Investigations
1st investigations to order
chest x-ray
Test
Evidence of unrecognised pulmonary TB or evidence of old healed TB (e.g., upper lobe fibrosis) may be present; such abnormalities should prompt sputum collection for smear, culture, and nucleic acid amplification testing.
Abnormalities may be seen in about one-quarter of adults with TB lymphadenitis. Over 80% of children with TB lymphadenitis may have an abnormal chest x-ray.[74][79]
Patients with pleural TB will usually have a small to moderate unilateral pleural effusion; up to 20% of patients can have parenchymal abnormalities.
In skeletal TB and central nervous system TB, over 50% of patients may have chest x-ray findings compatible with prior TB.
Disseminated TB is known as miliary TB because of the chest x-ray appearance, which shows multiple 1-2 mm nodules throughout the lung fields (resembling millet seeds) that are small granulomas. While an abnormal chest x-ray may be seen in up to 85% of patients with disseminated TB, only 30% will have a miliary pattern.[69]
Result
abnormal typical for TB; abnormal atypical for TB; normal
sputum smear
sputum culture
Test
Sputum culture is performed to evaluate for pulmonary TB (and potential infectiousness). May be spontaneous or induced.
Almost 5% of HIV-negative patients with EPTB and normal chest x-ray have sputum cultures that grow out Mycobacterium tuberculosis.[43] Sputum culture may be positive in 20% to 30% of cases of pleural TB without parenchymal involvement on chest x-ray; patients with parenchymal involvement may have a positive sputum culture 50% to 95% of the time.[16][70][71]
Result
positive; no growth; other mycobacteria
FBC (full blood count)
Test
Leukocytosis (without left shift) and anaemia each seen in 10%. Other abnormalities include elevated monocyte and eosinophil counts. Lymphopenia or pancytopenia may be seen in disseminated disease.
Result
normal or low haemoglobin and leukocytosis
lymph node fine-needle aspiration
Test
Overall sensitivity exceeds 80% when specimens are sent for cytological and microbiological evaluation.
May be higher in HIV-positive patients.
Considered as initial test if fluctuant.[80][81][82]
Fine-needle aspiration may be performed with a 21- or 23-gauge needle and sent for smear, culture, and cytology.
Result
culture positive
pleural fluid analysis
Test
Pleural fluid is obtained by thoracentesis. Usually clear/straw-coloured.
Analysis will display an exudative effusion that is lymphocyte-predominant (early in the course of effusion, neutrophils may predominate).
Mesothelial cells >5% are almost never present except for HIV-infected.[76]
Usual results include a pH 7.3 to 7.4, elevated LDH, glucose <60 mg/dL.
Acid-fast bacilli (AFB) smear has very low yield while culture may be positive in about 30%. Culture sensitivity improved by bedside inoculation of a radiometric mycobacteria diagnostic system (e.g., BACTEC brand).
Adenosine deaminase (ADA) levels are frequently elevated in pleural TB (sensitivity and specificity approximately 90%).[49]
Free interferon gamma levels are frequently elevated in pleural TB. The sensitivity and specificity of free interferon gamma measurements are ≥89% and ≥97%, respectively, for detecting TB in pleural fluid.[41]
Result
clear/straw-coloured exudate; AFB smear and culture positive; elevated ADA level; elevated free interferon gamma level
ascitic fluid analysis
Test
Ascitic fluid analysis is non-specific and reveals exudate and low serum-ascitic albumin gradient (SAAG). However, in cirrhotics with TB peritonitis, low-protein ascites is seen.
