Tuberculosis laboratory findings

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mashal Awais, M.D.[2]; Alejandro Lemor, M.D. [3]

Overview

Routine laboratory exams are usually normal. The presence of acid-fast-bacilli (AFB) on a sputum smear or another specimen usually indicates TB disease and a positive culture for M. tuberculosis confirms the diagnosis. Other examples of laboratory tests are urinalysis, peritoneal fluid, or CSF analysis and Interferon-Gamma release assays (IGRA).

Laboratory Findings

Routine laboratory tests are usually normal. In some patients, the subsequent abnormalities could also be found:

• Mild normocytic anemia can be present in almost half of patients.
• Increased erythrocyte sedimentation rate (ESR)
• Mild leukocytosis
• Hyponatremia
• Hypercalcemia
• Elevated alkaline phosphatase levels
• Mild elevation of liver enzymes
• Findings of adrenal insufficiency in case of adrenal gland involvement (low cortisol and aldosterone levels)

Acid-Fast Bacilli

Acid-fast-bacilli in sputum smear

Presence of acid-fast-bacilli (AFB) on sputum smear or on another specimen usually indicates TB disease. Although acid-fast microscopy is easy and quick, it does not confirm a diagnosis of Tuberculosis as some acid-fast-bacilli are not M. tuberculosis. Consequently, a culture is done on all initial samples for confirmation of the diagnosis.

Sputum smears and cultures should be performed to detect acid-fast bacilli if the patient is producing sputum. The best method for this is fluorescence microscopy (auramine-rhodamine staining), which is more sensitive than conventional Ziehl-Neelsen staining.

In case of inability of sufficient sputum production, specimens can be obtained by inducing sputum, gastric washings, a laryngeal swab, bronchoscopy with bronchoalveolar lavage, or fine-needle aspiration of a collection. A comparative study reported that inducing three sputum samples is more sensitive than three gastric washings.

Other mycobacteria are also acid-fast. If the smear is positive, PCR or gene probe testing can differentiate M. tuberculosis from other mycobacteria. Even if sputum smear is negative, tuberculosis cannot be excluded without obtaining negative cultures.

Culture

A positive culture for M. tuberculosis confirms the diagnosis of TB disease. Culture examinations are crucial and should be done on all specimens, regardless of AFB smear results. Laboratories are necessary to report positive results on smears and cultures within 24 hours by telephone or fax to the primary health care provider and to the state or local TB control program, as needed by law.

Many types of cultures are available for M. tuberculosis, including Löwenstein-Jensen (LJ), Kirchner, or Middlebrook media. . Culture of Mycobacteria often takes 4--8 weeks to grow and can help distinguish from several types of mycobacteria. Other kinds of culture are available, this include automated systems in which the mycobacteria grow at a faster rate. MB/BacT, BACTEC 9000, as well as the Mycobacterial Growth Indicator Tube (MGIT). The microscopic-observation drug-susceptibility (MODS) culture is considered a faster and more accurate method .

Culture: Distinctive clusters of colorless Mycobacterium tuberculosis

Löwenstein-Jensen media with Mycobacterium tuberculosis

A sample of pleural exudate should be analyzed by cytopathology or at a cell count lab. Samples are often lymphocyte predominant, and cytopathology is more accurate than cell count labs at detecting lymph. If there is more fluid present, then an AFB lab is more appropriate. Sometimes, a pleural exudate lab test find sterile pyuria (particularly in HIV positive patients), but overall this finding is fairly uncommon. Most extra-pulmonary TB is paucibacillary, hence the yield of tests is very low, and a negative test result does not exclude tuberculosis infection.

Drug Resistance

For all patients, the initial M. tuberculosis isolate should be tested for drug resistance. It is necessary to identify drug resistance as early as possible to ensure effective treatment. Drug susceptibility testing has to be repeated for patients who do not respond adequately to treatment or who have positive culture results despite 3 months of therapy. Susceptibility results from laboratories have to be reported to the primary health care provider and the state or local TB control programs.

Fluid Analysis

• Peritoneal Fluid: Leukocyte count: 150-4000 mm³, lymphocytic pleocytosis, protein > 3.0 g/dL, and increased LDH.
• Cerebrospinal fluid: High protein, low glucose, high number of lymphocytes, and elevated LDH level

Urinalysis

• Regarding renal tuberculosis, the classic laboratory finding is sterile pyuria with microscopic hematuria.

Interferon-Gamma Release Assays (IGRAs)

Interferon-Gamma Release Assays (IGRAs) are whole-blood tests that aids in diagnosing Mycobacterium tuberculosis infection, but they do not differentiate latent tuberculosis infection (LTBI) from tuberculosis disease. Two IGRAs tests that are approved by the U.S. Food and Drug Administration (FDA) and commercially available in the U.S include the QuantiFERON®-TB Gold In-Tube test (QFT-GIT) and the T-SPOT®.TB test (T-Spot).

IGRAs measure a person’s immune reactivity to M. tuberculosis antigen. White blood cells from most individuals that have been infected with M. tuberculosis will produce interferon-gamma (IFN-g) when mixed with antigens (substances that can produce an immune response) derived from M. tuberculosis.

To do this test, fresh blood samples should be mixed with antigens and controls. The antigens, testing methods, and interpretation criteria for IGRAs are different.

Differences in Currently Available IGRAs

	QuantiFERON	T-SPOT
Initial Process	Process whole blood in 16 hours	Process peripheral blood mononuclear cells (PBMCs) within 8 hours, or if T-Cell Xtend® is used, within 30 hours
M. tuberculosis Antigen	Single mixture of synthetic peptides representing ESAT-6, CFP-10 & TB7.7.	Separate mixtures of synthetic peptides representing ESAT-6 & CFP-10
Measurement	Interferon-γ concentration	Number of IFN-g producing cells (spots)
Possible Results	Positive, negative, indeterminate	Positive, negative, indeterminate, borderline
Table adapted from CDC

Advantages and Disadvantages of IGRAs

Advantages	Disadvantages
It requires a single patient visit to perform the test. The results can be available within 24 hours. There are no boosted responses that are measured by subsequent tests. A history of previous BCG (bacillus Calmette-Guérin) vaccination does not yield a false-positive IGRA test result.	The blood samples should be processed within 8-30 hours after collection while white blood cells are still viable. Errors in collecting or transporting blood specimens or in performing and interpreting the assay may reduce the accuracy of IGRAs. There is limited data on the use of IGRAs to predict who will progress to TB disease in the future. There is also limited data on the use of IGRAs for: Children younger than 5 years of age Persons recently exposed to M. tuberculosis Immunocompromised persons Serial testing It may be expensive
Table adapted from CDC Interferon-Gamma Release Assays

CDC Recommendations on When to Use IGRA Tests Adapted from CDC Interferon-Gamma Release Assays

• IGRAs can also be used in stead of (but not in addition to) TST in all conditions in which CDC recommends TST as an aid in diagnosing M. tuberculosis infection, with preferences and particular considerations noted below.
• