Tuberculosis (TB) remains one of the world’s deadliest infectious diseases, claiming millions of lives annually despite the availability of effective diagnostic tools, preventive strategies and curative treatments. Caused by Mycobacterium tuberculosis, TB primarily targets the lungs but can affect almost any organ, manifesting in both pulmonary and extrapulmonary forms. The global fight against TB is hindered by challenges such as delayed diagnosis, poor treatment adherence, drug resistance and socio-economic disparities.
In our previous article, we examined the causes, risk factors, pathophysiology, complications and clinical manifestations of TB, offering insight into how this disease develops and spreads. Building on that foundation, this article shifts focus to the diagnosis, pathology, pharmacological and non-pharmacological treatments, preventive strategies and essential precautions in TB management.
Despite being both preventable and curable, TB continues to persist, making a thorough understanding of its diagnosis and treatment critical to reducing its global burden and improving patient outcomes.
Diagnosis of TB
Accurate and timely diagnosis of tuberculosis is crucial not only for initiating appropriate treatment but also for preventing transmission and controlling outbreaks, especially in high-burden regions. ¹⁻⁷ TB diagnosis requires a multifaceted approach combining clinical evaluation with radiological, microbiological, molecular and immunological methods.
1. Medical History and Physical Examination
a) Medical History: Clinicians assess hallmark symptoms such as a persistent cough (often >2 weeks), fever, night sweats, weight loss and hemoptysis. A detailed history of previous TB exposure, past treatments, travel to or residence in endemic areas and comorbidities like HIV or diabetes is crucial.
b) Physical Examination: May reveal non-specific signs such as weight loss, fever or abnormal breath sounds. However, these findings alone are insufficient and must be corroborated by laboratory and imaging tests.
2. TB Diagnostic Tests
a) Skin and Blood Tests
● Tuberculin Skin Test (TST): Involves intradermal injection of purified protein derivative (PPD) to elicit a delayed-type hypersensitivity reaction. Interpretation can be confounded by prior BCG vaccination or exposure to non-tuberculous mycobacteria.
● Interferon-Gamma Release Assays (IGRAs): Blood-based tests (e.g., QuantiFERON-TB Gold, T-SPOT.TB) that measure T-cell release of interferon-gamma in response to TB-specific antigens. Preferred in BCG-vaccinated individuals due to higher specificity.
b) Radiological Tests
● Chest X-Ray (CXR): Frequently used to detect pulmonary abnormalities such as infiltrates, cavitations or lymphadenopathy. While sensitive, it lacks specificity and cannot confirm TB on its own.
● AI in Radiology: Artificial intelligence algorithms enhance CXR interpretation, assisting in early detection and triage in resource-limited or high-TB-burden areas.
c) Bacteriological and Molecular Tests
● Sputum Smear Microscopy (SSM): Identifies acid-fast bacilli (AFB) under a microscope. Its sensitivity varies (32%–89%) and is improved with LED fluorescence microscopy or AI-assisted image analysis.
● Culture for M. tuberculosis: Considered the gold standard. Solid media take 4–8 weeks; liquid culture systems like MGIT 960 reduce turnaround to 1–2 weeks. Culture enables species identification and drug susceptibility testing.
● Nucleic Acid Amplification Tests (NAATs): Rapid molecular methods (e.g., Xpert MTB/RIF, Truenat MTB) that detect M. tuberculosis DNA and rifampicin resistance in less than 2 hours. Widely recommended for initial diagnosis, especially in drug-resistant or HIV-associated TB.
● GeneXpert MTB/RIF Test: A rapid, automated molecular test that detects Mycobacterium tuberculosis DNA and resistance to rifampicin, a key first-line anti-TB drug, in under two hours. It uses real-time PCR technology, requires minimal technical expertise and is effective even in smear-negative samples. WHO recommends it as the initial diagnostic tool in high-risk populations, including people with HIV, children and those with suspected drug-resistant TB.
● Biopsy: In cases of extrapulmonary TB (e.g., lymph node, bone or CNS TB), tissue biopsy may be required for histopathological analysis and microbiological testing to confirm diagnosis.
3. Molecular and Genomic Diagnostic Techniques
a) Line Probe Assays (LPAs): Detect mutations linked to resistance against rifampicin and isoniazid, allowing faster identification of multidrug-resistant TB (MDR-TB).
b) Next-Generation Sequencing (NGS): Delivers comprehensive genomic profiling, identifying resistance mutations across multiple genes and assisting in tracking transmission dynamics.
c) MALDI-TOF MS: Enables rapid and accurate identification of Mycobacterium species from cultured isolates, shortening diagnostic delays.
4. Immunological Diagnosis
a) Antibody Detection Tests: Not endorsed by the WHO due to inconsistent performance, including poor sensitivity and specificity.
b) Antigen Detection Tests (e.g., LAM): Especially useful in severely immunocompromised individuals, such as those with advanced HIV. FujiLAM, a lateral flow assay, detects lipoarabinomannan (LAM) antigen in urine, facilitating faster TB diagnosis in HIV-positive patients.
5. Emerging and Supportive Technologies
a) Artificial Intelligence (AI): Augments TB diagnosis by automating interpretation of chest radiographs, enhancing sputum smear microscopy and assisting in drug resistance prediction.
b) Point-of-Care and Rapid Diagnostic Tools: Handheld, battery-operated devices like Truenat and Xpert Omni are increasingly deployed in rural and underserved regions, supporting decentralization of TB care and reducing diagnostic delays.
c) Mobile Health (mHealth) and Digital Adherence Technologies (DATs): Tools like 99DOTS and video-supported therapy (VOT) improve treatment adherence and monitoring, crucial for preventing drug resistance.
Pathology of Tuberculosis (TB) – Relevance to Diagnosis
Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), exhibits hallmark pathological features, especially in the lungs that play a crucial role in clinical diagnosis, radiological assessment and histopathological confirmation.8,9
1. Primary Infection and Granuloma Formation
● Pathology: Inhaled bacilli are engulfed by alveolar macrophages. A cellular immune response leads to granuloma formation, often with central caseous necrosis surrounded by epithelioid cells, Langhans giant cells and lymphocytes.
● Diagnostic Relevance:
◦ Histology: Caseating granulomas with acid-fast bacilli (AFB) are a hallmark on biopsy.
◦ Tuberculin Skin Test (TST) or Interferon-Gamma Release Assays (IGRA) detect immune sensitization during granuloma development.
◦ Chest X-ray: May show Ghon focus or Ranke complex (calcified granuloma + lymph node) in healed primary TB.
2. Latent TB Infection (LTBI)
● Pathology: MTB remains dormant within walled-off granulomas.
● Diagnostic Relevance:
◦ Patients are asymptomatic, but TST/IGRA positive.
◦ Imaging may show calcified nodules or lymph nodes as incidental findings.
3. Post-Primary (Reactivation) TB
● Pathology: Usually affects the upper lobes. Features include caseous necrosis, cavitary lesions and fibrosis. Extensive inflammation leads to lung destruction and cavity formation.
● Diagnostic Relevance:
◦ Chest X-ray/CT: Shows apical cavitary lesions, infiltrates and fibrosis.
◦ Sputum AFB smear and NAAT (e.g., GeneXpert): Positive due to high bacterial load in cavities.
◦ Bronchoscopy and biopsy: Reveal granulomatous inflammation with caseous necrosis.
4. Immunopathology and Tissue Damage
● Pathology: Immune-mediated injury leads to hypersensitivity, necrosis and chronic inflammation.
● Diagnostic Relevance:
◦ Clinical signs such as persistent cough, hemoptysis, fever and weight loss correlate with underlying tissue damage.
◦ Histological samples show necrosis, lipid-laden foamy macrophages and chronic inflammatory infiltrates.
