CONTENTS

• Epidemiology & risk factors
• Clinicoradiologic forms
  • Natural history of tuberculosis
  • Primary pulmonary TB
  • Tuberculous pleural effusion ➡️
  • Chronic tuberculous empyema ➡️
  • Healed tuberculosis (Ghon complex)
  • Postprimary TB
  • Miliary TB
    • Acute miliary TB
    • Subacute/chronic miliary TB
  • Tracheobronchial involvement
  • Laryngeal TB
• Diagnosis of active pulmonary TB: overview
  • Red flags to consider the diagnosis of TB
  • Initial tests to obtain
  • Evaluation of disease activity in patient known to have TB
  • Differential diagnostic considerations
• Specific tests
  • Sputum smear for AFB (acid-fast bacilli)
  • Sputum PCR
  • AFB culture
  • Bronchoscopy
  • Tuberculin skin test
  • IGRA (interferon gamma release assay)
• Treatment of active TB
• Other topics:
  • Tuberculous meningitis
  • Tuberculomas
  • TB & HIV
• Questions & discussion

abbreviations used in the pulmonary section: 3

• ABPA: Allergic bronchopulmonary aspergillosis 📖
• AE-ILD: Acute exacerbation of ILD 📖
• AEP: Acute eosinophilic pneumonia 📖
• AFB: Acid Fast Bacilli
• AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
• ANA: Antinuclear antibody 📖
• ANCA: Antineutrophil cytoplasmic antibodies 📖
• ARDS: Acute respiratory distress syndrome 📖
• ASS: Antisynthetase Syndrome 📖
• BAL: Bronchoalveolar lavage 📖
• BiPAP: Bilevel positive airway pressure 📖
• CEP: Chronic eosinophilic pneumonia 📖
• CF: Cystic fibrosis 📖
• COP: Cryptogenic organizing pneumonia 📖
• CPAP: Continuous positive airway pressure 📖
• CPFE: Combined pulmonary fibrosis and emphysema 📖
• CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
• CTEPH: Chronic thromboembolic pulmonary hypertension 📖
• DAD: Diffuse alveolar damage 📖
• DAH: Diffuse alveolar hemorrhage 📖
• DIP: Desquamative interstitial pneumonia 📖
• DLCO: Diffusing capacity for carbon monoxide 📖
• DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
• EGPA: Eosinophilic granulomatosis with polyangiitis 📖
• FEV1: Forced expiratory volume in 1 second 📖
• FVC: Forced vital capacity 📖
• GGO: Ground glass opacity 📖
• GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
• HFNC: High flow nasal cannula 📖
• HP: Hypersensitivity pneumonitis 📖
• IPAF: Interstitial pneumonia with autoimmune features 📖
• IPF: Idiopathic pulmonary fibrosis 📖
• IVIG: Intravenous immunoglobulin 📖
• LAM: Lymphangioleiomyomatosis 📖
• LIP: Lymphocytic interstitial pneumonia 📖
• MAC: Mycobacterium Avium complex 📖
• MCTD: Mixed connective tissue disease 📖
• NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
• NSIP: Nonspecific interstitial pneumonia 📖
• NTM: Non-tuberculous mycobacteria 📖
• OP: Organizing pneumonia 📖
• PAP: Pulmonary alveolar proteinosis 📖
• PE: Pulmonary embolism 📖
• PFT: Pulmonary function test 📖
• PLCH: Pulmonary Langerhans Cell Histiocytosis 📖
• PPFE: Pleuroparenchymal fibroelastosis 📖
• PPF: Progressive pulmonary fibrosis 📖
• PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
• RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
• RP-ILD: Rapidly progressive interstitial lung disease 📖
• TNF: tumor necrosis factor
• UIP: Usual Interstitial Pneumonia 📖

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epidemiology

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risk factors for tuberculosis

• [1] Geography:
  • Born in a country with high TB rates (may be the strongest risk factor).
  • Lived in an endemic area.
  • Extensive travel to a highly endemic area.
• [2] Personal history of tuberculosis.
• [3] Close contacts with active tuberculosis.
• (Note: Risk factors will vary between different locales. Many factors such as working in prisons or homelessness are no longer risk factors within the United States, because the rate of tuberculosis has fallen.)

risk factors for TB progression, reactivation, or extrapulmonary TB

• HIV (increases risk ~50-100 fold).
• Transplantation (increases risk ~50-fold).
• Chronic renal failure (increases risk ~15-fold).
• TNF-inhibitors (increases risk ~5-fold, more discussion: 📖). (ERS handbook 3rd ed.)
• Diabetes (increases risk ~3-fold). (Murray 2022)
• Other risk factors:
  • Other immunosuppressive medications (e.g., >15 mg/day prednisone for >1 month).
  • Alcoholism.
  • Malignancy (especially hematologic).
  • Older age.
  • Malnutrition (e.g., postgastrectomy).
  • Silicosis.
  • Sarcoidosis. (28185620)

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natural history of tuberculosis

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following initial infection: primary TB vs. latent TB

• Following initial infection, one of two outcomes occurs:
• (1) Latent TB infection (LTBI)
  • ~90% of patients will contain the infection.
  • Bacteria remain sequestered within the patient's body indefinitely (within fibrotic granulomas).
• (2) Progressive primary TB infection
  • ~10% of patients progress to develop active TB infection within 2 years (usually <18 months). (Fishman 2023)
  • Progressive primary TB often results in extrapulmonary TB.
  • Risk factors for progressive disease:
    • (1) Immunological risk factors for progression or reactivation (listed in the section above ☝️).
    • (2) Large initial inoculation of M. tuberculosis.

