Extrapulmonary Tuberculosis

What's on this Page

7 Interesting Facts of Extrapulmonary Tuberculosis

Extrapulmonary tuberculosis is infection caused by Mycobacterium tuberculosis that affects organs and tissues outside the lung parenchyma
Common sites of infection include lymph nodes, pleura, pericardium, central nervous system, bones and joints, and abdominal organs
Symptoms can be constitutional such as fever, malaise, anorexia, and weight loss and/or specific to site of extrapulmonary infection
Definitive diagnosis can only be made by showing presence of Mycobacterium tuberculosis in patient specimen via culture or polymerase chain reaction
- Several ancillary diagnostic tests including biomarker assays and imaging techniques are useful in cases of paucibacillary specimens
Treatment of most cases of extrapulmonary disease involves 6-month standard therapy with antituberculosis drugs including isoniazid, pyrazinamide, rifampin, and ethambutol
- 9- to 12-month therapy is recommended for central nervous system tuberculosis, with the addition of corticosteroids for the first 4 to 8 weeks
- 9-month therapy is recommended by some experts for bone and joint tuberculosis
Complications vary by site of infection and include:
- Esophagomediastinal fistula and tracheoesophageal fistula in tuberculous lymphadenitis
- Fibrothorax in pleural tuberculosis
- Tamponade (early) or constrictive pericarditis (late)
- Tuberculous vasculopathy, luminal thrombosis, and stroke in central nervous system disease
- Paraplegia or tetraplegia and kyphosis in spinal tuberculosis
- Infertility, hydronephrosis, and interstitial nephritis in genitourinary tuberculosis
- Obstruction, perforation, and fistula formation in gastrointestinal disease
Prognosis is generally favorable for most extrapulmonary sites of infection if prompt treatment is initiated
- Central nervous system infection carries a higher risk of mortality than other sites of infection
- Undetected, untreated progressive miliary disease is usually fatal

Pitfalls

Experienced clinicians are key to establishing diagnosis and guiding therapy as extrapulmonary tuberculosis manifestations may be hard to recognize and differentiate from other conditions
Progressive miliary tuberculosis may present as generalized sepsis or acute respiratory distress syndrome; if chest radiograph does not show typical millet-seed pattern, diagnosis may be missed without a high index of suspicion

Extrapulmonary tuberculosis is infection caused by Mycobacterium tuberculosis that affects organs and tissues outside the lung parenchyma
- Accounts for approximately 20% of cases of tuberculosis in the United States
  - Lymphatic system, bones and joints, and pleura are the most common sites involved
  - Occurs in 15% of immunocompetent patients with tuberculosis and in 50% to 70% of immunocompromised patients with tuberculosis
- Multiple extrapulmonary sites may be involved clinically or subclinically

Classification

By site
- Tuberculous lymphadenitis (Related: Tuberculous Lymphadenitis)
  - Lymph nodes are the most common site of extrapulmonary infection
  - Accounts for 8.5% of all tuberculosis cases in the United States
- Pleural tuberculosis
  - 1 of the most common sites of extrapulmonary infection
  - Accounts for approximately 5% of tuberculosis cases in the United States
  - May be a manifestation of early postprimary infection (ie, serofibrinous pleurisy, usually in adolescents or young adults), or may occur in the setting of chronic pulmonary tuberculosis (usually in older adults)
- Tuberculous pericarditis
  - May occur as a result of direct extension from a pulmonary, pleural, mediastinal, or spinal focus, or by miliary spread
  - Uncommon manifestation but may be acutely life-threatening
  - Accounts for fewer than 1% of tuberculosis cases and fewer than 5% of pericarditis cases in the United States; most common cause of large pericardial effusions in Africa and Asia
- Nervous system tuberculosis (Related: Central Nervous System Tuberculosis)
  - Meninges are the most common site of infection in the nervous system, but it may also occur in the brain (tuberculoma) and spinal cord (arachnoiditis)
  - Accounts for 5% to 10% of extrapulmonary cases worldwide
- Bone and joint tuberculosis
  - Vertebrae (Pott disease) and weight-bearing bones and joints are most commonly affected
  - Accounts for 2.2% to 4.7% of all tuberculosis cases and 10% to 15% of extrapulmonary cases in the United States and Europe
- Abdominal tuberculosis
  - Peritoneal tuberculosis
    - May occur in conjunction with infection of abdominal or pelvic organs
    - Accounts for about 5% of extrapulmonary cases in the United States and about 1% to 2% of all cases worldwide
  - Gastrointestinal tuberculosis
    - May involve any portion of the gastrointestinal tract
    - Uncommon in the modern era
  - Genitourinary tuberculosis
    - Accounts for less than 5% of cases of extrapulmonary tuberculosis in the United States and the United Kingdom
- Miliary tuberculosis (widespread disseminated tuberculosis)
  - Widespread progressive infection caused by lymphohematogenous dissemination
  - May occur early in the course of disease (most common in children), or in chronic infection in the context of diminished immune function (eg, advanced age, immunosuppression)
  - Accounts for approximately 3% or less of tuberculosis cases

Diagnosis

Clinical Presentation

History

Patients may have a history of tuberculosis contacts or a personal history of tuberculosis infection; up to one-half of patients have concurrent active pulmonary tuberculosis
- As with pulmonary tuberculosis, extrapulmonary disease occurs more commonly in undeveloped countries; in developed countries, it is more common in immigrants from more highly endemic areas
Patients may initially present with constitutional symptoms that include fever, night sweats, anorexia, and weight loss
Clinical manifestations of extrapulmonary disease also include symptoms specific to organ system affected; symptoms of multiple sites, including pulmonary symptoms (eg, hemoptysis, chest pain) may occur concurrently
Tuberculous lymphadenitis
- Presentation includes painless chronically swollen lymph nodes
- Additional nonspecific constitutional symptoms include fever, weight loss, and night sweats (more common in patients with HIV)
- Typical duration of symptoms from time of presentation is 1 to 2 months
Pleural tuberculosis
- Commonly presents as an acute illness with symptoms that include dyspnea, cough, chest pain (pleuritic), and fever
Tuberculous pericarditis
- Onset may be subtle, with gradually progressive dyspnea and pedal edema
- Occasionally presents abruptly, with symptoms of tamponade: extreme dyspnea, chest pain, abdominal pain, light-headedness, or syncope
Nervous system tuberculosis
- Tuberculous meningitis (infection of the meninges)
  - Initial symptoms include malaise, headache, and fever followed by stiff neck, altered mental status, and—in some cases—symptoms associated with cranial nerve involvement (eg, diplopia)
  - Eventually disease leads to focal neurologic deficits and deterioration of mental status into stupor or coma
  - May progress rapidly to fulminant disease and death or may take a more indolent, chronic course over weeks or months
- Intracranial tuberculomas (conglomerate caseous foci that form in the brain)
  - Symptoms depend on location within the brain
  - Common presentations include headache and seizures
- Spinal arachnoiditis (inflammatory disease that results in encasement at various levels of the spinal cord)
  - Clinical manifestations of nerve root or cord compression including pain or paresthesia, distal muscle weakness, and bowel or bladder dysfunction
Bone and joint tuberculosis
- Tuberculous vertebral osteomyelitis (Pott disease)
  - Symptoms are typically insidious, and disease progression is slow
  - Symptom duration is typically 2 to 7 months
  - Back pain is most common symptom and occurs in 83% to 100% of cases
  - Fever and other constitutional symptoms are much less common unless extraspinal regions are also affected
- Peripheral osteoarticular tuberculosis
  - Presents as progressive chronic discomfort and swelling, most commonly as monoarthritis of hip or knee (90% of cases)
  - Fever and systemic symptoms are not usually present
Abdominal tuberculosis
- Tuberculous peritonitis
  - Symptoms include abdominal distention, abdominal pain, and fever
- Genitourinary tuberculosis
  - When associated with renal involvement, infection may be asymptomatic or present with dysuria, hematuria, or flank pain
  - Female genital tuberculosis may present with pelvic pain and vaginal bleeding
  - Male genital tuberculosis may present with lower urinary tract symptoms or with testicular swelling and discomfort
- Gastrointestinal tuberculosis
  - Commonly presents with abdominal pain accompanied by diarrhea, weight loss, and fever
  - Melena and rectal bleeding may also be present
Miliary disease presents as a systemic illness with fever, weight loss, and other constitutional symptoms
- May be accompanied by localizing signs of specific organ system involvement (eg, cough, chest pain, respiratory distress, headache, abdominal pain) or by the appearance of generalized sepsis without a clear focus, or may present as an indolent but progressive fever of unknown origin

Physical examination

Physical examination may show evidence of more than 1 site of extrapulmonary tuberculosis with or without findings of active pulmonary disease
Tuberculous lymphadenitis
- Physical examination finds 1 or several lymph nodes that are larger than 2 cm in diameter
  - Most common site is the cervical region; supraclavicular and submandibular sites are also common
  - Usually asymmetrical
  - Nodes are typically nontender and may or may not be fluctuant
  - May be associated with sinus tract drainage
Pleural tuberculosis
- Physical examination may find dullness to percussion, decreased breath sounds, and/or a pleural friction rub
Tuberculous pericarditis
- Neck vein distention, muffled heart tones, and peripheral edema are typical; a diastolic knocking sound is heard in some cases of chronic constrictive pericarditis and the presence of ascites is a common finding
- With tamponade, patients may exhibit altered mental status, paradoxical pulse (decrease in systolic blood pressure by more than 10 mm Hg during inspiration), and cool cyanotic extremities
Nervous system tuberculosis
- Tuberculosis meningitis
  - Physical examination may show confusion or altered level of consciousness, cranial nerve defects, meningismus, focal weakness, or movement disorders (eg, tremors)
  - Funduscopy may find choroid tubercles, which are more common in tuberculous meningitis associated with miliary tuberculosis
- Intracranial tuberculomas
  - Physical findings (eg, focal weakness) depend on location of the lesion; papilledema may be evident in advanced cases
- Spinal arachnoiditis
  - Common signs include peripheral neurologic deficits: decreased sensation, weakness (eg, paraplegia, hemiplegia, tetraplegia), and bladder distention
Bone and joint tuberculosis
- Vertebral osteomyelitis
  - Physical findings may include focal tenderness over the involved spine, gibbus formation (spinal deformity caused by collapse of infected vertebral bodies), as well as neurologic deficits such as paraplegia
  - Occasionally, cold abscesses in paraspinal tissues dissect to the skin, forming areas of fluctuance with or without fistulous tracts; these may erupt far from the site of vertebral involvement
- Peripheral osteoarticular tuberculosis
  - Boggy effusion with impaired range of motion
  - Draining fistula may be evident
Abdominal tuberculosis
- Tuberculous peritonitis
  - Patients may have abdominal wall rigidity caused by peritoneal irritation, and occasionally patients may present with an inflammatory abdominal mass
  - Doughy abdomen is characteristic on palpation
- Gastrointestinal tuberculosis
  - Physical examination may find a palpable mass in the right lower quadrant (found in 25%-50% of patients)
- Genitourinary tuberculosis
  - Males may present with scrotal swelling; females may present with a palpable adnexal mass
Miliary disease
- Findings may be nonspecific (eg, fever, cachexia) or may reflect involvement of a specific organ system or anatomic region
- Presence of choroidal tubercles is pathognomonic; these tubercles appear on funduscopic examination as yellow lesions with indistinct borders, singly or in clusters
- Lymphadenopathy and hepatosplenomegaly are often prominent, particularly in children

Causes

Extrapulmonary spread of primary pulmonary infection caused by Mycobacterium tuberculosis, either by the lymphohematogenous route, direct extension of a contiguous focus, or mucosal inoculation by infectious secretions

Risk factors and/or associations

Age

Overall, mean age in patients with extrapulmonary disease in the United States is 44 years
Tuberculous lymphadenitis
- Peak age of onset is 20 to 40 years
Pleural tuberculosis
- Mean age in United States is 49.9 years
Central nervous system tuberculosis (tuberculosis meningitis)
- In populations with high tuberculosis prevalence, most cases occur between birth and age 4 years
- In populations with lower tuberculosis prevalence, most cases occur in adults
Bone and joint tuberculosis
- Tuberculous bone infections
  - Bimodal age distribution in developed countries
    - Commonly affects nonimmigrants older than 55 years in developed countries
      - People are more likely to become infected at an older age
    - Commonly affects immigrants between ages 20 and 35 years in developed countries (infection occurs before emigration)
- Tuberculous vertebral osteomyelitis (Pott disease)
  - Mean age from 45 to 60 years
  - Some studies report a bimodal age distribution
    - Peak from age 20 to 30 years when related to immigration and/or HIV infection
    - Second peak from age 60 to 70 years
Abdominal tuberculosis
- Peritoneal tuberculosis has a higher incidence in younger adults in developing countries, with an average age of 25 to 44 years
- Mean age of patients with gastrointestinal tuberculosis is 43.9 years
- Genitourinary tuberculosis generally affects adults between the second and fourth decades of life (mean age, 40.7 years)
Miliary tuberculosis is associated with 3 age groups: infants and young children; adolescents and young adults; elderly adults

Gender

Tuberculous lymphadenitis
- More common in women than men in the United States; female-to-male ratio is 1.4 to 1
Abdominal tuberculosis
- Female-to-male ratio is 1.09 to 1
In other forms of extrapulmonary tuberculosis diagnosed in the United States, males outnumber females slightly (52% of cases)

Ethnicity/race

Nonwhite populations appear to be associated with increased likelihood of extrapulmonary disease

Other risk factors/associations

HIV infection
- 20- to 37-fold greater risk of developing tuberculosis in people infected with HIV than among those without HIV infection
In developed countries, extrapulmonary tuberculosis is seen more commonly in foreign-born people

