Tuberculosis (TB)

A 32-year-old man presents with a 2-month history of persistent cough, low-grade fever, night sweats, loss of appetite, and weight loss. He reports occasional blood-streaked sputum and fatigue. On examination, he appears thin and mildly febrile, with crackles over the upper lung fields. Chest X-ray shows upper-lobe infiltrates with cavitary lesions. Sputum NAAT is positive for Mycobacterium tuberculosis. What is the diagnosis?

The diagnosis is pulmonary tuberculosis (TB).

1. Definition

1.      Tuberculosis is a chronic infectious disease caused mainly by Mycobacterium tuberculosis.

2.      It most commonly affects the lungs, but may involve almost any organ.

3.      TB may occur as:

1.      TB infection (TBI), previously termed latent TB infection, with persistent immune response to M. tuberculosis antigens but no evidence of clinically manifest TB disease

2.      TB disease, with clinically and/or microbiologically evident disease

4.      M. tuberculosis is transmitted through inhalation of airborne infectious particles generated by people with infectious pulmonary or laryngeal TB.

2. Etiology / Risk Factors

1.      Causative organism: Mycobacterium tuberculosis

2.      Important risk factors include:

1.      Close contact with infectious TB

2.      HIV infection

3.      Malnutrition

4.      Diabetes mellitus

5.      Immunosuppression, especially TNF-α inhibitors

6.      Chronic kidney disease

7.      Silicosis

8.      Smoking

9.      Crowded living conditions

10.  Previous inadequately treated TB

3. Pathophysiology

1.      Inhaled bacilli reach the alveoli.

2.      Bacilli are engulfed by macrophages but can survive intracellularly.

3.      Cell-mediated immunity develops.

4.      Activated macrophages and lymphocytes form granulomas.

5.      Classic pathology includes:

1.      Caseating granulomas

2.      Epithelioid histiocytes

3.      Langhans-type giant cells

6.      These findings are characteristic but not pathognomonic.

7.      Infection may:

1.      Become contained as TB infection (TBI)

2.      Progress to active primary TB disease

3.      Reactivate later as reactivation TB

8.      Reactivation TB classically affects the upper lobes and may cause cavitation.

4. Clinical Features

4.1 Respiratory Features

1.      Persistent cough

2.      Sputum production

3.      Hemoptysis

4.      Chest pain

5.      Dyspnea in extensive disease

4.2 Constitutional Features

1.      Fever

2.      Night sweats

3.      Weight loss

4.      Loss of appetite

5.      Fatigue

4.3 Extrapulmonary and Disseminated TB

1.      Lymph node TB → painless lymphadenopathy

2.      Pleural TB → pleural effusion

3.      TB meningitis → headache, fever, altered consciousness

4.      Spinal TB (Pott disease) → back pain, vertebral destruction

5.      Genitourinary TB → sterile pyuria

6.      Abdominal TB → abdominal pain, ascites

7.      Miliary TB → hematogenous dissemination

8.      Pericardial TB → pericardial inflammation or effusion

5. Diagnosis

5.1 Diagnostic Approach

1.      Suspect TB based on:

1.      Compatible symptoms

2.      Risk factors

3.      Chest imaging

2.      Obtain microbiological confirmation whenever possible.

3.      Rapid molecular testing (NAAT) is preferred for initial microbiological diagnosis.

4.      Assess for drug resistance, particularly rifampicin resistance.

5.2 Microbiological Tests

1.      NAAT / rapid molecular test

1.      Rapidly detects M. tuberculosis

2.      Some assays simultaneously detect drug resistance

2.      AFB smear

1.      Rapid

2.      Smear positivity generally indicates a higher bacillary burden

3.      AFB smear cannot distinguish M. tuberculosis from other acid-fast mycobacteria

3.      Culture

1.      Important reference microbiological method