postprimary TB

• (1) Reactivation of latent TB infection:
  • ~5% of patients with latent TB infection will develop active tuberculosis subsequently (>2 years after the initial infection). This often occurs decades after the initial exposure.
  • Progression from a latent state to an active infection can occur if the immune system becomes impaired (e.g., due to immunosuppressive medications or HIV).
• (2) Reinfection with a new strain of TB:
  • Among patients who previously contracted TB and have some immunity to TB, infection with a new TB strain will manifest similarly to reactivation of a latent TB. (27153783)

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primary pulmonary tuberculosis

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~30% of adult TB cases in developed countries are actually primary TB. (28076011) However, immunocompetent people usually won't require hospitalization for primary TB. 

clinical presentation

• Basics:
  • This may present as an “atypical pneumonia.”
  • Primary infection is often asymptomatic, mild, and self-limiting. Only ~5-10% of patients will seek medical attention.
• Most common clinical manifestations:
  • Fever (~70%) is usually low-grade, but may persist for weeks.
  • Dyspnea and nonproductive cough.
  • Pleuritic chest pain in ~25% of patients (about half of whom may have a pleural effusion).
• Less common manifestations:
  • Pharyngitis.
  • Arthralgias.
  • Erythema nodosum.
  • Phlyctenular conjunctivitis (conjunctival nodules).
  • Dactylitis (“sausage digits”).

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radiology of primary TB

four imaging manifestations of primary TB

• (1) Lymphadenopathy – discussed here: 📖
• (2) Parenchymal disease – discussed below.
• (3) Miliary disease – discussed here: 📖
• (4) Pleural effusion – discussed in the section below.

parenchymal disease

• Description:
  • A dense, homogeneous consolidation that may be segmental, lobar, or ill-defined.
  • The consolidation itself is generally indistinguishable from consolidation due to bacterial pneumonia. (27153783)
  • Cavitation may occasionally occur (~10%), especially if infection persists beyond the time when cell-mediated immunity develops (this indicates primary progressive TB). (Murray 2022) Small cavities are often visible only on CT scan. (28185620) Cavitation occurs within existing consolidation, so it doesn't demonstrate an upper lung zone predominance. (28076011)
  • Resolution of consolidation is extremely slow (taking as long as two years). (28076011)
• Location:
  • Usually unilateral (bilateral in only 2% of patients).
  • Any lobe can be affected, but the lower or middle lobes are most often involved.
  • Involvement is usually confined to a single segment or lobe. (28185620)
• Parenchymal disease with lymphadenopathy should raise suspicion for tuberculosis, as opposed to a bacterial pneumonia. (Further discussion of lymphadenopathy here: 📖)

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healed tuberculosis (Ghon complex)

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Ghon focus

• Peripheral granuloma (tuberculoma) in the lung parenchyma, representing residual from a primary tuberculosis infection.
• Over time, this will often undergo calcification.
• The Ghon focus is usually located in the mid to lower lung zones (the same distribution as peripheral infiltrates seen in primary tuberculosis).

Ghon complex (aka Ranke complex)

• This refers to the combination of a Ghon focus plus calcification of a draining hilar or mediastinal lymph node.
• The differential diagnosis includes prior histoplasmosis infection. (27153783)

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postprimary tuberculosis

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common presentations:

• Postprimary tuberculosis may run an insidious course over weeks to months. Some patients may be relatively asymptomatic. Presenting features commonly include the following:
• Chronic cough:
  • Most patients eventually develop cough.
  • Cough may initially be nonproductive, but eventually is productive of yellow or yellow-green sputum.
• Constitutional symptoms may be prominent (“consumption”).
  • Anorexia, weight loss, night sweats, and/or fevers.
• Nonresolving pneumonia (patients may receive several rounds of antibiotics prior to diagnosing tuberculosis).

other clinical features

• Dyspnea is generally a late sign, reflective of either extensive disease or tracheobronchial obstruction. (28185620)
• Hemoptysis:
  • Occurs in ~25%, but rarely as a presenting symptom.
  • Usually occurs late in the disease course.
  • Mechanisms of hemoptysis:
    • Rupture of a vessel in a cavity (Rasmussen aneurysm).
    • Aspergilloma in an old tuberculous cavity.

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radiology of postprimary TB

parenchymal infiltrates +/- cavitation

• Distribution:
  • Bilateral upper lobe disease is common. However, unilateral disease can occur.
  • Apical and (especially) posterior segments of the upper lobes are typically involved (~85%), followed by the superior segments of lower lobes.
  • Cavitary disease can involve the upper and lower lobes, but it would be rare (5%) to present solely with cavitary lesions of the lower lung fields. (28076011) Likewise, exclusive involvement of the anterior upper lobes would be rare.
• Infiltrates:
  • 75% have upper lobe infiltrates.
  • Consolidation may be seen, which is usually patchy and poorly marginated. (28076011)
  • Ground-glass infiltrates may be caused by fine perilymphatic micronodular infiltrates (discussed further below).
• Cavitation occurs in ~33-50% of patients:
  • Initially the cavity walls have moderate thickness. Eventually, healing may leave behind a thin-walled cavity.
  • Air-fluid levels are seen in ~15% of patients. If seen, this may raise the possibility of superinfection with bacterial or fungal infection. (Walker 2019; 25623513)

endobronchial TB (tree-in-bud pattern)

• A nodular, tree-in-bud pattern is characteristic.
  • This may be the most common pattern seen on CT scan among patients newly diagnosed with TB. Centrilobular nodules are seen in up to ~95% of patients with active TB (although this statistic may be artificially inflated due to under-recognition of perilymphatic micronodular patterns). (28076011)
  • A tree-in-bud pattern may help establish the presence of active disease. With treatment, this usually disappears within ~5 months. (Walker 2019)
• Bronchial wall thickening may be seen.
• There is a bidirectional relationship between tree-in-bud nodules and cavitation:
  • Cavitation expels caseous material into the bronchial tree, which may lead to tree-in-bud opacities. Thus, endobronchial TB usually occurs in patients with extensive disease, especially cavitary lesions. Typically, upper lung disease occurs with bronchogenic spread to lower lung fields (due to infected secretions).
  • Tree-in-bud nodules can progress to confluence and eventually cavitate.

