expanded regimens including two new agents.

Untreated Disease

• TB has a historically high untreated mortality rate exceeding 50%.
• Factors contributing to poor outcomes in the absence of therapy include progressive respiratory failure, disseminated disease, and opportunistic infections in immunocompromised hosts.

Treated Disease

• TB is curable with appropriate therapy, especially when initiated early.
• In the United States (2009), the case fatality rate for reported TB cases was approximately 4.6% (529 deaths among 11,528 cases).
• The overall prognosis is favourable in patients with drug-susceptible TB who complete the full course of treatment. Most patients recover without significant residual impairment, particularly in pulmonary TB without extensive lung destruction.

Mortality Risk Factors

• Older age, advanced radiographic disease (e.g., cavitation or miliary spread), delayed diagnosis or treatment initiation, and intensive care needs (e.g., mechanical ventilation) are associated with increased mortality.
• Comorbidities such as end-stage renal disease, diabetes mellitus, malnutrition, and HIV-related immunosuppression worsen outcomes.
• In a cohort from Malawi, a 6% mortality rate was noted among TB patients; mortality was associated with reduced baseline TNF-α responses, high respiratory rate at diagnosis, and low body mass index—suggesting that systemic inflammation and malnutrition are key contributors to early death.

Recurrence and Relapse

• Recurrence after treatment is relatively uncommon with directly observed therapy (DOT), with reported rates between 0–14% in published series.
• In low TB-burden countries, most recurrences within 12 months of completion are due to relapse from the original strain.
• In high-burden settings, reinfection with a new strain is more commonly responsible for post-treatment TB recurrence.

Extrapulmonary and Drug-Resistant TB

• Patients with extrapulmonary TB generally have higher morbidity and mortality compared to those with isolated pulmonary involvement, depending on the site (e.g., TB meningitis or miliary TB).
• Drug-resistant TB (MDR-TB and XDR-TB) is associated with longer treatment duration, increased risk of adverse drug reactions, poorer adherence, and higher mortality rates.

Predictors of Poor Prognosis

• Advanced immunosuppression (especially HIV/AIDS)
• Prior history of TB treatment or relapse
• Malnutrition (especially low BMI)
• Delayed presentation or severe clinical presentation (e.g., tachypnoea, hypoxaemia)
• Poor inflammatory response (e.g., low TNF-α production in response to mycobacterial antigens)

Haemoptysis

• Haemoptysis may occur during active TB or as a late sequela in previously treated patients.
• Most episodes are minor (blood-streaked sputum), though massive haemoptysis may arise from vascular erosion, commonly involving a Rasmussen aneurysm.
• Other causes include bronchiectasis, aspergilloma formation in old cavities, scar carcinoma, or broncholith rupture.
• Diagnostic evaluation involves sputum examination, bronchoscopy, and CT angiography.
• Management ranges from conservative therapy (bed rest, cough suppression, antituberculous treatment) to interventional procedures such as bronchial artery embolisation or surgical resection in severe or refractory cases.
• Bronchial artery embolisation can achieve haemostasis in over 70% of patients; however, recurrence is not uncommon, and surgical intervention carries high risk, especially when performed emergently.

Transmission

• Transmission risk is highest during the early phase of active pulmonary or laryngeal TB.
• Infectiousness declines after at least two weeks of effective therapy, symptom improvement, and serial negative sputum smears.
• Preventive measures include isolation (home or hospital-based), avoidance of close contact with vulnerable populations, and initiation of contact tracing through public health services.

Pneumothorax

• TB-related pneumothorax is caused by rupture of subpleural cavities or liquefied caseous foci into the pleural space.
• Can result in bronchopleural fistula and empyema formation.
• Spontaneous pneumothorax due to TB is now rare, though it remains more common in endemic areas.
• Chest tube insertion is the mainstay of management; persistent fistulas may require prolonged drainage or surgical correction.

Immune Reconstitution Inflammatory Syndrome (IRIS)

• IRIS describes paradoxical worsening of TB symptoms or lesions following immune recovery, most notably in HIV-positive individuals after initiating ART.
• Common symptoms include fever, worsening pulmonary infiltrates, lymphadenopathy, and pleural effusion.
• Typically emerges within 2–8 weeks of TB therapy initiation and may occur in both HIV-positive and HIV-negative individuals.
• Diagnosis is clinical, after ruling out secondary infections or treatment failure.
• Treatment is usually supportive; corticosteroids (e.g., prednisone 1–2 mg/kg/day) may be used in moderate to severe cases.

Bronchiectasis

• Localised bronchial dilation can follow either primary TB (due to nodal compression) or reactivation TB (due to parenchymal destruction and fibrosis).
• Most frequently involves upper lobes, aligning with the typical location of reactivation disease.
• Presents with cough, recurrent infections, and, in some cases, haemoptysis.
• Diagnosis is confirmed via high-resolution CT.

Empyema

• May complicate TB pleuritis or arise following persistent bronchopleural fistula.
• Presents with fever, chest pain, and pleural effusion.
• Managed by tube thoracostomy; surgery may be needed in complicated cases with loculations or fibrous peel formation.

Extensive Pulmonary Destruction and Gangrene

• Occurs due to chronic, untreated TB or aggressive disease with vascular thrombosis leading to necrosis.
• Pulmonary gangrene is characterised by rapid cavity formation, tissue sloughing, and systemic toxicity.
• CT imaging may reveal mobile masses within cavities.
• High mortality necessitates aggressive antimicrobial therapy and often surgical resection.

Right Middle Lobe (RML) Syndrome

• Caused by compression of the RML bronchus by adjacent lymphadenopathy, often tuberculous.
• Leads to recurrent RML collapse and infection.
• Diagnosis is via bronchoscopy; lobectomy may be needed in refractory cases.

Respiratory Failure

• ARDS secondary to TB is rare but has a poor prognosis.
• Miliary TB is more frequently associated with respiratory failure than cavitary disease.
• Requires intensive care support and parenteral anti-TB therapy due to compromised absorption.

Septic Shock

• TB can mimic bacterial sepsis, particularly in immunocompromised patients.
• Associated with high mortality (>75%) and often delayed diagnosis.
• Extrapulmonary involvement is common; management includes early anti-TB therapy and supportive care.

Broncholithiasis

• Occurs when calcified lymph nodes erode into bronchi, typically following healed TB.
• Leads to cough, haemoptysis, or recurrent pneumonia.
• Often diagnosed with bronchoscopy or imaging.

Chronic Pulmonary Aspergillosis (CPA)

• CPA may develop in patients with residual TB cavities, especially those with persistent symptoms post-treatment.
• Aspergillus colonises these cavities, leading to chronic cough, haemoptysis, and systemic symptoms.
• Diagnosis involves CT imaging and serological tests for Aspergillus-specific IgG.

Venous Thromboembolism (VTE)

• TB induces a prothrombotic state, increasing the risk of DVT and PE.
• Studies indicate a nearly threefold increase in VTE risk in TB patients.
• Mechanisms may involve inflammation-induced endothelial injury, immobility, and altered coagulation profiles.

Malignancy

• TB-associated chronic inflammation and fibrosis are linked with increased lung cancer risk, especially adenocarcinoma.
• TB-related DNA damage from reactive oxygen species and prolonged cytokine signalling may contribute to carcinogenesis.
• The association persists after adjusting for confounders like smoking.

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