Diagnostic Procedures

Primary diagnostic tools

General approach
- Definitive diagnosis can only be made by demonstrating presence of Mycobacterium tuberculosis in patient specimens obtained from suspected sites of involvement
- Diagnosis may be difficult as sites of infection can be relatively inaccessible and contain low concentrations of organisms; however, every effort should be made to obtain a specimen that will confirm diagnosis and will be likely to yield culture growth for antimicrobial susceptibility testing
  - Acid-fast smears and mycobacterial cultures are taken on relevant clinical specimens (eg, fluids, tissue) in all cases of suspected extrapulmonary tuberculosis
    - Obtaining growth in culture allows for drug-sensitivity testing, but it may take as long as 6 weeks for growth to appear on standard media
    - Molecular techniques are often able to speed diagnosis, as are newer culture techniques and media; consult laboratory about availability and appropriate specimen collection
  - Analyze relevant body fluids for cell counts and chemistries. Tests for biomarkers such as adenosine deaminase and interferon-γ may be performed, but these tests are neither sensitive nor specific; they provide supporting but not diagnostic information
    - Adenosine deaminase on fluids from suspected site of infection (eg, cerebrospinal, pleural, pericardial, peritoneal)
    - Free interferon-γ levels on pleural and pericardial fluid in patients suspected of having tuberculosis at these sites
    - Cutoff values vary with type of fluid
  - Histologic demonstration of caseating granulomas in biopsied tissues provides supportive evidence
- All patients should have chest radiography to look for evidence of pulmonary tuberculosis
  - Other imaging studies focus on symptomatic areas to document a likely focus of infection and guide collection of tissue or fluid samples for laboratory testing
- Tuberculin skin test or an interferon-γ release assay is done as part of the initial evaluation in most patients unless there is a documented history of tuberculosis
  - Positive tuberculin skin test results or interferon-γ release assays indicate infection with Mycobacterium tuberculosis, regardless of the site of suspected infection
  - Particularly helpful in providing supporting evidence before cultures are available or in culture-negative cases
  - Tuberculin skin test result may be falsely negative in patients who are immunocompromised or those with miliary tuberculosis
- Consider testing for underlying HIV infection, which increases risk for extrapulmonary tuberculosis and complicates treatment; HIV testing is recommended for all patients in whom a diagnosis of tuberculosis is confirmed
- Routine blood tests such as CBC and blood chemistries are not diagnostic but are appropriate in work-up of patients with systemic illness; liver function tests, creatinine level, and platelet count are important baseline measurements for managing antituberculous medication
  - Anemia may be seen; WBC count may be within reference range, high, or low
  - Patients with progressive miliary disease presenting with a septic picture may have laboratory abnormalities of disseminated intravascular coagulopathy (ie, thrombocytopenia, abnormal coagulation studies)
  - Elevated alkaline phosphatase level may reflect miliary disease in the liver
  - Hyponatremia is common in advanced disease
- Additional diagnostic tools and preferred methods of detection depend on suspected site of infection
Site-specific considerations:
- Tuberculous lymphadenitis
  - Acid-fast stain and mycobacterial culture of the lymph node is the gold standard of diagnosis and should always be done first
    - Obtain polymerase chain reaction if available, as it can speed the diagnostic process and result can be positive even if culture result is negative
    - Fine-needle aspiration is a first line diagnostic technique for obtaining specimens
    - Excisional biopsy, while more invasive, has the advantage of providing histology; presence of caseating granulomas supports diagnosis
- Pleural tuberculosis
  - Acid-fast stain and mycobacterial culture of biopsied pleural tissue are the preferred diagnostic method (gold standard)
    - May use Cope or Abrams needle to obtain blind-needle biopsy
      - Pleural biopsy via thoracoscopy has been shown to improve diagnostic accuracy compared to the blind-needle method
        Provides biopsy of a larger area, higher culture yields, and visualization of entire pleural surface
    - Thoracentesis and evaluation of pleural fluid evaluation is less invasive but also less sensitive
      - Fluid is usually exudative with lymphocytic pleocytosis
      - With the exception of patients with HIV, results from microscopy of pleural fluid for acid-fast bacilli are positive in fewer than 10% of cases
      - Culture sensitivity ranges from 12% to 70%
      - Polymerase chain reaction has low sensitivity but high specificity; positive result confirms infection
      - Elevated levels of adenosine deaminase (of 40 units/L or higher) or interferon-γ (cutoff variable) support diagnosis
        Adenosine deaminase: sensitivity and specificity of 89% to 99% and 88% to 97% respectively
        Free interferon-γ: sensitivity and specificity are estimated respectively at 89% and 97%
    - Can also assess sputum for Mycobacterium tuberculosis even in the absence of obvious parenchymal involvement
      - Yield of sputum culture in induced samples approaches 55%
  - Presence of caseating granulomas in the pleura and elevated levels of adenosine deaminase or interferon-γ in pleural fluid can be considered essentially diagnostic even in the absence of positive culture results
- Tuberculous pericarditis
  - Chest radiograph may suggest a pericardial effusion, which is confirmed by echocardiogram
  - Obtain CT or MRI to evaluate for pericardial thickening
  - Perform pericardiocentesis in all patients
    - Pericardial fluid is exudative with a lymphocytic pleocytosis; fluid may be bloody
    - Acid-fast smear result is positive in less than half of cases
    - Mycobacterial culture result is positive in up to 75% of cases, using advanced techniques and media
    - Adenosine deaminase level of 40 units/L or more provides supporting evidence ⁶
    - Interferon-γ levels of 50 pg/L or higher provide supporting evidence
    - Polymerase chain reaction is of unproven value in evaluating pericardial fluid
  - Pericardial biopsy may be necessary for culture and histology if pericardial fluid is not diagnostic
- Nervous system tuberculosis
  - Tuberculous meningitis
    - Lumbar puncture is indicated in all patients in whom tuberculous meningitis is considered, unless contraindicated
      - Lymphocytic pleocytosis, elevated protein level, and low glucose level (less than 50% of plasma glucose) are characteristic
      - Definitive diagnosis requires detection of acid-fast bacilli in cerebrospinal fluid via smear or culture
      - Nucleic acid amplification is recommended as it may hasten diagnosis
        Nucleic acid assays are also indicated when risk of drug-resistant tuberculosis is high (test can specifically detect rifampicin-resistance genotype)
    - Conduct contrast-enhanced CT imaging of the brain and spine in all patients with suspected tuberculous meningitis before start of treatment or within 48 hours of therapy
  - Brain tuberculoma and spinal tuberculous arachnoiditis
    - Imaging of the brain and spine via contrast-enhanced CT scan or MRI aid in diagnosis through detection of characteristic parenchymal lesions, ventriculitis, and spinal involvement, and by providing real-time guidance for biopsy
- Bone and joint tuberculosis
  - Diagnosis of spinal tuberculosis (Pott disease) is suggested by a combination of characteristic clinical and neuroimaging findings
    - CT scan or MRI shows presence of discovertebral lesions and paravertebral abscesses
  - Confirmation of the cause requires evidence of acid-fast bacilli via microscopy or culture of patient specimen (generally obtained via CT-guided needle biopsy)
  - Diagnosis of peripheral osteoarticular tuberculosis relies on mycobacterial culture of synovial fluid, synovial tissue, or bone
    - Tissue biopsy with histology is preferable to joint aspiration alone because culture may be inconclusive
- Abdominal tuberculosis
  - Diagnosis of gastrointestinal, genitourinary, and peritoneal tuberculosis relies heavily on imaging, followed by biopsy showing acid-fast bacilli on stain and culture, as well as typical histologic findings of caseating granulomas
  - In tuberculous peritonitis, peritoneal fluid usually has a cell count of more than 400 cells/mL with a lymphocytic predominance; protein level is usually elevated
    - Acid-fast staining has a low yield (about 10%); culture may be 66% to 83% using advanced techniques
    - Adenosine deaminase level greater than 30 units/L has high sensitivity and specificity in the absence of cirrhosis or immunosuppression
    - Polymerase chain reaction is of unproven benefit in peritoneal fluid evaluation
  - In urogenital tuberculosis, urinalysis may show aseptic pyuria; mycobacterial urine culture results may be positive, but sensitivity is low
    - Early morning collection of urine improves sensitivity
- Miliary tuberculosis
  - Imaging may show classic millet-seed pattern in lungs, liver, spleen, or kidneys
  - In addition to testing clinically suspected foci, consider the following:
    - Blood cultures for mycobacteria
    - Transbronchial biopsy for mycobacterial culture and histology
    - Bone marrow biopsy for mycobacterial culture and histology
  - Progressive miliary tuberculosis may present as generalized sepsis or acute respiratory distress syndrome; if chest radiograph does not show typical millet-seed pattern, diagnosis may be missed without a high index of suspicion