perilymphatic micronodular patterns

• These are more common than traditionally recognized (perhaps occurring in up to half of patients). (35001143)
• Perilymphatic micronodular patterns are associated with postprimary TB in immunocompetent patients. (35001143) This makes sense, because perilymphatic granuloma formation requires immunocompetence.
• It's useful to understand the difference between perilymphatic micronodular patterns versus centrilobular micronodular patterns:
  • Centrilobular micronodular patterns generate a tree-in-bud pattern. This reflects endobronchial tuberculosis, correlating with detection of AFB in the sputum.
  • Perilymphatic micronodular patterns often generate a unique, textured ground-glass appearance that is patchy in nature. They are often not associated with AFB in the sputum.
• Various signs are used to refer to specific configurations of perilymphatic micronodular involvement:
  • Galaxy sign 📖 is defined as a parenchymal nodule composed of coalescent small nodules. It is usually 1-2 cm large, but can be larger. (23059737) One dominant nodule appears to be surrounded by tiny satellite nodules. (21377343)
  • Cluster sign 📖 refers to clusters of micronodules that are close to each other but are nonconfluent (so, unlike the galaxy sign, they don't create a central nodule). (32665780) This mimics ground glass opacity, but it has a more coarse and stippled appearance.
  • Nodular reverse halo sign 📖 results from a cluster of micronodules with a confluent rim (example below). (32665780)

pleural effusion

• Effusion occurs in ~15%, usually unilateral.
• Usually associated with parenchymal abnormalities.

lymphadenopathy

• Lymphadenopathy is uncommon among immunocompetent patients with postprimary TB, occurring in only ~5-10% of patients. (Murray 2022, Walker 2019)
  • More on lymphadenopathy in tuberculosis here: 📖
• Lymph node calcification may be seen, reflective of prior primary tuberculosis.

tuberculoma

• Tuberculoma is a nodule that may be the sole radiographic manifestation of postprimary TB in ~5% of patients. (Walker 2019, 28076011)
• 80% are single, but 20% are multiple.
• Size ranges from 0.5 – 4 cm.
• Typically, tuberculomas are sharply marginated round/oval lesions. However, surrounding satellite lesions are present in up to 80% of cases (which may help elucidate the granulomatous nature of the lesion). (27153783)
• Calcification eventually occurs in ~25%. (27153783)

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miliary TB (aka disseminated, generalized, or hematogenous TB)

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Miliary TB involves hematogenous dissemination, leading to the development of innumerable small lesions (tubercles) in several organs. These lesions look like millet seeds – hence the name. As a form of extrapulmonary tuberculosis, miliary TB is more likely to occur in immunocompromised patients. (Further discussion of the radiological miliary pattern and its differential diagnosis is here: 📖)

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acute miliary tuberculosis

• Basics:
  • Acute miliary tuberculosis is an aggressive process that may lead to multiorgan failure, ARDS, and HLH (hemophagocytic lymphohistiocytosis).
  • This can reflect a progressive primary TB infection in young adults. Miliary TB may occur following ~4% of primary TB infections.
• Epidemiological risk factors include:
  • Immunosuppression (e.g., HIV, chronic steroid use).
  • Pregnancy. (36337132)
• Radiology:
  • (1) Innumerable miliary lesions are seen.
  • (2) Miliary lesions may progress to ground glass opacities and consolidation. This is an ominous finding, which predicts the development of clinical ARDS and respiratory failure.
  • Other features of primary TB (e.g., airspace opacity or lymphadenopathy) may occur. More on imaging in primary TB here 📖.
• Treatment:
  • Urgent initiation of antibiotics for TB.
  • Supportive care for respiratory failure.
  • Adjunctive steroid may be considered in the context of ARDS. (36337132)

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subacute/chronic miliary tuberculosis (aka non-reactive tuberculosis, aka “cryptic tuberculosis”) 

• This is usually a subacute process that progresses over months. Miliary TB may be superimposed upon postprimary TB, if a focus of TB erodes into a blood vessel, leading to hematogenous dissemination.
• Clinical features:
  • Constitutional symptoms are typically the most prominent feature (e.g., fever, weight loss, night sweats).
  • Pulmonary symptoms (dry cough and dyspnea) are seen in up to 60% of patients.
  • Tuberculous meningitis may occur in 10-30% of patients, often as a late feature that precedes death.
• Radiology:
  • Chest X-ray has limited sensitivity (~50%). CT scan has greater sensitivity.
  • Additional imaging features of postprimary TB may also be seen (e.g., cavitation, parenchymal infiltrates). 📖

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tracheobronchial involvement

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Tracheobronchial stenosis can result from extrinsic compression by lymphadenopathy or, more commonly, from intrinsic granulomatous changes within the airway. The evolution of intrinsic airway disease is discussed below.

hyperplastic stage

• Upper airway involvement may occur in the context of active pulmonary TB (e.g., hilar lymphadenopathy, cavitary lesions). This may cause ulceration and necrosis.
• CT may show irregular, circumferential thickening of the large airways with luminal narrowing. Most patients have involvement of the distal trachea as well as the proximal right or left mainstem bronchi (with almost invariable involvement of the carina). (27153783)
• Clinically, this may cause airflow limitation, a barking cough, and sputum production. (Fishman 2023)
• Treatment focuses on antibiotic therapy for active pulmonary TB.

fibrostenotic stage

• Fibrostenosis occurs in the context of chronic disease (e.g., pulmonary fibrosis and bronchiectasis). (Shepard 2022)
• This may cause multifocal involvement of the large airways.
• CT may show smooth wall thickening, with thin airway walls.
• Treatment may require bronchoscopic dilation and/or stenting, or even tracheostomy.