A lymphocytosis (>30% lymphocytes) may be seen about half the time. Especially in cirrhotics, a polymorphonuclear count >250/mL may be seen and thus mimics spontaneous bacterial peritonitis. Ascites will rarely be acid-fast bacilli (AFB) positive (0% to 6%) and estimated sensitivity of culture ranges from 10% to 92%.[15][83]
Adenosine deaminase (ADA) levels are frequently elevated in peritoneal TB. The sensitivity and specificity of ADA are ≥79% and ≥83%, respectively, for detecting TB in peritoneal fluid.[41]
Free interferon gamma levels are frequently elevated in peritoneal TB. A meta-analysis of six studies estimated the sensitivity and specificity of elevated free interferon gamma levels in peritoneal fluid as 93% and 99%, respectively.[41]
Demonstrates how to perform diagnostic and therapeutic abdominal paracentesis.
Result
SAAG; cell count with differential; AFB smear and culture positive; elevated ADA levels; elevated free interferon gamma level
bone films
Test
Skeletal TB causes lytic destruction without sclerotic reactions.
In vertebral involvement, calcifications within paraspinous collections or anterior wedging of vertebral bodies.
If the hip or knee is involved, plain films may show subchondral erosions and joint space narrowing.
Result
normal; abnormal (including lytic areas, anterior wedging of vertebrae, joint space narrowing)
cerebrospinal fluid analysis
Test
Patients undergo lumbar puncture if central nervous system (CNS) TB is suspected or in disseminated disease to evaluate for CNS involvement.
Typical cerebrospinal fluid (CSF) profile in TB meningitis includes low cell count with a lymphocyte predominance (100-500 cells/microlitre), low glucose (40-50 mg/dL), and elevated protein (100-800 mg/dL). In the first 10 days of infection, polymorphonuclear cells may predominate.[24]
Detection of acid-fast bacilli (AFB) in CSF is improved by sending more fluid (e.g., at least 6 mL), and repeating the lumbar puncture. There are reports of the sensitivity of AFBs being 58% to 87% in TB meningitis if three or more lumbar punctures are performed. AFB culture has 70% sensitivity.[24][54][68]
Following initiation of treatment, CSF changes will be evident for 10-14 days and AFB smear may remain positive for at least 1 week.[54]
Adenosine deaminase (ADA) levels are frequently elevated in CSF.[41]
How to perform a diagnostic lumbar puncture in adults. Includes a discussion of patient positioning, choice of needle, and measurement of opening and closing pressure.
Result
low cell count with a lymphocyte predominance (100-500 cells/microlitre), low glucose (40-50 mg/dL), and elevated protein (100-800 mg/dL); AFB smear and culture positive; elevated ADA levels
urinalysis
Test
Urinalysis abnormal in more than 90% of patients with genitourinary TB including haematuria and pyuria. Pyuria without bacteriuria suggestive of TB.
Urine is sent for acid-fast bacilli (AFB) smear and culture. Nucleic acid amplification tests of the urine, where available, can be helpful adjunctive tools.[44]
Urinalysis may also be smear/culture positive in disseminated TB.
Result
white blood cell; red blood cell; AFB smear and culture positive; protein
nucleic acid amplification test (NAAT)
Test
Several rapid NAATs are available for the diagnosis of TB, and some are also able to detect resistance to some TB drugs. Although NAATs were originally designed and approved for respiratory specimens, they may also be requested on specimens from other sites where involvement of TB is suspected (e.g., cerebrospinal fluid, lymph node aspirate, lymph node biopsy, pleural fluid, peritoneal fluid, pericardial fluid, synovial fluid or urine).[42] In the US, use of NAATs for extrapulmonary specimens is not approved by the US Food and Drug Administration, and use would be off-label.
Xpert MTB/RIF and Xpert Ultra are rapid NAATs recommended by WHO as initial diagnostic tests in adults and children with signs and symptoms of EPTB.[42] They are also recommended by WHO for detection of rifampicin resistance.[42] Cochrane reviews of Xpert MTB/RIF and Xpert Ultra found that sensitivity of the tests in diagnosing EPTB varied across different site specimens, but the specificity was high.[44][45]
[ 
]
Line probe assays (LPAs) are strip-based tests that can detect TB and determine drug resistance profiles. LPAs are recommended by WHO only for detecting resistance to anti-TB drugs.[42]
Result
positive for Mycobacterium tuberculosis; negative
Investigations to consider
lymph node biopsy
Test
Total excisional biopsy can be done because there is a high risk for ulceration or sinus tract formation with incomplete biopsy.
