What are the diagnostic criteria for active Tuberculosis (TB) disease?

From the Guidelines

Determining active tuberculosis (TB) disease requires a comprehensive diagnostic approach, and clinicians should suspect active TB in patients with persistent cough, hemoptysis, fever, night sweats, weight loss, and fatigue, with chest radiography as the initial test, as it has high sensitivity for detecting manifestations of active TB 1. To diagnose active TB, multiple tests are typically involved, including:

• Chest X-ray showing upper lobe infiltrates or cavitary lesions
• Sputum microscopy for acid-fast bacilli (AFB)
• Sputum culture for Mycobacterium tuberculosis
• Nucleic acid amplification tests like GeneXpert MTB/RIF Tuberculin skin tests and interferon-gamma release assays (IGRAs) can indicate TB infection but cannot distinguish between latent and active disease. For definitive diagnosis, a positive culture remains the gold standard, though it takes 2-8 weeks for results 1. In cases where sputum collection is difficult, bronchoscopy with bronchoalveolar lavage may be necessary, and for extrapulmonary TB, appropriate tissue sampling is required. Once diagnosed, patients should immediately begin treatment with a standard four-drug regimen (isoniazid, rifampin, ethambutol, and pyrazinamide) for two months, followed by isoniazid and rifampin for four additional months 1. Early diagnosis is crucial as untreated active TB is both potentially fatal and highly contagious, particularly through airborne transmission during coughing. The decision to initiate combination antituberculosis chemotherapy should be based on epidemiologic information, clinical, pathological, and radiographic findings, and the results of microscopic examination of acid-fast bacilli (AFB)–stained sputum and cultures for mycobacteria 1. A purified protein derivative (PPD)-tuberculin skin test may be done at the time of initial evaluation, but a negative PPD-tuberculin skin test does not exclude the diagnosis of active tuberculosis 1. If the suspicion of tuberculosis is high or the patient is seriously ill, combination chemotherapy using one of the recommended regimens should be initiated promptly, often before AFB smear results are known and usually before mycobacterial culture results have been obtained 1. A positive AFB smear provides strong inferential evidence for the diagnosis of tuberculosis 1. If the diagnosis is confirmed by isolation of M. tuberculosis or a positive nucleic acid amplification test, treatment can be continued to complete a standard course of therapy 1. When the initial AFB smears and cultures are negative, a diagnosis other than tuberculosis should be considered and appropriate evaluations undertaken 1. If no other diagnosis is established and the PPD-tuberculin skin test is positive, empirical combination chemotherapy should be initiated 1. If there is a clinical or radiographic response within 2 months of initiation of therapy and no other diagnosis has been established, a diagnosis of culture-negative pulmonary tuberculosis can be made and treatment continued with an additional 2 months of INH and RIF to complete a total of 4 months of treatment, an adequate regimen for culture-negative pulmonary tuberculosis 1. If there is no clinical or radiographic response by 2 months, treatment can be stopped and other diagnoses including inactive tuberculosis considered 1. In patients who are immunocompromised, particularly those with AIDS and very low CD4 counts, chest radiographs may be deceptively normal 1. Chest radiography has high sensitivity but relatively poor specificity because of the overlap of findings with nontuberculous pulmonary infection 1. The yield of chest radiography in high-risk patients ranges from 1% to 7%, although it is not clear how many of these cases would have been suspected on the basis of clinical symptoms alone 1. Lobar pneumonia with associated hilar and/or mediastinal adenopathy or cavitary air space disease involving the apical posterior segments of the upper lobe or superior segment of the lower lobe should raise particular concern 1. When chest radiography confirms the clinical suspicion of active TB, it is sufficient to warrant respiratory isolation pending sputum cultures 1.

From the Research

Determining Active TB Disease

• The diagnosis of active TB disease can be determined using various tests, including the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) 2, 3, 4, 5, 6.
• IGRAs have been shown to have a better predictive ability than TST for the progression of latent infection to active tuberculosis disease 2.
• The use of IGRAs, such as QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB, can help identify individuals with latent TB infection who are at risk of progressing to active TB disease 3, 5, 6.
• A study found that the agreement between QFT-GIT and TST was low using a 10 mm cutoff, but intermediate using a 15 mm cutoff 5.
• Another study found that IGRAs, especially T-SPOT.TB, are more effective at detecting TB infection than TST 3.
• The chest radiograph can be used to interpret a TST in the 5-9 mm range and can help predict subsequent reactivation of tuberculosis (TB) 4.
• A systematic review and meta-analysis found that IGRAs can be used to identify latent TB infection that progresses to active tuberculosis, but the results should be interpreted with caution due to uncertainty, risk of bias, and unexplained heterogeneity 6.

Comparison of TST and IGRA

• TST and IGRA have different sensitivities and specificities for detecting TB infection 2, 3, 5.
• IGRAs have been shown to be more sensitive than TST, especially in BCG-vaccinated individuals 3, 5.
• The specificity of IGRAs is also higher than that of TST, but there is overlap between confidence intervals 3.
• A study found that the odds ratio for the development of active tuberculosis was higher for QFT-GIT positive patients than for TST positive patients 5.

Clinical Implications

• The use of IGRAs can help identify individuals with latent TB infection who are at risk of progressing to active TB disease, and can inform treatment decisions 2, 3, 5, 6.
• The chest radiograph can be used to interpret a TST in the 5-9 mm range and can help predict subsequent reactivation of tuberculosis (TB) 4.
• Clinicians should consider using IGRAs, especially in individuals who are at high risk of TB or who have been vaccinated with BCG 3, 5.