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laryngeal tuberculosis

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epidemiology

• This mostly affects men in their 40s-50s.
• Risk factors include smoking and alcohol use.

symptoms

• Hoarseness.
• Odynophagia, globus sensation.
• Cough.
• Dysphonia.
• Edema may cause airway obstruction. (32252935)

laryngoscopy/bronchoscopy

• Laryngeal TB most often involves the anterior larynx or posterior larynx, followed by the vocal cords and epiglottis. (32252935)
• Active pulmonary tuberculosis may associate with multiple ulcerated lesions. (32252935) Alternatively, a single, nonspecific polypoid lesion may occur in the absence of lung disease. (32252935)

diagnosis

• Biopsy of the epiglottic lesion for culture and histology (including AFB staining) should usually yield the diagnosis.
• Sputum for AFB smear and culture may be positive (especially if there is concomitant pulmonary tuberculosis).

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diagnosis of active pulmonary tuberculosis: overview

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red flags: when to consider the diagnosis of pulmonary TB 

epidemiological risk factors

• Personal history of prior tuberculosis.
• Close contact with active tuberculosis.
• Residence in a country with a high rate of TB.
• Substantial immunocompromise (especially: HIV, transplantation, anti-TNF therapy).

pneumonia with:

• Treatment failure (including only partial response to fluoroquinolone or steroid).
• Gram stain showing weakly gram-positive or gram-neutral rods (“ghosts”).
• Chronicity (>2-3 weeks); this may be suggested by low albumin and elevated globulin levels. (Bothamley 2023)

radiological features

• Hilar and mediastinal lymphadenopathy.
• Cavitation.
• Calcification of the hilar/mediastinal lymph nodes. 📖
• Perilymphatic micronodular patterns (galaxy sign, cluster sign, nodular reverse halo sign).

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initial tests to obtain for evaluation of active pulmonary TB

thoracic radiology

• Chest radiograph as an absolute minimum.
  • Two-view radiography (frontal and lateral films) is abnormal in 95% of patients. (Behr 2022)
  • ⚠️ Immunosuppression may decrease the performance of imaging studies.
• CT scan with contrast is preferred.

sputum

• Three sputum specimens for AFB smear and culture (including one early morning sputum).
• One sputum specimen should be sent for PCR as well if TB is suspected.

pleural fluid

• Fluid from any effusions may be helpful (analysis described above 📖).

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evaluation of disease activity in patient with prior TB 

For a patient with a known history of tuberculosis, it's essential to determine whether the tuberculosis is active or quiescent. This is fundamentally similar to the evaluation for active TB in general (as discussed above), but it's a bit more complicated: (28185620) 

symptoms

• Symptoms suggestive of active disease (e.g., fever, weight loss, cough, sputum production).
• However, symptoms may also result from chronic complications of tuberculosis (e.g., bronchiectasis, aspergilloma, bacterial superinfection).

radiology

• Features that favor active disease: (28076011)
  • Progression compared to prior radiology.
  • A tree-in-bud pattern (with treatment, this usually disappears within ~5 months). (Walker 2019)
  • Perilymphatic micronodular patterns.
  • Cavitation (especially a thick-walled cavity, or new cavity).
  • Consolidation (although this may persist for ~2 years despite effective therapy).
  • Pleural effusion.
  • Lymphadenopathy.
  • Miliary nodules.
• Features that suggest inactive disease: (28076011)
  • Stability of radiographic findings over six months.
  • Fibronodular scarring, which may involve:
    • Upper lobe fibrosis (with volume loss and traction bronchiectasis).
    • Well-defined nodular opacities may be seen.
    • Cavities may eventually lead to thin-walled cysts. Aspergilloma formation may occur, as a superinfection of a chronic cyst. (Shepard 2019)
  • Calcified granulomas and/or lymph nodes.

microbiology

• Positive sputum AFB smear or culture establishes active disease.
• ⚠️ Note that PCR isn't recommended for evaluation of disease activity.

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differential diagnostic considerations

TB can mimic a wide variety of disorders, so the differential diagnosis is potentially endless. Some more notable differential diagnostic considerations are as follows:

infection

• Typical bacterial pneumonia (including necrotizing pneumonia).
• Anaerobic lung abscess.
• Mycobacteria:
  • NTM (nontuberculous mycobacteria).
  • Inactive prior tuberculosis.
• Fungal pneumonia:
  • Endemic mycoses:
    • Histoplasmosis.
    • Blastomycosis.
    • Coccidiomycosis.
  • Cryptococcus neoformans.
  • Mold:
    • Aspergillosis (especially chronic cavitary pulmonary aspergillosis).
    • Mucormycosis.
• Actinomycosis.
• Nocardia.

inflammatory

• Sarcoidosis.
• GPA (granulomatosis with polyangiitis).
• Rheumatoid arthritis.

malignancy

• Squamous cell carcinoma.
• Lymphoma.

airway diseases

• COPD.
• Bronchiectasis.

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sputum smear for acid-fast bacilli (AFB)

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basics

• AFB smear is fast and may help clarify whether the patient requires airborne precautions.
• WHO guidelines recommend obtaining three samples over a 24-hour period, with one sample obtained in the early morning. (Shah 2019) Tests should ideally be obtained at least 8 hours apart. (28166561)
• If three AFB smears are negative, this doesn't exclude active pulmonary tuberculosis. However, it does mean that the likelihood of transmitting infection is low, so airborne isolation can be discontinued (even while culture results are still pending).
• Induced sputum is required for patients who aren't spontaneously producing sputum. Success in obtaining a sample is high if sufficient volumes of 3% saline are utilized (e.g., 6 ml of 3% saline via an ultrasonic nebulizer). (Behr 2022) Induced sputum is generally well tolerated, but it can cause bronchospasm among asthmatic patients. (Murray 2022) Please note that sputum induction is quite similar to the use of hypertonic saline to promote airway clearance – a therapeutic procedure which is commonly performed among very unwell patients. The sensitivity of induced sputum for detection of AFB (acid-fast bacilli) is lower than spontaneously produced sputum, since sputum is diluted by saline. Nonetheless, induced sputum is more sensitive than other techniques (e.g., gastric lavage, nasopharyngeal aspiration). (Behr 2022)

sensitivity

• Three AFB smears have a sensitivity of ~65% for culture-positive pulmonary tuberculosis. (The first smear obtains ~50% sensitivity, the second smear adds ~10% sensitivity, and the third adds ~5% sensitivity.)
• Sensitivity is highest in cavitary disease.
• Sensitivity may be lower in the context of HIV, wherein cavitation is less common.