Drains are not to be left in place.
Tissues are sent for acid-fast bacilli (AFB) smear, culture, sensitivity, and histology.
Histology cannot differentiate between TB and non-tuberculous mycobacteria.
Result
granulomas; smear or culture AFB positive
pleural biopsy
Test
Percutaneous biopsy performed with Abrams or Cope needle.
Sensitivity improves with greater number of samples (6 or more).
Acid-fast bacilli (AFB) culture (60% sensitivity) and histology (80% sensitivity) are done with combined sensitivity 87%.[76][84]
Result
granulomas; AFB smear or culture positive
synovial biopsy
Test
Synovial biopsy should be done to diagnose TB arthritis.
Biopsy may yield culture positive in 90% to 95%, and should be performed if the diagnosis of TB arthritis remains in question.[16]
Result
acid-fast bacilli smear or culture positive
liver biopsy
Test
May be useful in diagnosing disseminated TB.
May be culture positive in 40% and granulomas seen in 88% of biopsies.[71]
Result
granulomas; smear or culture acid-fast bacilli positive
bone marrow biopsy
blood culture
Test
Positive in disseminated disease in 58% of patients.[70]
Result
positive; negative
peritoneal biopsy
Test
Performed with laparotomy or laparoscopy. Good for rapid diagnosis of peritoneal TB as caseating granulomas may be seen in up to 100% and acid-fast bacilli (AFB) in 67%. Samples are submitted for culture.
Visual appearance may be highly suggestive of TB and may demonstrate yellow-white nodules, erythematous patches, or adhesions.
Blind peritoneal biopsies are not performed.[15]
Result
caseating granulomas; AFB positive
gastric aspirate
Test
Used in patients unable to produce sputum (e.g., young children). Based on overnight collection of swallowed respiratory secretions in the stomach. In early morning after 8-10 hours of fasting, 10-20 mL sterile water infused into stomach through nasogastric tube, and 50 mL aspirated. After neutralisation, the aspirate is sent for same studies as sputum.
Result
positive for acid-fast bacilli
bronchoscopy
Test
May be useful in patients who have evidence of pulmonary TB in addition to EPTB and where the diagnosis remains uncertain.
Also useful in patients with miliary TB for expedited diagnosis (smear positive or granulomas on transbronchial lung biopsies) in up to 80%.[85]
Result
positive for acid-fast bacilli
thoracoscopy
Test
Reserved for when pleural biopsy is non-diagnostic.
Thoracoscopy may show tubercles on the parietal pleura.
May be most sensitive tool for diagnosis of pleural TB and useful in assessing for malignant aetiology.[76]
Result
visual appearance; pathology results; acid-fast bacilli smear and culture results
drug susceptibility testing
Test
Performed on all initial isolates.
Susceptibility testing is to the first-line drugs (isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin) and results reported as fully sensitive, partial resistance, or full resistance depending on minimum inhibitory concentration.
If there is documented resistance to any first-line medicines, or if there is suspicion that patient has resistant strain, or if TB cultures remain positive after 3 months of treatment, susceptibility test against second-line drugs are performed. In the US, 10% to 15% of isolates are isoniazid-resistant and 1% are multidrug-resistant.
Result
drug sensitivities
genotyping
Test
Genotyping or DNA fingerprinting is useful in outbreak investigation and laboratory cross-contamination. There is evidence that some families of TB may have increased virulence. Most states offer genotyping of isolates.
Result
match with other strain
HIV test
Test
It is recommended that all patients with TB have an HIV test within 2 months of diagnosis.