Laboratory

Mycobacterial culture
- Gold standard for definitive diagnosis of Mycobacterium tuberculosis
- Allows antimicrobial susceptibility testing
Nucleic acid amplification testing
- Widely used in diagnosis of tuberculosis and can provide results within hours
- Can detect Mycobacterium tuberculosis in fluids or tissues
  - Sensitivity varies by specimen type
    - Sensitivity is high for lymph node specimens and poor for pleural and peritoneal fluid samples
  - Use on samples other than sputum may be off-label
- Some commercially available kits can detect antimicrobial resistance; consult laboratory for patients at risk of drug-resistant tuberculosis (eg, previously treated; disease acquired in Africa, Asia, Central America)
- Xpert MTB/RIF assay is currently one of the most commonly used test kits
Interferon-γ release assay
- Detect immune response to tuberculosis infection
- Confirms previous exposure to (and infection with) Mycobacterium tuberculosis
- Positive serum assay result does not necessarily indicate active infection
- Preferred when testing immunosuppressed patients, in whom tuberculin skin testing may have false-negative result
- Better for bacillus Calmette-Guérin–vaccinated patients, in whom tuberculin skin testing may be falsely positive, especially if done within 10 years of vaccination
- Preferred over skin testing for those who have low rates of returning to have skin tests read (eg, drug users, homeless persons)
- Not appropriate for children younger than 2 years; acceptable in children aged 2 to 5 years, but skin test is preferred
Biomarkers
- Adenosine deaminase assay (considered to be a marker of cell-mediated immunity) may be helpful to evaluate pleural, pericardial, or peritoneal fluid
- Interferon-γ as a biomarker has a mean sensitivity and specificity of 89% and 97%, respectively
- In general, these assays are inferior to other diagnostic tools including polymerase chain reaction and acid-fast bacilli culture and staining for confirmation of extrapulmonary tuberculosis

Imaging

Tuberculous lymphadenitis
- Contrast-enhanced CT scan of abdominal lymph nodes shows peripheral enhancement with multilocular appearance and heterogeneous attenuation compared to lymphoma
- Neck ultrasonography findings compared to lymph node metastasis include:
  - Intranodal cystic necrosis
  - Posterior enhancement
  - Homogeneity
  - Matting
Pleural tuberculosis
- Chest imaging
  - Plain radiographs show pleural effusion with or without parenchymal disease or hilar/mediastinal lymphadenopathy
  - CT scan can show associated parenchymal lesions and lymphadenopathy
  - Common CT findings include:
    - Circumferential pleural thickening (32.6% of patients)
    - Mediastinal pleural involvement (31.9% of patients)
    - Nodular thickening (8.9% of patients)
    - Pleural thickening over 1 cm (2.2% of patients)
  - Ultrasonography can show fibrin bands, septations, and loculated pleural effusion
Tuberculous pericarditis
- Findings on imaging vary with duration and extent of disease (eg, effusive versus constrictive)
  - Effusive disease
    - Chest radiographs show an enlarged cardiac silhouette
      - Findings of pulmonary tuberculosis are present in 30% of cases, pleural effusion in 40% to 50%, and mediastinal lymphadenopathy in nearly 100%
    - Echocardiography shows pericardial effusion
  - Constrictive disease
    - Radiographic evidence of pulmonary tuberculosis is often absent
    - Calcification of the pericardium, although suggestive of constrictive pericarditis caused by tuberculosis, is uncommon
    - Pericardial thickening to 3 mm or more is a common finding best seen on CT or MRI
Nervous system tuberculosis
- Tuberculous meningitis
  - Contrast-enhanced CT or MRI of brain and spine
    - Choroid plexus enhancement with ventricular enlargement suggests tuberculous meningitis
    - Diffuse, thick, meningeal enhancement is a common finding in cases of tuberculous meningitis
- Tuberculoma
  - CT scan
    - Isodense, hyperdense, or mixed-density
    - Ring-enhancement with contrast material
  - MRI
    - Mixed, mostly low-signal intensity with central zone of high intensity and surrounding high-intensity edema (T2 weighted)
    - Ring-enhancement with contrast material
- Spinal arachnoiditis
  - MRI shows obliteration of subarachnoid space, loculation of cerebrospinal fluid, loss of distinct cord outline, and matting of nerve roots
Bone and joint tuberculosis (Pott disease)
- CT scan
  - Characteristic irregularity of inferior and anterior aspect of vertebral bodies
  - Bone destruction can be seen well on CT scan including fragmentary, osteolytic, sclerotic, and subperiosteal patterns
- MRI of spine
  - Abnormal signal intensities appear hypointense on T1-weighted images
  - Abnormal signal intensities appear hyperintense on T2-weighted sequences with heterogeneous enhancement of the vertebral body
- Radiography of bones in peripheral osteoarticular tuberculosis may reveal:
  - Soft tissue swelling
  - Osteopenia
  - Periosteal thickening
  - Periarticular bone destruction
  - Late cases may show cold abscesses and fistulae
Abdominal
- Peritoneal tuberculosis
  - Common CT scan findings include:
    - Smooth peritoneal thickening with marked enhancement after contrast material
    - Densification of fat plane in mesenteric root
    - Enlargement of lymph nodes with central necrosis or calcification
- Gastrointestinal tuberculosis
  - CT scan
    - Usually shows symmetrical or asymmetrical parietal thickening and extrinsic compression by enlarged lymph nodes
    - Enlarged lymph nodes may represent heterogeneous masses associated with mesenteric thickening
- Genitourinary tuberculosis
  - Best visualized by CT or MRI
    - May reveal diffuse and asymmetrical thickening of vesical wall when affecting the bladder
    - Female genital system may show diffuse parietal thickening with marked contrast uptake as well as dilation of both uterine tubes
    - Male genital system may show cystic lesions with peripheral enhancement as well as dystrophic and nonspecific calcifications
Miliary tuberculosis
- Classic reticulonodular millet-seed pattern of small (2 mm) densities may be seen on chest radiographs; high-resolution CT is more sensitive
- CT or MRI of the abdomen and pelvis may show similar miliary pattern in liver and spleen; there also may be evidence of gastrointestinal or genitourinary infection
- CT or MRI of brain and/or spine may show evidence of meningeal involvement

Functional testing

Tuberculin skin test
- 0.1 mL (5 tuberculin units) of purified protein derivative is administered intradermally onto volar aspect of the forearm. Reaction is interpreted after 48 to 72 hours, at which time induration (not erythema) is measured
- Positive tuberculin skin test findings include:
  - Induration of 15 mm or larger if there are no known risk factors
  - Induration of 10 mm or larger in any of the following settings:
    - Children younger than 4 years
    - Foreign-born people from high-prevalence areas arriving in the United States within 5 years
    - Health care workers
    - Residents of group facilities
    - IV drug users
    - Homeless people
    - Clinical conditions that increase risk of progression to active tuberculosis
    - Children and adolescents exposed to adults in high-risk categories
  - Induration of 5 mm or larger in a person who has had recent close contact with a patient with tuberculosis, who has abnormal chest radiograph findings consistent with previous tuberculosis infection, or who is immunosuppressed
- Positive test result indicates exposure to (and infection with) Mycobacterium tuberculosis; determination of whether infection is latent or active is based on clinical presentation, chest radiograph, and other imaging and microbiologic testing
- Negative test result in an immunosuppressed person may be a result of anergy
- Not contraindicated in people who previously received bacillus Calmette-Guérin vaccination (interpretation is the same as in a person without a history of bacillus Calmette-Guérin vaccination)

Procedures

Collection of a sample of cells for identification, analysis, and culture
- Excisional biopsy: an entire lump or suspicious area is removed
- Incisional biopsy (also called core biopsy): a sample of tissue is removed with preservation of histologic architecture of sample tissue
- Needle biopsy (also called aspiration biopsy): a sample of tissue or fluid is removed with a needle without preservation of histologic architecture of sample tissue cells
Suspected tuberculosis
Uncontrolled bleeding diathesis
Bleeding at site of biopsy
Hematoma formation
Spread of infection (seeding) to adjacent tissue
Evidence of acid-fast bacilli in biopsied tissues
- Histologic analysis shows caseating granulomas accompanied by acid-fast bacilli or positive polymerase chain reaction result
- Positive culture finding confirms identification of Mycobacteria tuberculosis
Insertion of a small-gauge needle between the ribs, through the thorax, and into the pleural space to access pleural fluid for diagnostic purposes
Procedure can be done with or without ultrasonographic guidance
Presence of pleural effusion on chest radiograph, CT scan, or other imaging
Most cases of pleural effusion should be accessed and analyzed via thoracentesis owing to their infectious and neoplastic potential
- Suspected pleural tuberculosis is an indication for thoracentesis with or without pleural biopsy
No absolute contraindications
Relative complications
- Uncorrected coagulopathy
- Mechanically ventilated patient
Pain at puncture site
Bleeding (eg, hematoma, hemothorax, hemoperitoneum)
Pneumothorax
Reexpansion pulmonary edema
Infection (empyema or soft-tissue infection)
Spleen or liver puncture
Vasovagal events
Retained intrapleural catheter fragments
Fluid is exudative, with high protein levels
Polymorphonuclear cells dominate during the first 2 weeks after symptom onset, but as disease progresses, a shift toward lymphocytic predominance occurs
Acid-fast smear results are rarely positive; culture sensitivity is 12% to 70%
Elevated levels of adenosine deaminase or interferon-γ provide supportive but inconclusive evidence
Insertion of a hollow-bore needle between the vertebral bodies into the subarachnoid space to obtain a specimen of cerebrospinal fluid
Suspected meningitis
Uncontrolled coagulopathy
Skin infection at site of needle insertion
Patient at risk of brain herniation
Best predictors of precipitating herniation (even with normal CT scan result) include:
- Deteriorating level of consciousness (particularly to a Glasgow Coma Scale score of 11 or less)
- Brainstem signs (eg, pupillary changes, abnormal posturing, irregular respirations)
- Very recent seizure
Post–dural puncture headache
Back pain
Radicular injury
Infection
- Epidural abscess
- Meningitis
- Diskitis
- Vertebral osteomyelitis
Epidural hematoma
Cerebral herniation
Epidermoid tumor formation
Cerebrospinal fluid characterized by elevated protein levels and lymphocytic pleocytosis
Evidence of acid-fast bacilli on microscopy of cerebrospinal fluid
- Nucleic acid amplification tests may enhance detection
Identification of Mycobacterium tuberculosis on culture confirms diagnosis

Differential Diagnosis

Most common

Nontuberculous mycobacterial infection
- Refers to all species in the genus of Mycobacterium that result in infection, excluding Mycobacterium tuberculosis
- Similar to tuberculosis, nontuberculous mycobacterial infection commonly causes pulmonary manifestations, lymphadenitis, and skin and soft-tissue infections
- Nontuberculous mycobacterial infections are definitively differentiated from tuberculosis infection by polymerase chain reaction, culture, and gene probe assays
  - Skin test results for tuberculosis and interferon-γ release assays are negative
Sarcoidosis
- Inflammatory disease in which granulomas form in various organs, most commonly lungs and lymph nodes
- Similar systemic symptoms to tuberculous lymphadenitis and pleural tuberculosis such as fever, malaise, anorexia, and weight loss
- Distinguished from tuberculosis by biopsy of involved site that shows noncaseating granulomas with confluence
Lymphoma (Related: Hodgkin Lymphoma)
- Malignancy of the lymphatic system (Related: Diffuse Large B-Cell Lymphoma)
- Like abdominal tuberculosis and tuberculous lymphadenitis, lymphomas commonly present with lymphadenopathy, fever, weight loss, and malaise
- Both may show evidence of granulomatous inflammation
- Lymphoma is differentiated from tuberculosis by characteristic architectural and staining features; flow cytometry and other techniques refine diagnosis
Metastatic malignancy
- Spread of malignancy from primary site to contiguous or widespread foci
- Like tuberculosis, may present with pleural or pericardial effusion, ascites, regional lymphadenopathy, or vertebral collapse
- Distinguished from tuberculosis by presence of neoplastic cells in effusions or tissue
Crohn disease (Related: Crohn Disease)
- Inflammatory bowel disease that affects intestinal lining
- Similar to abdominal tuberculosis (gastrointestinal), patients with Crohn disease present with abdominal pain, diarrhea, and melena in addition to fever, malaise, and weight loss
- Most reliable technique to differentiate Crohn disease from intestinal tuberculosis is biopsy of intestinal lesions
  - Crohn disease is characterized by distortion of mucosal architecture, crypt abscesses with neutrophils, and noncaseating granulomas

How is extrapulmonary tuberculosis treated?

