What are the stages of Mycobacterium tuberculosis infection?

Stages of Tuberculosis

Mycobacterium tuberculosis infection progresses through two distinct stages: latent tuberculosis infection (LTBI) and active tuberculosis disease, with the transition between these stages determined primarily by host immune response and risk factors for reactivation. 1

Stage 1: Latent Tuberculosis Infection (LTBI)

LTBI represents asymptomatic infection where the host immune system has successfully contained the bacteria without eradication. 1

Clinical Characteristics

• Patients are completely asymptomatic with no clinical signs or symptoms of disease 1
• Positive tuberculin skin test (TST) or interferon-gamma release assay (IGRA) indicating immune recognition of M. tuberculosis antigens 2, 1
• Normal chest radiograph without infiltrates, cavitation, or lymphadenopathy 1
• Negative bacteriologic studies (AFB smear and culture) 1
• Patients are not infectious to others 1

Natural History and Reactivation Risk

• The lifetime risk of progression from LTBI to active disease is 5-15% 1
• The majority of reactivation occurs within the first 5 years after initial infection 1
• Risk factors that dramatically increase progression to active disease include: HIV infection, recent infection within 2 years, immunosuppressive therapy (TNF-α antagonists, corticosteroids ≥15 mg prednisone daily, post-transplant medications), age <5 years, untreated or inadequately treated prior TB with fibrotic lesions on chest X-ray, silicosis, and diabetes mellitus 2

Diagnostic Approach

• TST or IGRA testing should be targeted only to high-risk populations who would benefit from treatment if positive 2
• High-risk groups include: close contacts of active TB cases, foreign-born persons from high-prevalence countries, residents/employees of congregate settings (correctional facilities, long-term care, homeless shelters), healthcare workers serving high-risk populations, medically underserved populations, and children exposed to high-risk adults 2
• Active TB disease must be excluded before diagnosing LTBI through symptom screening, chest radiography, and if indicated, sputum testing 3, 4

Stage 2: Active Tuberculosis Disease

Active TB represents uncontrolled bacterial replication with tissue destruction, clinical symptoms, and potential for transmission to others. 1

Primary Tuberculosis

• Occurs in individuals without prior immunity, typically children and immunocompromised adults 5
• Develops within 5 years of initial infection 5
• Radiographic pattern shows lobar pneumonia, mediastinal and hilar lymphadenopathy 1
• Peak risk occurs during adolescence 5

Reactivation (Post-Primary) Tuberculosis

• Results from reactivation of dormant bacilli in previously infected individuals 6
• Classic radiographic findings: apical posterior upper lobe or superior-segment lower lobe fibrocavitary disease 1
• CT imaging shows tree-in-bud nodules indicating endobronchial spread 1
• More common in adults with waning immunity or new immunosuppression 6

Clinical Manifestations

The cardinal symptoms of active TB include:

• Cough lasting ≥2-3 weeks (most common presenting symptom) 1, 4
• Fever (often evening fever) 4
• Night sweats 1, 4
• Weight loss and anorexia 1, 4
• Hemoptysis (particularly with cavitary disease) 1, 4
• Chest pain and shortness of breath 3
• Fatigue 3

Diagnostic Criteria

The gold standard for diagnosis is positive mycobacterial culture from sputum or other clinical specimens. 1, 4

Microbiological Testing Algorithm

• Collect three sputum specimens on different days for AFB smear microscopy and mycobacterial culture 2, 3, 4
• Perform nucleic acid amplification testing (NAAT) on at least one specimen for rapid diagnosis within 1-2 days 3, 4
• Approximately 60% of culture-positive patients have positive AFB smears in the United States 2
• HIV-infected patients may have lower rates of positive AFB smears due to less cavitary disease 2

Radiographic Evaluation

• Chest radiograph findings suggestive of active TB: upper-lobe infiltration with cavitation, patchy or nodular infiltrates in apical or subapical posterior upper lobes or superior segment of lower lobe 2
• HIV-infected patients may show atypical presentations with infiltrates in any lung zone, mediastinal/hilar adenopathy, or rarely normal chest radiograph 2

Infectiousness Determination

Patients are considered infectious when they meet the following criteria: 2

High-Risk Infectious Patients

• Pulmonary or laryngeal TB with cough or undergoing cough-inducing procedures 2
• Positive AFB sputum smear 2
• Cavitation on chest radiograph 2
• Not on chemotherapy, just started chemotherapy, or poor clinical/bacteriologic response to therapy 2

Factors Increasing Infectiousness

• Disease in lungs, airways, or larynx 2
• Presence of cough or forceful expiratory measures 2
• Failure to cover mouth/nose when coughing 2
• Inappropriate or short duration of chemotherapy 2
• Cough-inducing procedures causing aerosolization 2

Duration of Infectiousness

• The period required for effective therapy to render patients non-infectious varies between individuals 2
• Some TB patients are never infectious, while those with unrecognized or inadequately treated drug-resistant TB may remain infectious for weeks or months 2
• Effective therapy reduces coughing, sputum production, and bacterial load, but timing to non-infectiousness must be assessed individually 2
• Patients require isolation until three consecutive sputum smears collected on different days are negative and clinical improvement is evident 4

Extrapulmonary Tuberculosis

• Patients with extrapulmonary TB are usually not infectious unless they have: concomitant pulmonary disease, nonpulmonary disease in the respiratory tract or oral cavity, or open abscess/lesion with high organism concentration and extensive drainage 2

Special Populations

Children

• May be less likely than adults to be infectious but transmission from children can occur 2
• Evaluate using same parameters as adults: pulmonary/laryngeal TB, cough, positive AFB smear, cavitation, adequacy of therapy 2
• Children with typical primary tuberculous lesions without indicators of infectiousness usually do not need isolation 2
• Parents and visitors of pediatric TB patients should be evaluated immediately as they are often the source case 2

HIV-Coinfected Patients

• HIV coinfection does not appear to affect infectiousness of TB patients 2
• However, HIV-infected patients have increased risk for extrapulmonary disease 7
• May have atypical radiographic presentations and lower rates of positive tuberculin tests 2

Critical Clinical Pitfalls to Avoid

• Never exclude TB based on negative AFB smears alone—culture is mandatory as only 60% of culture-positive cases have positive smears 2, 3
• Never assume non-infectiousness immediately after starting treatment—wait for three consecutive negative sputum smears on different days 3, 4
• Never use TST or IGRA to diagnose active TB disease—these tests cannot distinguish active from latent infection 3, 4
• Never delay treatment in high-suspicion cases while awaiting culture results—begin empiric four-drug therapy when clinical and radiographic findings strongly suggest TB 3, 4
• Never rely on a single negative sputum specimen to exclude TB—collect three specimens on different days 3, 4
• Maintain high suspicion in HIV-infected patients who may have atypical presentations or false-negative skin tests 4