HIV infection and its treatment alter the management of active TB. Treatment of HIV is crucial to the mortality and morbidity of HIV-infected TB patients.[48]
Result
positive
lateral flow urine lipoarabinomannan (LF-LAM) assay
Test
Lateral flow tests that detect lipoarabinomannan (LAM) antigen in urine have emerged as potential point-of-care tests. One Cochrane review found the lateral flow urine lipoarabinomannan (LF-LAM) assay to have a sensitivity of 42% in diagnosing TB in HIV-positive individuals with TB symptoms, and 35% in HIV-positive individuals not assessed for TB symptoms.[46] WHO recommends that LF-LAM can be used to assist in the diagnosis of active TB in HIV-positive adults, adolescents and children.[42] This approach is supported by another Cochrane review, which found reductions in mortality and an increase in treatment initiation with use of LF-LAM in inpatient and outpatient settings.[47] Culture would still be required for drug susceptibility testing (DST).
Result
positive
empiric treatment
Test
Many patients with EPTB will be started on empiric antituberculous therapy prior to a confirmation of positive TB culture, as it takes TB culture several weeks to be positive.
In a patient whose diagnosis has not been confirmed but TB suspicion remains high, an empiric initiation of TB treatment is reasonable after adequate sampling is completed (e.g., AFB smear is positive, TB PCR is positive, or pathology shows caseating granulomas but the TB culture is pending).[16]
At 2 months of treatment if there is a clinical or radiographic response and no other aetiology is present, the presumptive diagnosis of TB is made. If there is no response at 2 months of treatment, another diagnosis is sought.
Result
clinical response
CT scan chest or abdomen
Test
In peritoneal TB, CT may show ascites (wet type), bulky mesenteric thickening and lymphadenitis (dry type), or omental thickening.
In gastrointestinal TB, CT may show bowel wall thickening.
Result
abnormal
abdominal ultrasound
colonoscopy
Test
Used to diagnose TB enteritis with biopsy.
Common sites of involvement are the ileocecal and anorectal areas.
Findings on colonoscopy include ulcers, strictures, pseudopolyps, and fistulas.
Result
visual appearance; biopsy results
pericardial fluid analysis
Test
Pericardial fluid is obtained by pericardiocentesis. Pericardial fluid should be sent for acid-fast bacilli (AFB) smear (sensitivity 0% to 42%), culture (sensitivity 50% to 65%), and adenosine deaminase (ADA). Using a threshold to define an elevated ADA level of 40 U/L, the sensitivity and specificity of an elevated ADA level in pericardial fluid are 88% and 83%, respectively.[41]
Result
positive AFB smear and elevated ADA level suggests TB pericarditis; positive culture confirms diagnosis of TB pericarditis
pericardial biopsy
Test
Pericardial tissue should be sent for histological examination (sensitivity 73% to 100%) and culture.[41]
Result
presence of granuloma and/or positive acid-fast bacilli suggests TB pericarditis; positive culture confirms diagnosis of TB pericarditis
tuberculin skin testing
Test
Used for investigation for latent TB infection. A negative tuberculin skin testing (TST) does not rule out active TB.
The TST uses intra-dermal injection of purified protein derivative to evaluate for delayed hypersensitivity response in order to diagnose prior exposure to TB. Different cut-offs in size of induration are used to define a positive test, depending on the patient's risk factors.
Response to TST may be diminished in patients with factors such as HIV infection or poor nutrition.[72]
Result
millimetres of induration
interferon-gamma release assays
Test
Used for investigation for latent TB infection. A negative Interferon-gamma release assay (IGRA) does not rule out active TB.
IGRAs measure the release of interferon-gamma from T cells reacting to TB antigens.
Result
positive, negative, indeterminate
TB antigen-based skin tests (TBST)
Test
TBSTs are a new class of tests that have been developed to measure the cell-mediated immunological response to M tuberculosis specific antigens. The World Health Organization recommends that TBSTs may be used to test for latent TB infection, reporting that the diagnostic accuracy of TBSTs is similar to that of IGRAs and greater than that of the TST.[73]
Result
positive
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