Eradicate infection and minimize risk of complications
Secondary goals include preventing development of drug resistance and preventing transmission to others

Disposition

Admission criteria

Far-advanced disease with a high level of asthenia that requires aggressive supportive care

Inability to adhere to treatment and isolation requirements

Criteria for ICU admission

Miliary disease presenting as sepsis or acute respiratory distress
Advanced meningeal involvement with reduced level of consciousness and seizure activity

Recommendations for specialist referral

Refer all patients to infectious disease specialist or other physician with expertise in tuberculosis management
Public health reporting is required, and public health involvement may expedite management in cases of known or suspected drug resistance

Treatment Options

Mainstay treatment of extrapulmonary tuberculosis is antituberculous medication

Multidrug regimen is always used to improve efficacy and avoid emergence of antimicrobial resistance

Patients with central nervous system infection and severe complications (eg, hydrocephalus, collapsing vertebrae with spinal cord impingement) require prompt surgical intervention

Treatment guidelines have been published by multiple entities, including WHO and National Institute for Health and Clinical Excellence; in the United States, American Thoracic Society, CDC, and Infectious Diseases Society of America guidelines prevail

Standard antituberculous drugs include isoniazid, rifampin, pyrazinamide, and ethambutol

2 months of isoniazid, rifampin, pyrazinamide, and ethambutol followed by 4 months of isoniazid and rifampin is standard for most forms of extrapulmonary tuberculosis
Duration may be extended in some cases, notably in tuberculous meningitis (9-12 months); some experts favor a 9-month duration for bone and joint disease as well
Addition of corticosteroids is recommended for the first 1 to 2 months in tuberculous meningitis and some cases of pericarditis (eg, large pericardial effusions, signs of constriction, high levels of inflammatory cells or other inflammatory markers)
Preferred treatment regimen of drug-resistant forms consists of a fluoroquinolone (moxifloxacin or levofloxacin), bedaquiline, linezolid, clofazimine, and cycloserine for a duration of 15 to 21 months after culture conversion (for pulmonary tuberculosis)

Drug therapy

Antituberculosis drugs (antibiotics)
- Isoniazid
  - Isoniazid Oral solution; Infants, Children, and Adolescents: 10 to 15 mg/kg/dose (Max: 300 mg/dose) PO once daily or 5 days/week, or alternatively, 20 to 40 mg/kg/dose (Max: 900 mg/dose) PO 3 days/week or twice weekly.
  - Isoniazid Oral tablet; Adults: 5 mg/kg/dose (Max: 300 mg/dose) PO once daily or 5 days/week, or alternatively, 15 mg/kg/dose (Max: 900 mg/dose) PO 3 days/week or twice weekly.
  - Tuberculous meningitis is treated for 9 to 12 months
- Rifampin
  - Rifampin Oral capsule; Infants and Children: 10 to 20 mg/kg/dose (Max: 600 mg/dose) PO once daily or 5 days/week, or alternatively, 3 days/week or twice weekly. 20 to 30 mg/kg/dose PO once daily may be considered for infants and toddlers or meningitis and/or disseminated disease.
  - Rifampin Oral capsule; Adolescents: 10 to 20 mg/kg/dose (Max: 600 mg/dose) PO once daily or 5 days/week, or alternatively, 3 days/week or twice weekly.
  - Rifampin Oral capsule; Adults: 10 mg/kg/dose (Max: 600 mg/dose) PO once daily or 5 days/week, or alternatively, 3 days/week or twice weekly.
  - Tuberculous meningitis is treated for 9 to 12 months
- Pyrazinamide
  - Pyrazinamide Oral tablet; Adults weighing 40 to 55 kg (lean body weight): 1 g PO once daily or 5 days/week, or alternatively, 1.5 g PO 3 days/week or 2 g PO twice weekly.
  - Pyrazinamide Oral tablet; Adults weighing 56 to 75 kg (lean body weight): 1.5 g PO once daily or 5 days/week, or alternatively, 2.5 g PO 3 days/week or 3 g PO twice weekly.
  - Pyrazinamide Oral tablet; Adults weighing 76 to 90 kg (lean body weight): 2 g PO once daily or 5 days/week, or alternatively, 3 g PO 3 days/week or 4 g PO twice weekly.
  - Pyrazinamide Oral tablet; Adults weighing more than 90 kg (lean body weight): 15 to 30 mg/kg/dose PO once daily (Max: 3 g/day), or alternatively, 50 to 75 mg/kg/dose PO twice weekly.
- Ethambutol
  - Ethambutol Hydrochloride Oral tablet; Infants† and Children†: 15 to 25 mg/kg/dose (lean body weight) (Max: 1.6 g/dose) PO once daily or 5 days/week, or alternatively, 50 mg/kg/dose (lean body weight) PO 3 days/week (Max: 2.4 g/dose) or twice weekly (Max: 4 g/dose).
  - Ethambutol Hydrochloride Oral tablet; Adolescents: 15 to 25 mg/kg/dose (lean body weight) (Max: 1.6 g/dose) PO once daily or 5 days/week, or alternatively, 50 mg/kg/dose (lean body weight) PO 3 days/week (Max: 2.4 g/dose) or twice weekly (Max: 4 g/dose).
  - Ethambutol Hydrochloride Oral tablet; Adults weighing 40 to 55 kg (lean body weight): 800 mg PO once daily or 5 days/week, or alternatively, 1.2 g PO 3 days/week or 2 g PO twice weekly.
  - Ethambutol Hydrochloride Oral tablet; Adults weighing 56 to 75 kg (lean body weight): 1.2 g PO once daily or 5 days/week, or alternatively, 2 g PO 3 days/week or 2.8 g PO twice weekly.
  - Ethambutol Hydrochloride Oral tablet; Adults weighing 76 to 90 kg (lean body weight): 1.6 g PO once daily or 5 days/week, or alternatively, 2.4 g PO 3 days/week or 4 g PO twice weekly.
  - Ethambutol Hydrochloride Oral tablet; Adults weighing more than 90 kg (treatment-naive): 15 mg/kg/dose (Max: 1.5 g/dose) PO once daily.
Corticosteroids
- Dexamethasone
  - Tuberculous meningitis or pericarditis
    - Dexamethasone Oral tablet; Infants, Children, and Adolescents: 0.3 to 0.6 mg/kg/day PO for 4 to 6 weeks, then taper over 2 to 4 weeks.
    - Dexamethasone Oral tablet; Adults: 0.4 mg/kg/day PO with a taper over 6 to 8 weeks.