specificity

• Organisms that may be acid-fast include:
  • Mycobacteria:
    • Mycobacterium tuberculosis.
    • Nontuberculous mycobacteria (NTM).
  • Nocardia (weakly acid-fast).
  • Rhodococcus.
• Most often, a positive AFB smear will reflect either tuberculosis or nontuberculous mycobacteria (NTM). The likelihood of TB vs. NTM depends on the clinical context. For example, in a patient without risk factors for tuberculosis in the United States, a positive AFB smear will usually reflect nontuberculous mycobacteria.

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sputum PCR for tuberculosis

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sensitivity

• Sensitivity is >95% in patients with positive AFB smear.
• Sensitivity is 50-80% with negative AFB smear. PCR doesn't have high enough sensitivity to exclude tuberculosis – culture is still required. (Murray 2022)
• Detection threshold of different tests: (Behr 2022, ERS handbook 3rd edition)
  • AFB smear can detect ~5,000-10,000 bacterial/ml.
  • PCR can detect ~100 bacteria/ml.
  • Culture can detect ~10 bacteria/ml (so culture is the most sensitive test for sputum).

specificity

• Specificity is 98% if the AFB smear positive.
• Specificity is 95% if the AFB smear is negative. If the AFB smear is negative and the patient has low pretest probability of tuberculosis, then a positive PCR could represent a false-positive. (Murray 2022)

use of sputum PCR

• (1) Clarify the results of a positive AFB smear. In a patient with a positive AFB smear, PCR may rapidly help sort out whether the patient is likely to have tuberculosis or NTM (nontuberculous mycobacteria).
• (2) Evaluation of a patient with a negative AFB smear. In a patient with suspected active pulmonary tuberculosis, at least one sputum specimen should be sent for PCR (even if AFB smears are negative).
• (3) Rifampin resistance may be determined simultaneously using the GeneXpert system. This may provide early information regarding whether the patient has drug-resistant TB, but it's not infallible (false-positive results for rifampin resistance can occur, especially if there are very low levels of bacilli in the specimen). (Behr 2022) Most TB strains that are resistant to rifampin are also resistant to isoniazid, so detection of rifampin resistance implies the presence of multidrug resistant TB (MDR-TB). (34752322)
• (PCR shouldn't be used to monitor either treatment response or patient contagiousness after initiation of therapy.) (Behr 2022)

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AFB culture

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sputum AFB culture

• Performance:
  • Sensitivity is ~90%.
  • Specificity of ~98%. A single positive culture is generally considered definitive for active disease. However, cross-contamination may be possible, so the specificity isn't 100%. (Behr 2022)
• Culture takes some time:
  • Cultures in liquid media require ~2 weeks.
  • Cultures in solid media (not preferred currently) take 2-8 weeks.
• Culture is important to determine the sensitivity pattern against various antibiotics.
• PCR may be applied to positive culture results, to expedite the identification of TB and the identification of antibiotic resistance (e.g., using the Xpert MTB/RIF assay, as discussed above).

culture of non-sputum specimens 

• Yield is higher with tissue (e.g., pleural or pericardial biopsy).
• Yield is lower with pleural fluid or pericardial fluid. However, larger volumes of fluid may improve yield.

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bronchoscopy

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bronchoscopy is generally not indicated

• Bronchoscopy may sometimes be considered for patients who are not spontaneously expectorating sputum. However, bronchoscopy solely with the goal of inclusion/exclusion of tuberculosis is not evidence-based. Available data indicate that induced sputum has equivalent, or even higher sensitivity as compared to bronchoscopy. (19487708, Shah 2019; 7582296, 17479935, Behr 2022, 32450826)

indications for bronchoscopy

• (1) Broad differential diagnosis (e.g., tuberculosis vs. fungal infection).
• (2) Bulky mediastinal/hilar lymphadenopathy:
  • Bronchoscopy may allow for simultaneous bronchoalveolar lavage and also transbronchial needle aspiration (TBNA) to sample lymph nodes.
  • This may carry a risk of promoting the formation of a fistula between the bronchus and tuberculous lymphadenitis, but this risk is often acceptable in order to secure an accurate diagnosis. (32252934)
• 💡 If bronchoscopy is performed, three samples should ideally be sent for analysis: bronchoalveolar lavage (BAL), bronchial washings, and post-bronchoscopy sputum.