5. Lymphatic and Bronchial Spread
● Pathology: MTB spreads via lymphatics to hilar nodes or via airways, causing bronchial obstruction.
● Diagnostic Relevance:
◦ Endobronchial TB may mimic malignancy and require bronchoscopic biopsy.
◦ Lymph node TB is diagnosed via FNAC or excisional biopsy, showing caseating granulomas.
6. Healing and Chronic Changes
● Pathology: Granulomas may undergo fibrosis and dystrophic calcification. Chronic TB may lead to bronchiectasis, fibrosis and pulmonary dysfunction.
● Diagnostic Relevance:
◦ CT scans show fibrotic bands, bronchiectasis and calcified nodules.
◦ Pulmonary function tests (PFTs) may reveal restrictive or obstructive changes in chronic TB cases.
Pathology-Diagnosis Link
| Pathological Feature | Diagnostic Indicator |
| Granuloma with necrosis | Biopsy, histopathology |
| Caseous cavitation | CXR/CT, sputum AFB, GeneXpert |
| Foamy macrophages | Biopsy (associated with bacterial persistence) |
| Fibrosis and calcification | Radiology (old healed TB) |
| Endobronchial lesions | Bronchoscopy + biopsy |
Tuberculosis Treatment
Effective treatment of tuberculosis (TB) is critical to cure the individual, prevent transmission and avoid the development of drug resistance. Treatment plans depend on the drug sensitivity of the TB strain and typically involve long-term, combination antimicrobial therapy to ensure bacterial eradication and prevent relapse.10-15
1. First-Line Treatment for Drug-Sensitive TB (DS-TB)
For drug-sensitive TB, the World Health Organization (WHO) recommends a standard 6-month regimen using first-line drugs.
Treatment Regimen:
● Intensive Phase (2 months):
◦ Isoniazid (INH)
◦ Rifampicin (RIF)
◦ Pyrazinamide (PZA)
◦ Ethambutol (EMB)
● Continuation Phase (4 months):
◦ Isoniazid (INH)
◦ Rifampicin (RIF)
● Extended Continuation Phase (7 months):
May be considered if:
◦ Cavitary lesions are present on imaging
◦ Sputum culture is positive at 2 months
◦ PZA is not used or patient is immunocompromised (e.g., HIV, diabetes)
● Note:
◦ Fixed-dose combinations (FDCs) reduce pill burden and resistance risk.
◦ Directly Observed Therapy (DOT) enhances compliance, especially in high-burden areas.
◦ Pediatric TB: Uses dispersible tablets with weight-band dosing.
2.Second-Line Treatment for Drug-Resistant TB (DR-TB)
Second-line treatment is used for drug-resistant TB (MDR-TB and XDR-TB), requiring individualized regimens with longer durations and newer agents.
● Multidrug-Resistant TB (MDR-TB): Resistant to at least Isoniazid (INH) and Rifampicin (RIF).
● Extensively Drug-Resistant TB (XDR-TB): MDR-TB plus resistance to a fluoroquinolone and a second-line injectable.
WHO-Recommended Regimens:
a) Shorter All-Oral MDR-TB Regimen (9–11 months):
| Drug | Mechanism of Action |
| Bedaquiline (BDQ) | Inhibits ATP synthase |
| Levofloxacin/Moxifloxacin | Inhibits bacterial DNA gyrase |
| Clofazimine (CFZ) | Binds to mycobacterial DNA |
| Pyrazinamide (PZA) | Disrupts membrane energetics |
| Ethambutol (EMB) | Inhibits arabinosyl transferase |
| High-dose INH (if sensitive) | Inhibits mycolic acid synthesis |
| Ethionamide/Prothionamide | Inhibits cell wall synthesis |
b) Longer Individualized MDR-TB Regimen (18–20 months):
| Group A (Core) Drugs | Group B Drugs | Group C (Optional) |
| Bedaquiline | Clofazimine | Ethambutol |
| Linezolid | Cycloserine | Delamanid |
| Levofloxacin/Moxifloxacin | PAS |
c) XDR-TB Treatment (Customized):
● At least 4–5 effective drugs based on the resistance profile.