Comorbidities

Diabetes mellitus
- Consider overlapping drug toxicities when tuberculosis and diabetes are both present
- Administering rifampin may reduce efficacy of oral hypoglycemic drugs, resulting in hyperglycemia
- Give pyridoxine with isoniazid during tuberculosis treatment of patients with diabetes to prevent peripheral neuropathy
Patients with renal failure and severe renal insufficiency
- There is significant renal excretion of ethambutol and metabolites of pyrazinamides, thus doses and frequency need to be adjusted
Patients with liver disorders
- Obtain liver function tests at the start of treatment and if serum ALT level is greater than 3 times reference range before initiation of treatment; limit use of hepatotoxic drugs and carefully monitor
Patients with HIV/AIDS
- Because of frequent coexistence of HIV/AIDS and tuberculosis infections, positive test result for 1 should prompt careful assessment for the other
- Clinical or radiographic worsening of confirmed tuberculosis may occur after initiation of antiretroviral therapy owing to tuberculosis-related immune reconstitution inflammatory syndrome
  - Overall, evidence favors addition of antiretroviral therapy shortly after initiation of antituberculous therapy in adults with newly diagnosed HIV and tuberculosis
  - Risk of worsening tuberculosis is doubled when comparing early and delayed initiation of antiretrovirals, but overall survival is improved with early initiation in patients with CD4 lymphocyte counts less than 0.050 × 10⁹ cells/L
  - Guidelines recommend all patients with HIV and active tuberculosis should be started on antiretroviral therapy as soon as possible if they are not already on this therapy
    - Guidelines suggest beginning antiretroviral therapy within 2 weeks of starting antituberculous treatment for people with clinically advanced HIV infection (CD4 T lymphocyte cell counts less than 50 cells/mm³) and within 8 weeks for other patients
    - However, in patients with HIV infection and central nervous system tuberculosis, postpone introduction of antiretroviral therapy until after 8 weeks of antituberculous therapy, regardless of CD4 count, because there is risk of disabling or fatal neurologic complications caused by immune reconstitution inflammatory syndrome
  - Symptoms of immune reconstitution inflammatory syndrome may be treated with antiinflammatory drugs or, if severe, with steroids
- Administer tuberculosis drugs daily rather than on an intermittent schedule
- In patients who are not receiving antiretroviral therapy, a 9-month regimen is recommended (2-month intensive phase followed by 7-month continuation phase) rather than the conventional 6-month course
- Clinically significant drug interactions occur between antitubercular drugs and antiretroviral drugs
  - Rifamycin-class drugs upregulate metabolizing enzymes and drug transporters, leading to reduced concentrations of most antiretrovirals
  - However, rifamycins should be administered for at least the first 2 months of treatment
  - Consult an infectious disease specialist to manage medical treatment of both infections

Special populations

Patients who are pregnant or breastfeeding
- Pregnancy has not been found to affect the course or successful treatment of tuberculosis
- In treatment of active disease, initial drugs used in pregnancy include isoniazid, rifampin, and ethambutol, which cross the placenta but have no known teratogenic effects
- Use of pyrazinamide in pregnant patients has not been recommended in the United States although its use in pregnant patients without adverse events has been reported in some regions
  - Pyrazinamide is a category C drug. It is recommended for use in pregnant patients by WHO and the International Union Against Tuberculosis and Lung Disease
  - Current US guidelines suggest that in pregnant patients with severe disease, extrapulmonary disease, or concomitant HIV infection, the benefit of using pyrazinamide outweighs risk
  - If pyrazinamide is not included in the initial regimen, extend therapy to 9 months
- Do not discourage breastfeeding for patients being treated for active tuberculosis as long as they are not thought to be infectious
- Pregnant or breastfeeding patients receiving isoniazid should also receive pyridoxine

Monitoring

Baseline laboratory results include platelet count and levels of hepatic transaminases, alkaline phosphatase, bilirubin, and creatinine
Follow all patients clinically at a minimum of monthly intervals
In patients with abnormal baseline laboratory results or who have risk for increased hepatic toxicity, repeat monthly or more often
If transaminase levels exceed 5 times reference level (or 3 times reference level with symptoms of hepatotoxicity), discontinue hepatotoxic drugs; consult tuberculosis expert for further evaluation and management
If ethambutol is prescribed, assess baseline visual acuity and red/green color discrimination; repeat testing monthly
Response to therapy is monitored clinically; microbiologic demonstration of cure is rarely practical in extrapulmonary disease

Complications

Tuberculous lymphadenitis (Related: Tuberculous Lymphadenitis)
- Complications are generally intrathoracic and include dysphagia, esophagomediastinal fistula, and tracheoesophageal fistula
Pleural tuberculosis
- Complications include bronchopleural fistula, empyema, and fibrothorax
Tuberculous pericarditis
- Complications include tamponade (early) and constrictive pericarditis (late)
Nervous system tuberculosis (Related: Central Nervous System Tuberculosis)
- Nervous system infection is the most severe extrapulmonary manifestation of tuberculosis
- Complications of meningitis include tuberculous vasculopathy and luminal thrombosis
  - Vasospasms may lead to stroke during progression of disease
  - Hydrocephalus is also a common complication of tuberculous meningitis
- Complications of tuberculomas and spinal arachnoiditis include focal neurologic deficits that may be severe and extensive (eg, paraplegia)
Bone and joint tuberculosis
- Most common complications of spinal tuberculosis are related to neurologic manifestations, a result of compression of the spinal cord and other nerve roots (occurs in approximately 50% of cases)
  - Paraplegia and tetraplegia are common in patients with cervical or thoracic spinal tuberculosis (occurs in approximately 10%-27% of cases)
  - Additional complications include spinal deformity (kyphosis)
    - 3% to 5% of patients will have a final deformity more than 60°
Abdominal tuberculosis
- Complications of gastrointestinal tuberculosis include obstruction, perforation, and fistula formation
- Complications of genitourinary tuberculosis affecting the female reproductive tract include infertility, menstrual disorders, and gestational complications
- Complications of genitourinary tuberculosis affecting the kidney include hydronephrosis and tuberculous interstitial nephritis leading to renal failure
- May also lead to adrenal dysfunction
  - Adrenal involvement was reported in 6% of patients with active tuberculosis in a 28-year autopsy series
Miliary tuberculosis
- Complications may be those of a specific focus (eg, meningitis), but more commonly are those of sepsis: acute respiratory distress syndrome, multiorgan failure, and death (Related: Acute Respiratory Distress Syndrome in Adults)