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tuberculin skin test (aka, mantoux test, PPD)

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utility among inpatients with suspected active TB

• Guidelines don't recommend using either tuberculin skin testing or IGRA (interferon gamma release assay) to evaluate for active tuberculosis. (Behr 2022)
• Tuberculin skin testing has limited sensitivity and specificity (as discussed further below). Therefore, tuberculin skin testing may be considered only as a risk-stratification test in the evaluation of a patient who may have active tuberculosis. (Murray 2022) This is never intended to replace sputum evaluation (which remains the primary test for active pulmonary tuberculosis).
• Performance of skin testing may vary depending on the chronicity and stage of tuberculosis (for example, skin testing has increased sensitivity for tuberculous pleural effusion).

technique

• Purified protein derivative (PPD) should be injected intradermally, leading to a small wheal and flare reaction (subcutaneous administration may lead to a false-positive result).
• The test is read 48-72 hours later.
• The skin test is interpreted based on induration (not erythema). Running a pen over the skin may help delineate the induration.

general interpretation of the tuberculin skin test

• >5 mm may be considered positive if:
  • HIV positive.
  • Status post transplant.
  • Therapeutic TNF-inhibitor.
  • >15 mg/day prednisone for >1 month.
  • Close exposure with active pulmonary tuberculosis.
  • Fibrotic opacities in the upper lobes suggestive of prior tuberculosis.
• >10 mm may be considered positive if:
  • Malnutrition (weight <90% ideal body weight).
  • Diabetes, chronic renal failure, status post gastrectomy, malignancy, or silicosis.
  • Exposure is more likely (homelessness; IV drug use; resident or staff in a hospital, prison, nursing home, or shelter).
  • Prior residence in a high-prevalence country.
• >15 mm may be considered positive in other people. Induration >15 mm almost always reflects true exposure to tuberculosis (e.g., BCG vaccine is unlikely to cause this extent of induration).

sensitivity

• In the context of active tuberculosis:
  • 80% sensitivity in immunocompetent person.
  • 60% sensitivity in the presence of HIV.
• Factors which may reduce sensitivity include:
  • Improper administration.
  • Sarcoidosis.
  • Recent vaccination with a live virus (e.g., measles).
  • Systemic infection (viral, bacterial, or fungal) or recent viral infection.
  • HIV (especially with lower CD4 counts).
  • Immunosuppression, including chronic steroid use.
  • Alcoholism, chronic renal failure, malnutrition, malignancy, older age.
  • Recent exposure to tuberculosis (<8-10 weeks previously).

specificity

• A skin test reflects only prior exposure to tuberculosis – it cannot differentiate latent tuberculosis from active tuberculosis.
• Causes of a positive reaction include:
  • Prior exposure to tuberculosis.
  • Active tuberculosis.
  • Prior BCG vaccination, or use of BCG as therapy for malignancy.
  • Exposure to NTM (nontuberculous mycobacteria).

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IGRA – interferon gamma release assay

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basics

• This is a laboratory test that evaluates the production of interferon gamma in response to stimulation with antigens from tuberculosis. These tests cannot distinguish between latent infection versus active TB.
• Advantages of IGRAs over skin testing:
  • (1) IGRA isn't confounded by prior exposure to BCG (which is used as a tuberculosis vaccine in some countries, or for therapy against certain malignancies).
  • (2) IGRA contains an internal positive control to determine if there is global anergy due to immunosuppression.
  • (3) IGRA may have higher sensitivity among immunocompromised patients. (ERS handbook 3rd ed.)

sensitivity

• Sensitivity for active tuberculosis: ~80%.
• Quantiferon gold tests reactivity to a nonspecific mitogen. If this is unreactive, it suggests generalized immune anergy – in which case the sensitivity of the overall test is lower.
• Causes of false-negative include:
  • HIV (especially with lower CD4 counts).
  • Active tuberculosis (anergy).
  • Immunosuppression (especially biologic agents).

specificity

• Overall specificity is high (~95%).
• Specificity may be somewhat greater if the assay is strongly positive.
• IGRA assays are not confounded by prior BCG vaccination or MAC (Mycobacterium avium complex). However, IGRA can be positive due to some nontuberculous mycobacteria (e.g., M. kansasii, M. szulgai, M. marinum).

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treatment of active tuberculosis

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empiric therapy?

• Broad utilization of empiric therapy made more sense in a bygone era where the only test for tuberculosis was culture on solid media (which could take up to 6 weeks). With modern diagnostic tests (e.g., PCR and liquid broth culture, with results in <2 weeks), empiric therapy makes less sense.
• For immunocompromised patients presenting with CAP (community-acquired pneumonia), empiric therapy for possible TB is not suggested. However, an exception would be a patient with HIV and a history of recent TB exposure who presents with severe CAP, as well as clinical and radiological features compatible with tuberculosis. (32561442) 
• Empiric therapy may be sensible for a patient with miliary disease that is progressing to ARDS, in the appropriate clinical context.

usual therapy

• Induction therapy typically involves a four-drug combination (RIPE) for two months, as listed below. This is often followed by a continuation phase, including dual therapy with isoniazid and rifampin.
  • Isoniazid 300 mg/day plus pyridoxine 50 mg/day (pyridoxine decreases the risk of peripheral neuropathy).
  • Rifampin 600 mg/day 💉 (reduces relapse, allowing for a shorter course of therapy).
  • Pyrazinamide 25 mg/kg.
  • Ethambutol 15 mg/kg.
• Monitoring for hepatotoxicity:
  • Liver function tests should be obtained at baseline and monitored serially.
  • Rifampin, isoniazid, and pyrazinamide are all potentially hepatotoxic. However, the complication rate of these medications is generally not increased among patients with liver disease.
  • For symptomatic hepatitis or transaminitis >5 times the upper limit of normal, treatment may need to be discontinued, with subsequent reintroduction of medications individually. (Fishman 2023)
• Chronic monitoring and tapering/adjustment of antibiotic therapy is generally directed by an infectious diseases consultant.
• All patients should be screened for HIV.

MDR & XDR TB 

• MDR (multidrug resistant TB)
  • Defined as resistance to at least isoniazid and rifampin.
• XDR (extensively drug-resistant TB)
  • Defined as resistance to at least isoniazid, rifampin, any fluoroquinolone, and at least one second-line injectable drug (amikacin, capreomycin, kanamycin).

steroid may be indicated in selected cases of extrapulmonary TB:

• Potential indications:
  • CNS tuberculosis (primary indication for steroid; more on this below).
  • TB iridocyclitis.
  • TB pericarditis (steroid usually isn't used).
  • TB lymphadenitis (e.g., if enlarged lymph nodes are obstructing or threatening to obstruct bronchi). (ERS handbook 3rd ed.)
• Steroids should be combined with effective antimicrobial therapy for TB (in collaboration with infectious disease specialists).

