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Tuberculosis: Differential Diagnoses & Workup
Updated: Jan 26, 2009
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Differential Diagnoses
Workup
Laboratory Studies
- In the ED setting, clinical suspicion and risk factors for tuberculosis and chest radiography are indicated.
- Accept the diagnosis of TB and initiate treatment if chest radiograph or sputum sampling indicates active disease.
- Ziehl-Neelsen staining of sputum is a simple 5-step process that takes approximately 10 minutes to accomplish.
- Current standards of the skin test (PPD/tuberculin skin testing [TST]) are over 110 years old since Dr. Koch had discovered it: The mechanism of TST is based on the fact that latent TB infection induces a strong cell-mediated immune response by measuring the delayed-type hypersensitivity response to intradermal inoculation of tuberculin purified protein derivative (PPD). It is a crude mixture of >200 M tuberculosis proteins, which is checked 48 hours later; it is not sensitive in immune sensitized or immunosuppressed patients. In addition, it cannot differentiate those who have had the bacilli Calmette-Guérin (BCG) vaccination (Mycobacterium bovis) and Mycobacterium avium. This can reduce the number of unnecessarily treated patients with suspected TB with positive PPD test results and reduce the prevalence of patients with MDR-TB.
- Do not delay the diagnosis until the following day for patients at high risk for active disease.
- Attempt several sputum collections or induce sputum production by respiratory physiotherapy. The absence of a positive smear result does not exclude active TB infection.
- Approximately 35% of culture-positive specimens are associated with a negative smear result.
- Blood cultures using mycobacteria-specific, radioisotope-labeled systems help establish the diagnosis of active TB. Mycobacterial bacteremia (bacillemia) is detectable using blood cultures only if specialized systems are used. The bacilli have specific nutrient growth requirements not met by routine culture systems. Such blood cultures should be used for all patients with HIV who are suspected of having TB because bacillemia is particularly prevalent in this population. If available, such cultures should be used for any patient highly suspected of having active TB. One study found an incidence of 88% mycobacterial infection (66% TB, 22% Mycobacterium avium complex [MAC]) detected by blood culture in stage IV HIV disease).
- Urinalysis and urine culture can be obtained for those with genitourinary complaints. Patients are oftentimes asymptomatic; however, significant pyuria and/or hematuria with no routine bacterial organisms should prompt urine culture for acid-fast bacilli smears.
- All patients who are diagnosed with active TB and who are not known to be HIV positive should be considered for HIV testing. This testing can be implemented in the ED with rapid oral testing with appropriate HIV counseling.
Imaging Studies
- Chest radiography consistent with TB indicates active disease in the symptomatic patient even in the absence of a diagnostic sputum smear. Similarly, normal chest radiographic findings in the symptomatic patient does not exclude TB, particularly in a patient who is immunosuppressed.
- In primary active TB, radiographic features of pulmonary tuberculosis are nonspecific, sometimes even normal. The chest radiograph typically shows a pneumonialike picture of an infiltrative process in the middle or lower lung regions, often associated with hilar adenopathy and/or atelectasis.
- In classic reactivation TB, pulmonary lesions are located in the posterior segment of the right upper lobe, apicoposterior segment of the left upper lobe, and apical segments of the lower lobes. Cavitation is most common; healing of tubercular regions results in development of a scar with loss of lung parenchymal volume and calcification.
- In the presence of HIV or other immunosuppressant disease, lesions are often atypical. Up to 20% of patients who are HIV positive with active disease have normal chest radiographic findings.
- Old healed TB presents differently altogether with dense pulmonary nodules with or without calcifications in the hilar or upper lobes. Smaller nodules with or without fibrotic scars can be seen in the upper lobes. Nodules and fibrotic lesions are well demarcated, have sharp margins, and are dense. Persons with nodular or fibrotic scars with positive chest radiographic findings and positive PPD results should be treated as latent carriers. Calcified nodular lesions (granulomas) or apical pleural thickening has a lower risk of conversion.
- In disseminated/miliary tuberculosis, the chest radiograph commonly shows a miliary pattern, 2 mm nodules that are histologically granulomas disseminated like “millet seeds” throughout the lung; however, chest radiographic patterns can vary and also include upper lobe infiltrates with or without cavitation.
- In pleural tuberculosis, the pleural space can be involved in 2 ways: hypersensitivity response with pleuritic pain and fever or an empyema that can be seen on chest radiograph with associated pleural effusions.
Other Tests
Tuberculin skin testing (PPD/TST)
- Five units (0.1 mL) of purified protein derivative (PPD) injected intradermally may be used for screening or to supplement other diagnostic testing.
- Positive criteria are population dependent, but any induration of 5 mm or more is now suspect.
- Induration, not erythema, is measured 48-72 hours following injection, although positive test results can be declared up to a week after placement.
- Approximately 20% of patients with active TB, particularly those with advanced disease, may have normal PPD test results.
- Testing is unreliable in infants, patients with immunosuppressive conditions, and patients with serious illnesses.
ELIspot versus ELISA
More advances in tuberculosis detection in areas of mycobacterial genomics and human cellular immunology have enabled 2 new blood tests, enzyme-linked immunospot (ELIspot) and enzyme-linked immunosorbent assay (ELISA), to detect tuberculosis the next day with a high degree of specificity by measuring in vitro T-cell interferon (IFN)-γ in response to 2 TB unique antigens: early secretory antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10). These antigens are highly specific for M tuberculosis but absent from the bacilli Calmette-Guérin (BCG) vaccine and M avium. Both have high diagnostic specificity/sensitivity in active TB: ELISpot, 83-97%, is more sensitive than the ELISA, 70-89%.
ELIspot (also known as T-Spot TB) requires separation of components polymononuclear cells from blood, which are then incubated with the 2 antigens allowing the enumeration IFN-γ-secreting T cells. It is highly sensitive and highly specific.
ELISA uses whole blood incubated with ESAT-6 and CFP-10 for 24 hours and enables measurement of IFN-g γ concentration in supernatant after incubation with both ESAT-6 and CFP-10 incubation. Both tests are more specific than the PPD test because they are not confounded by the BCG vaccine. In active TB, ELISA (QuantiFERON-TB Gold) has similar sensitivity to the skin test, whereas ELIspot is significantly more sensitive. In latent TB, ELISA sensitivity is similar to the skin test, whereas ELISPOT is more sensitive.
- Advantages to interferon-γ release assays compared to PPD: One patient visit, ex vivo tests, no booster effect, and independent of BCG vaccination.
- Disadvantages of interferon-g: High cost, requires more laboratory resources, complicated process of lymphocyte separation, and lack of prospective studies.
- Meta-analysis of 59 studies indicates there is no test that distinguishes active TB from latent TB, no test has high sensitivity, interferon-γ assays (IGRAs) were more specific than PPD in patients who have had BCG vaccination, and the results of IGRAs and TST were frequently discordant; however, IGRAs show promise for future standardization in TB diagnosis.
- Other new and rapid tests are also available such as BACTEC-460 (Becton-Dickinson), ligase chain reaction; luciferase reporter assay (within 48 h) (Franklin Lakes). These tests have been developed for rapid drug-susceptibilities testing, which can be available within 10 days.
- Drug resistance tests such as the FASTPlaque TB-RIF for rifampin resistance can be used after growth in semiautomated liquid cultures such as BACTEC-460; rifampin resistance can be used as a surrogate marker for isoniazid resistance.
Population-based criteria for PPD positivity
- Patients who are HIV positive, have abnormal chest radiographic findings, or have recent contact with persons with active TB - 5-mm induration or more
- Patients who are intravenous drug users, residents of nursing homes, prisoners, impoverished persons, or members of minority groups - 10-mm induration or more
- Patients who are young and in good health - 15-mm induration or more
- Reactions in patients who have received the BCG vaccine are often difficult to interpret.
- In adults who received BCG vaccination at birth, consider a 10-mm induration or more a positive result.
- In persons receiving BCG vaccination as adults, consider a 30-mm induration (or larger) a positive result.
More on Tuberculosis |
| Overview: Tuberculosis |
 Differential Diagnoses & Workup: Tuberculosis |
| Treatment & Medication: Tuberculosis |
| Follow-up: Tuberculosis |
| Multimedia: Tuberculosis |
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Further Reading
Keywords
tuberculosis, TB, lung disease, pulmonary disease, pulmonary infection, treatment of TB, Mycobacterium tuberculosis, M tuberculosis, mycobacterial infection, Pott's disease, Pott disease, scrofula, miliary disease, extrapulmonary TB, multi–drug-resistant tuberculosis, MDR-TB, extensively drug resistant tuberculosis, XDR-TB