● Use of newer drugs like Pretomanid, Linezolid, Bedaquiline and Delamanid (e.g., BPaL regimen).
3.TB-HIV Co-Infection: Integrated Care
TB is a leading cause of death in people living with HIV.
● Antiretroviral therapy (ART) should be started within 2–8 weeks of initiating TB treatment.
● Rifampicin interacts with ART; use efavirenz-based or dolutegravir-based regimens with dose adjustments.
● Cotrimoxazole prophylaxis and Isoniazid Preventive Therapy (IPT) significantly improve outcomes.
● Watch for Immune Reconstitution Inflammatory Syndrome (IRIS) due to immune recovery.
4. Pediatric TB Treatment
● Dosing is weight-based with child-friendly dispersible tablets.
● Ethambutol may be omitted in HIV-negative children with low risk for resistance.
● Administer drugs daily with food; avoid milk or antacids.
● Use DOT (at least 5 days/week) to ensure adherence.
5. Pharmacological Profiles of Key Anti-TB Drugs
| Drug | Mechanism of Action | Major Adverse Effects |
| Isoniazid | Inhibits mycolic acid synthesis | Hepatotoxicity, peripheral neuropathy |
| Rifampicin | RNA polymerase inhibitor | Hepatotoxicity, orange body fluids |
| Pyrazinamide | Disrupts membrane energetics | Hepatotoxicity, hyperuricemia |
| Ethambutol | Inhibits arabinosyl transferase | Optic neuritis |
| Bedaquiline | Inhibits ATP synthase | QT prolongation |
| Linezolid | Protein synthesis inhibitor | Myelosuppression, neuropathy |
| Clofazimine | Binds DNA | Skin discoloration, GI upset |
| Delamanid | Mycolic acid synthesis inhibitor | QT prolongation |
| Pretomanid | Inhibits cell wall synthesis | Nausea, neuropathy, liver toxicity |
6. Barriers to Effective TB Treatment
● Adherence Issues: Long treatment duration, side effects and lack of support systems.
● Drug Shortages: Particularly in remote or under-resourced regions.
● Stigma and Discrimination: More severe in HIV-TB co-infection.
● Monitoring Difficulties: Managing resistance and adverse events remains complex.
Non-Pharmacological Treatment and Lifestyle Modifications in Tuberculosis
Non-pharmacological interventions complement drug therapy by addressing the broader physical, psychological and social aspects of TB management. These strategies help in improving patient outcomes, preventing transmission and promoting long-term recovery.
1. Nutritional Support
Malnutrition and TB often coexist in a vicious cycle, TB increases metabolic demands, while malnutrition weakens immunity.
● Protein: Promotes tissue repair and immune cell function.
● Calories: Support energy needs during prolonged illness.
● Micronutrients: Zinc, vitamin A, D, C, and iron are critical for immune defense.
● Diet Tips:
◦ High-protein diet (eggs, legumes, meat, dairy)
◦ Frequent small meals
◦ Supplements when needed (especially for underweight or HIV-TB co-infected patients)
2. Respiratory Hygiene and Cough Etiquette
TB spreads via airborne droplets. Patient education can dramatically reduce transmission.
● Cover mouth and nose with a tissue or elbow when coughing/sneezing.
● Proper sputum disposal using covered containers.
● Face masks (surgical/N95) in healthcare settings or public transport.
● Hand hygiene after coughing or handling sputum.
3. Isolation and Environmental Control
Reducing early-stage transmission is crucial, especially in overcrowded or poorly ventilated areas.
● Home isolation during the first 2–3 weeks of treatment (until the patient is no longer infectious).
● Ventilation: Maximize airflow in living spaces.
● Ultraviolet germicidal irradiation (UVGI): May be used in high-risk hospitals.