2.      Allows phenotypic drug-susceptibility testing

3.      Takes longer than molecular testing

5.3 Imaging

1.      Chest X-ray may show:

1.      Upper-lobe infiltrates

2.      Cavitary lesions

3.      Fibrosis

4.      Lymphadenopathy

5.      Pleural effusion

2.      Miliary TB may show diffuse “millet seed” nodules.

5.4 TST / IGRA

1.      Tuberculin skin test (TST)

2.      Interferon-gamma release assay (IGRA)

3.      These tests indicate TB infection.

4.      They cannot alone distinguish TB infection from active TB disease.

6. Differential Diagnosis

1.      Bacterial pneumonia

2.      Lung abscess

3.      Lung carcinoma

4.      Fungal infection

5.      Nontuberculous mycobacterial infection

6.      Sarcoidosis

7.      Bronchiectasis

7. Management

7.1 Core Principle

1.      Confirm the diagnosis, assess drug susceptibility, use appropriate combination therapy, monitor treatment response and toxicity, and prevent transmission.

7.2 Drug-Susceptible Pulmonary TB

1.      For most patients with drug-susceptible pulmonary TB, the conventional 6-month regimen consists of:

1.      Intensive phase, 2 months:

1.      Isoniazid (H)

2.      Rifampicin (R)

3.      Pyrazinamide (Z)

4.      Ethambutol (E)

2.      Continuation phase, 4 months:

1.      Isoniazid

2.      Rifampicin

3.      Shorthand: 2HRZE / 4HR

2.      Cavitary disease requires particular attention to microbiological response.

1.      For patients treated with the conventional HRZE/HR regimen who have cavitation on the initial chest radiograph and a positive sputum culture at the completion of 2 months of treatment, current U.S. CDC guidance recommends extending the continuation phase with isoniazid and rifampicin by an additional 3 months.

2.      This results in 2HRZE / 7HR, with 9 months of total treatment.

3.      Cavitation alone does not automatically require 9 months of treatment.

3.      Eligible patients may receive a 4-month rifapentine-moxifloxacin regimen:

1.      Initial phase: 8 weeks of HPZM

1.      Isoniazid (H)

2.      Rifapentine (P)

3.      Pyrazinamide (Z)

4.      Moxifloxacin (M)

2.      Continuation phase: 9 weeks of HPM

1.      Isoniazid

2.      Rifapentine

3.      Moxifloxacin

3.      Total treatment duration: 17 weeks

4.      Shorthand: 2HPZM / 2HPM

4.      The 4-month rifapentine-moxifloxacin regimen may be used in appropriately selected patients, including eligible patients 12 years of age or older and weighing at least 40 kg.

5.      Baseline cavitation alone does not exclude an otherwise eligible patient from the 4-month rifapentine-moxifloxacin regimen.

6.      Eligibility also depends on drug susceptibility, HIV status and ART interactions, disease site, pregnancy status, and other contraindications.

7.      Regimen selection depends on drug susceptibility, patient factors, disease site, treatment response, and current national or WHO guidance.

7.3 Important Drug Adverse Effects

1.      Isoniazid

1.      Hepatotoxicity

2.      Peripheral neuropathy

2.      Rifampicin

1.      Hepatotoxicity

2.      Orange-red discoloration of body fluids

3.      Drug interactions

3.      Pyrazinamide

1.      Hepatotoxicity

2.      Hyperuricemia

4.      Ethambutol

1.      Optic neuropathy

2.      Red-green color impairment

7.4 Pyridoxine

1.      Pyridoxine (vitamin B6) helps prevent isoniazid-induced peripheral neuropathy in patients at increased risk.

2.      It is particularly important during pregnancy and in patients with malnutrition, diabetes, HIV, alcohol use disorder, chronic kidney disease, or advanced age.

7.5 Drug-Resistant TB

1.      Perform appropriate drug-susceptibility testing.

2.      MDR/RR-TB requires an appropriate multidrug regimen guided by drug-susceptibility testing, patient eligibility, treatment history, and current guidelines.