Prognosis

General risk factors for increased 12-month mortality in extrapulmonary tuberculosis cases include HIV infection, disseminated disease, central nervous system/meningeal disease, previous history of tuberculosis, leukocytosis, malignancy, and hyperbilirubinemia
Prognosis of lymphadenitis is generally good, although response to therapy may be slow; a significant number of patients with lymphadenitis develop paradoxical worsening 6 weeks or so into therapy
Tuberculous meningitis (central nervous system extrapulmonary tuberculosis) has a mortality rate of approximately 20%, even with aggressive antibiotic therapy; uniformly fatal without treatment
Patients without neurologic deficit and deformity with spinal tuberculosis have a generally good prognosis
- Reported mortality of spinal tuberculosis is between 0 and 6%

Screening

At-risk populations

Purpose of screening is to identify persons with latent tuberculosis infection who would benefit from preventive treatment
Routine screening of the general population is not recommended in the United States because of low prevalence and difficulty of interpreting results
2 populations should be screened:
- Those at risk of latent tuberculosis infection
- Those who would be at increased risk of progression to active disease
No gold standard screening test exists
CDC recommends that either a tuberculin skin test or an interferon-γ release assay (but not both) be administered to appropriate patients, including:
- People who are in close contact with a person who has active tuberculosis
  - Rapid contact investigation to identify these people should be coordinated by local public health departments, state public health departments, or both
- People with chest radiograph suggestive of an earlier tuberculosis infection
- Immigrants and refugees from areas of high disease prevalence
- Visitors to high-prevalence areas
- Patients who are immunosuppressed, including all people with HIV infection
- Health care workers who are exposed to high-risk patients
- Users of illicit IV drugs
- Residents of homeless shelters, correctional facilities, and long-term care facilities
- People with specific comorbidities, such as chronic renal failure; diabetes; cancer of the head, neck, or lung; leukemia; lymphoma; silicosis; and gastrectomy or jejunoileal bypass
WHO also recommends that either a tuberculin skin test or an interferon-γ release assay can be used to test for latent tuberculosis infection
Applicants for either immigrant visas or refugee status are required by US law to undergo a medical examination with tuberculosis screening before being allowed to travel to the country
- Children aged 2 to 14 years: history, physical examination, and interferon-γ release assay; add chest radiograph if interferon-γ release assay result is positive, signs/symptoms of tuberculosis are present, or in patients with known HIV infection
- Patients aged 15 years and older: history, physical examination, and chest radiograph
- Applicants of all ages require sputum culture if radiographs suggest tuberculosis
For children, the American Academy of Pediatrics advises:
- In children younger than 5 years, tuberculin skin testing is preferred (interferon-γ release assay is acceptable for children older than 2 years)
- In children aged 5 years or older and who are given bacillus Calmette-Guérin vaccine, interferon-γ release assay is preferred (but tuberculin skin testing is acceptable)
- In children aged 5 years or older and who are unlikely to return to have skin test evaluated, interferon-γ release assay is preferred (but tuberculin skin testing is acceptable)
- Combination testing (tuberculin skin test plus interferon-γ release assay) may be appropriate if:
  - Initial and repeat interferon-γ release assay results are indeterminate or invalid
  - Initial test (tuberculin skin test or interferon-γ release assay) result is negative plus 1 of the following:
    - Clinical suspicion of tuberculosis
    - Child has a tuberculosis risk factor and is at high risk of progression and poor outcome (especially therapy with an immunomodulating biologic agent such as a TNF-α antagonist)
  - Initial tuberculin skin test is positive plus 1 of the following:
    - Patient is aged 5 years or older and has a history of bacillus Calmette-Guérin vaccination
    - Additional evidence is needed to increase adherence with therapy

Screening tests

Tuberculin skin test using purified protein derivative
- Not contraindicated in people who previously received bacillus Calmette-Guérin vaccination (interpretation is same as in person without history of vaccination), but an interferon-γ release assay is preferred
- 0.1 mL (5 tuberculin units) of purified protein derivative is administered intradermally onto volar aspect of forearm. Reaction is interpreted after 48 to 72 hours, at which time induration (not erythema) is measured
- Positive screening tuberculin skin test findings include:
  - Induration of 15 mm or larger if there are no known risk factors
  - Induration of 10 mm or larger in any of the following settings:
    - Children younger than 5 years
    - Foreign-born people from high-prevalence areas arriving in the United States within 5 years
    - Health care workers
    - Residents of group facilities
    - IV drug users
    - Homeless people
    - Clinical conditions that increase risk of progression to active tuberculosis
    - Children and adolescents exposed to adults in high-risk categories
  - Induration of 5 mm or larger in a person who has had recent close contact with a patient with tuberculosis, a person with abnormal chest radiograph findings consistent with previous tuberculosis infection, or an immunosuppressed person
- Negative screening tuberculin skin test in an immunosuppressed person may be a result of anergy
Interferon-γ release assay
- Appropriate for testing patients aged 5 years or older
- Appropriate for children aged 2 years or older when initial skin test is negative but there is clinical suspicion of disease, or child has tuberculosis risk factor and is at high risk of progression and poor outcome
- Preferred when testing patients who are immunosuppressed
- Preferred for patients who have been vaccinated with bacillus Calmette-Guérin vaccine
- May be preferable when testing patients unreliable for return in 48 to 72 hours
If either tuberculin skin test or interferon-γ release assay result is positive, obtain chest radiograph
If chest radiograph result is negative, patient is considered to have latent tuberculosis infection. If chest radiograph result is positive, patient undergoes further testing to confirm or rule out active pulmonary tuberculosis

Prevention

Prevention of extrapulmonary tuberculosis rests on prevention of pulmonary tuberculosis and treatment of latent tuberculosis
Early detection and treatment of active pulmonary tuberculosis prevents transmission to contacts
- Physicians should maintain a high degree of suspicion for tuberculosis in people with clinically compatible disease who are at risk for the disease
- CDC guidelines for preventing transmission of tuberculosis in patients with suspected or proven active pulmonary tuberculosis include:
  - Outpatient setting
    - Patient should wear a simple surgical mask to prevent extrusion of exhaled droplet nuclei
  - Inpatient setting
    - Patients should be in respiratory isolation (airborne pathogen precautions, negative pressure room) until 3 consecutive negative results for sputum acid-fast bacilli smears on specimens obtained at least 8 hours apart (1 of which is obtained as an early morning specimen) have been shown
    - Visitors and health care workers should wear a fitted N95 respirator mask
    - Patients should wear a simple surgical mask to prevent extrusion of exhaled droplet nuclei
Bacillus Calmette-Guérin vaccination
- Effective in preventing miliary and meningeal tuberculosis in infants and children by preventing progression of primary infection (not available in United States)
- Routine administration is recommended in many countries worldwide when prevalence of tuberculosis is high
Treatment of latent tuberculosis prevents development of extrapulmonary tuberculosis
- Decision to treat latent infection requires balancing risk of toxicity against likelihood of developing active infection
- CDC and National Tuberculosis Controllers Association make recommendations regarding groups of patients that warrant treatment for latent tuberculosis and treatment regimens

Sources

1: Lee JY: Diagnosis and treatment of extrapulmonary tuberculosis. Tuberc Respir Dis (Seoul). 78(2):47-55, 2015