4. Psychosocial Support
TB patients often experience stigma, isolation, depression or treatment fatigue.
● Counseling services for emotional resilience.
● Peer support groups to share experiences and coping strategies.
● Mental health referrals for anxiety or depression.
● Family education to build a supportive home environment.
5. Smoking Cessation and Alcohol Avoidance
Smoking and alcohol worsen TB outcomes.
● Smoking: Damages lung tissue, impairs immune responses, increases TB incidence and mortality.
● Alcohol: Weakens immunity and interacts with anti-TB drugs, worsening liver toxicity.
6. Physical Rehabilitation and Pulmonary Care
TB can cause lasting lung damage, especially in MDR/XDR cases.
● Pulmonary rehabilitation: Breathing exercises, incentive spirometry and chest physiotherapy.
● Yoga and mindfulness: May help relieve fatigue, anxiety and improve respiratory function.
● Gradual reconditioning: Builds stamina after prolonged illness or hospitalization.
Precautions in TB Management
1. Early Detection and Prompt Treatment
● Screening of symptomatic individuals (persistent cough, fever, weight loss, night sweats).
● Immediate testing using sputum microscopy, GeneXpert or culture-based diagnostics.
● Rapid initiation of appropriate drug regimen.
2. Contact Tracing and Screening
● Close contacts (household or workplace): Must be screened regularly.
● Preventive therapy (e.g., isoniazid preventive therapy – IPT) for latent TB, especially in children and HIV-positive individuals.
3. Attention to Vulnerable Populations
● Immunocompromised (HIV, cancer, diabetes)
● Undernourished individuals
● Healthcare workers
● Inmates in prisons or residents of long-term care facilities
4. Monitoring and Managing Drug Side Effects
● Regular liver function tests for hepatotoxicity (especially with INH, RIF, PZA)
● Monitoring for optic neuritis (ethambutol), QT prolongation (bedaquiline, delamanid) and neuropathy (linezolid, INH)
● Patient education on early symptoms of side effects
5. Use of DOT (Directly Observed Therapy)
● Improves adherence
● Reduces risk of drug resistance and relapse
● Ensures timely reporting of side effects
TB Prevention Strategies
1. BCG Vaccine (Bacillus Calmette-Guérin)
● Live attenuated vaccine given at birth in many countries
● Offers protection against severe childhood TB forms (e.g., TB meningitis, miliary TB)
● Efficacy against pulmonary TB in adults varies by region.
2. Infection Control in Healthcare Settings
● Use of N95 respirators and personal protective equipment (PPE)
● Airborne infection isolation rooms (AIIRs) with negative pressure
● Cough screening and fast-tracking symptomatic patients
● UV light disinfection and HEPA filters in high-risk areas
3.Targeted Screening Programs
● Focus on high-risk populations:
◦ HIV-positive individuals
◦ Prisoners
◦ Healthcare workers
◦ Migrants and refugees from TB-endemic regions
◦ People with diabetes or on immunosuppressive therapy
4. Improving Living and Working Conditions
● Reduce overcrowding
● Improve housing quality, access to clean water and sanitation
● Promote balanced diet and health education
Conclusion
Tuberculosis continues to pose a significant global health challenge despite advancements in diagnostics, treatment and prevention. This article highlighted the multifaceted nature of TB diagnosis including clinical, radiological, microbiological, molecular and immunological methods, as well as the relevance of pathological findings in guiding clinical decision-making. The evolution of diagnostic technologies, such as rapid molecular tests and AI integration, offers promising avenues to detect TB earlier and more accurately. Meanwhile, effective treatment, whether for drug-sensitive, drug-resistant or TB-HIV co-infected cases relies on tailored pharmacological regimens, adherence strategies and patient-centered care. As global health efforts intensify, a deeper understanding of TB’s diagnosis, pathology and treatment will remain essential for controlling the disease and ultimately moving closer to eradication.
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