3.      Current WHO guidance prioritizes shorter, all-oral regimens for eligible patients.

4.      BPaLM consists of:

1.      Bedaquiline

2.      Pretomanid

3.      Linezolid

4.      Moxifloxacin

5.      BPaLM is an initial 6-month regimen choice for eligible patients with MDR/RR-TB.

6.      Fluoroquinolone drug-susceptibility testing is strongly encouraged:

1.      If fluoroquinolone susceptibility is confirmed, BPaLM may be continued

2.      If fluoroquinolone resistance is confirmed, moxifloxacin is removed and BPaL is continued

7.      BDLLfxC is another WHO-recommended 6-month regimen option and consists of:

1.      Bedaquiline

2.      Delamanid

3.      Linezolid

4.      Levofloxacin

5.      Clofazimine

8.      The BDLLfxC regimen is modified according to fluoroquinolone drug-susceptibility results:

1.      If fluoroquinolone susceptibility is unknown, treatment may begin with BDLLfxC

2.      If fluoroquinolone susceptibility is confirmed, clofazimine may be stopped and treatment continued as BDLLfx

3.      If fluoroquinolone resistance is confirmed, levofloxacin is stopped and treatment continued as BDLC

9.      The BDLLfxC-based regimen is particularly important for some patients who are not eligible for BPaLM/BPaL, including certain children younger than 14 years and pregnant or breastfeeding patients.

10.  Modified 9-month or individualized longer regimens may be required depending on drug resistance, intolerance, disease site, previous treatment, and eligibility for shorter regimens.

11.  Treatment should follow current WHO and national guidelines.

8. TB and HIV

1.      HIV greatly increases the risk of active TB disease.

2.      Advanced HIV may cause:

1.      Atypical pulmonary findings

2.      Less upper-lobe cavitation

3.      Extrapulmonary TB

4.      Disseminated or miliary TB

3.      Patients with TB should undergo HIV testing.

4.      TB/HIV management requires:

1.      Anti-TB treatment

2.      Antiretroviral therapy (ART)

3.      Attention to rifamycin-ART drug interactions

9. Infection Control

1.      Use appropriate airborne precautions for suspected infectious pulmonary or laryngeal TB.

2.      Important measures include:

1.      Early diagnosis and effective treatment

2.      Appropriate isolation

3.      Adequate ventilation

4.      Respiratory protection for healthcare workers

3.      Perform contact investigation.

10. Monitoring

1.      Monitor clinical improvement and weight.

2.      Assess treatment adherence.

3.      Monitor microbiological response when indicated.

4.      Monitor drug toxicity.

5.      Assess liver function when indicated.

6.      For patients receiving ethambutol:

1.      Obtain baseline visual acuity and color discrimination

2.      Ask about visual symptoms during treatment

3.      Repeat formal visual assessment when clinically indicated, particularly with prolonged therapy or increased risk of toxicity

4.      Use closer monitoring in patients with risk factors such as renal impairment

7.      Review drug interactions, especially with rifamycins.

8.      In patients with cavitary pulmonary TB receiving the conventional regimen, the 2-month sputum culture result is particularly important when assessing relapse risk and treatment duration.

11. Complications and Sequelae

1.      Massive hemoptysis

2.      Bronchiectasis

3.      Post-TB lung disease

4.      Pulmonary fibrosis

5.      Chronic airflow limitation

6.      Respiratory failure

7.      Recurrent pulmonary infections

8.      Death

12. Prevention

1.      Early diagnosis and effective treatment

2.      Contact investigation

3.      Treatment of TB infection when indicated

4.      Infection-control measures

5.      BCG vaccination

1.      Provides important protection in children, particularly against TB meningitis and disseminated or miliary TB

2.      Protection against pulmonary TB is variable

13. Key Clinical Insight

Chronic cough with fever, night sweats, weight loss, hemoptysis, and upper-lobe cavitary disease should strongly raise suspicion for pulmonary TB, which should be confirmed microbiologically and assessed for drug resistance.

References

1.      World Health Organization. WHO consolidated guidelines on tuberculosis: Module 3: diagnosis. Geneva: World Health Organization; 2025. ISBN: 978-92-4-010798-4.

2.      World Health Organization. WHO consolidated operational handbook on tuberculosis: Module 4: treatment and care. Geneva: World Health Organization; 2025. ISBN: 978-92-4-010814-1.

3.      Centers for Disease Control and Prevention. Treatment for Drug-Susceptible Tuberculosis Disease. Atlanta, GA: Centers for Disease Control and Prevention. Accessed September 17, 2026.