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tuberculous meningitis

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basics

• Tuberculous meningitis can occur in patients who are immunocompetent, although immunosuppressed patients may have an accelerated disease course.
• Most patients have evidence of tuberculosis elsewhere, as well as within the CNS.
• Meningitis accounts for ~75% of CNS tuberculosis presentations, whereas the remaining ~25% are due to tuberculomas (space-occupying granulomas). (31964490)

clinical presentation

• Tuberculous meningitis may present as an insidious chronic meningitis or as an acute fulminant meningitis. (34623101) Symptoms often follow a systemic prodrome lasting >6 days. (34623095) Clinical features may include the following:
• Meningeal symptoms: Fever (~80%), headache, neck stiffness.
• Basilar meningitis:
  • Cranial nerve palsies. CN VI is most commonly affected (35%), followed by CN VII and CN III. (34623105)
  • Infarction due to vasculitis involving the basilar vessels may occur in ~30% of cases. Basal ganglia infarcts often occur, which may cause dystonia, tremor, or chorea. (34623105)
• Obstruction to CSF flow may cause clinical hydrocephalus (which may lead to stupor and coma).
• Seizures occur in roughly a third of patients, usually >1 month after disease onset.
• Subacute myeloradiculopathy (aka tuberculous spinal arachnoiditis) can occur, with inflammatory exudates surrounding the spinal cord and nerve roots. (33522738)
• Hyponatremia occurs in about half of patients, mostly due to SIADH (syndrome of inappropriate antidiuretic hormone secretion). (34623105)

lumbar puncture

• Basic tests:
  • A lymphocytic pleocytosis is typically seen (e.g., 10-500 cells/mm3). However, more dramatic pleocytosis is also possible. (27321918) Alternatively, cell counts may rarely be normal, due to severe immunosuppression. (34623105, 34623101)
  • Protein is significantly elevated (e.g., 100-500 mg/dL). Strikingly elevated protein levels may indicate spinal block. (34623097)
  • CSF glucose is reduced in >80% of patients, sometimes severely. (34623101)
  • Opening pressures are usually elevated.
• Specific testing:
  • CSF PCR may allow for prompt diagnosis, with ~50-90% sensitivity (varying depending on the specific assay). (31964490) This is the best test for rapid diagnosis of tuberculous meningitis.
  • CSF microscopy for AFB (acid-fast bacilli) has a sensitivity of ~15%.
  • CSF culture has a higher sensitivity (~50%), but it's extremely slow to grow. (33896533) Nonetheless, cultures should be obtained, since it may eventually be useful to help guide antibiotic selection. Obtaining multiple specimens with high volume may increase yield. (34623097)

imaging: CT scan

• CT may be normal initially.
• Hydrocephalus may occur, commonly also with effacement of the basal and Sylvian cisterns. (31964490)
• Contrasted CT may show enhancement of the basal leptomeninges (with or without calcifications). Precontrast basal hyperdensity may also occur.
• Infarctions may be seen.
• Tuberculomas may be seen (more on this in the section below). (31964490)

imaging: MRI 

• FLAIR sequences are more sensitive than CT for detection of exudates in the basal cisterns.
• Contrast administration may reveal thick, nodular, intense enhancement along the cisterns and extending into the Sylvian fissures (figure below). (31964490)
• MRI is more sensitive than CT scan for infarctions (seen in ~40% of patients, often in the periventricular or basal ganglia). (31378872)

differential diagnosis of basilar meningitis

• Infections, especially:
  • Tuberculosis.
  • Fungal meningitis.
• Neurosarcoidosis.
• Meningeal carcinomatosis; lymphoma.

diagnostic criteria: uniform case definition for tuberculous meningitis

• Diagnostic criteria should never be utilized rigidly. However, criteria may be useful to organize clinical and imaging data, especially for clinicians without extensive experience with tuberculous meningitis.
• To be eligible for application of these criteria, patients should have signs and symptoms of meningitis. Additionally, alternative diagnoses should be excluded (e.g., bacterial and cryptococcal meningitis).
• Criteria are listed below. For patients in whom neuroimaging is obtainable, the total score may be interpreted as follows:(34623101)
  • Definite diagnosis: requires microbiological confirmation of tuberculosis.
  • Probable diagnosis: Score of 12 or higher.
  • Possible diagnosis: Score of 6-11.
• Clinical criteria (maximum subscore of 6)
  • Symptom duration >5 days: 4 points.
  • Systemic symptoms suggestive of TB (including weight loss, night sweats, or cough >2 weeks): 2 points.
  • Close contact with someone with TB in the past year: 2 points.
  • Focal neurologic deficit (other than cranial nerve palsies): 1 point.
  • Cranial nerve palsy: 1 point.
  • Altered consciousness: 1 point.
• CSF criteria (maximum subscore of 4)
  • Clear appearance: 1 point.
  • 10-500 cells/mm3: 1 point.
  • Lymphocytic predominance: 1 point.
  • Protein >100 mg/dL: 1 point.
  • CSF-to-plasma glucose ratio <50%, or absolute CSF glucose <40 mg/dL: 1 point.
• Neuroimaging (maximum subscore of 6)
  • Hydrocephalus: 1 point.
  • Basal meningeal enhancement: 2 points.
  • Tuberculoma: 2 points.
  • Infarct: 1 point.
  • Precontrast basal hyperdensity: 2 points.
• Evidence of TB elsewhere (maximum subscore of 4)
  • Chest x-ray suggestive of active tuberculosis:
    • Signs of TB: 2 points.
    • Miliary TB: 4 points.
  • Imaging evidence of TB outside of the central nervous system: 2 points.
  • Acid-fast bacilli identified, or TB cultured from another source (e.g., sputum, lymph node): 4 points.
  • Positive TB PCR from outside of the central nervous system: 4 points.

management

• ⚠️ Airborne isolation should be instituted, since ~40% of patients may have concurrent pulmonary tuberculosis. (27321918)
• Multidrug therapy for tuberculosis is needed (e.g., rifampin, isoniazid, pyrazinamide, ethambutol).
• Adjunctive steroid
  • Steroid is generally recommended, due to studies demonstrating a mortality benefit.
  • For example, 20-40 mg/day prednisolone may be used, with a gradual taper off over 2-6 months. (Shah 2019)
  • Steroid might not be safe in the context of immunosuppression (e.g., TB plus HIV).
• Hydrocephalus may require drainage (e.g., with a ventriculoperitoneal shunt).
• Aspirin has been demonstrated to reduce the risk of ischemic stroke. (34623101)
• HIV & TB meningitis therapy is discussed further below. 📖
• Hyponatremia may require therapy.
• A checklist has been published that may help guide management. (31984242) It's freely available here: 📄

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tuberculomas

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basics

• Tuberculomas are granulomatous reactions which develop into space-occupying lesions. (31964490) They are usually <1 cm, with 10% of lesions 1-3 cm. (34623101) One-third of patients have a solitary lesion, but most have several lesions.

epidemiology

• Tuberculomas occur in 10% of patients with tuberculous meningitis. (34623101)
• They may occur as the sole manifestation of tuberculosis.
• Tuberculomas can emerge or enlarge following initiation of treatment of tuberculosis (as a feature of immune reconstitution inflammatory syndrome).

clinical presentation may include: 

• Focal neurologic deficits (which vary, depending on location).
• Headache, fever.
• Seizures are common.

imaging

• Imaging findings may evolve over time, depending on the stage of the tuberculoma (table above). Differentiation from other infectious diseases (e.g., toxoplasmosis) can be challenging.
• On CT:
  • Tuberculomas often appear as one or more round/lobulated hyperdensities.
  • Chronic lesions may have central calcification. Central calcification surrounded by hypodensity with rim enhancement may create a “target sign.”
  • Contrast may reveal punctate, ring-enhancing, or solid lesions.
• On MRI:
  • Lesions may be hypointense on T2 (reflective of a solid caseating lesion) or hyperintense on T2 (reflective of a liquified lesion).
  • Contrast administration causes irregular ring enhancement.
  • Larger lesions with liquified cores may show restricted diffusion.

lumbar puncture

• CSF is generally normal, in the absence of simultaneous tuberculous meningitis.

treatment

• Treatment is generally similar to that of tuberculous meningitis (as discussed above). This involves initiation of a multidrug regimen against TB, often along with adjunctive steroid.

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TB in the context of HIV

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imaging of TB varies depending on the CD4 count: 

CD4 >200-350/uL: resembles post-primary TB

• Upper lobe predominant disease with cavitation.
• Endobronchial spread may be seen as tree-in-bud opacities. (Shepard 2019)
• Lymphadenopathy is uncommon.
• Miliary disease is uncommon.
• (More on postprimary TB radiology: 📖)

CD4 <200-350/uL: resembles primary or primary-progressive TB

• Basics:
  • The immune system is unable to contain the infection. This commonly leads to dissemination beyond the lungs (including miliary tuberculosis 📖). Progressive primary infection may occur.
• Symptoms: Patients may have usual symptoms of tuberculosis (e.g., chronic productive cough, night sweats, fever, and weight loss). However, nonspecific symptoms may overshadow pulmonary symptoms.
• Microbiological diagnosis:
  • Sputum smear for acid-fast bacilli may have low yield (due to a lack of cavitation). Sputum or bronchoalveolar lavage fluid is often smear-negative, yet culture positive. (ERS handbook 3rd ed.) PCR testing may improve yield.
  • Tuberculin skin test is often negative.
  • Mycobacterial blood cultures may occasionally be positive.
  • In some cases, tissue biopsy may be needed for diagnosis (e.g., lymph node biopsy). (Shah 2019)
• Radiology: (Murray 2022)
  • Cavitation is uncommon, especially when the CD4 count is <200/uL.
  • Opacities may predominate in the middle or lower lung, or diffuse opacities may occur.
  • Lymphadenopathy is frequently seen (e.g., ~80% on CT scan). Mediastinal lymphadenopathy is more frequent (as opposed to the usual hilar lymphadenopathy). (Shah 2019)
  • Pleural effusions can occur.
  • A miliary pattern may be seen. (Shepard 2019)
  • (More on the radiology of primary tuberculosis: 📖)

CD4 <50 cells/uL: increasingly nonspecific/subtle

• Radiologic findings become increasingly nonspecific, potentially including:(Shepard 2019)
  • Diffuse consolidation.
  • Ground glass opacities.
  • Pleural effusion.
  • Miliary tuberculosis.
• Chest X-ray may be normal, which is a poor prognostic sign (the body isn't reacting to the presence of tuberculosis). CT scan among such patients will generally reveal abnormalities (e.g., lymphadenopathy, miliary nodules). (Walker 2019)

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treatment of TB & untreated HIV 

• Antiretroviral therapy should generally be initiated within 2 weeks for patients with a CD4 count <50, or by 8-12 weeks for patients with a CD4 count >50.
• Patients with tuberculosis infection of the central nervous system usually shouldn't begin antiretroviral therapy during the first 2 months of anti-TB treatment (since that would lead to a very high risk of morbidity due to CNS inflammation as a result of immune reconstitution inflammatory syndrome).

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

Guide to emoji hyperlinks 

•  = Link to online calculator.
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•  = Link to IBCC section about a drug.
•  = Link to IBCC section covering that topic.
•  = Link to FOAMed site with related information.
• 📄 = Link to open-access journal article.
• = Link to supplemental media.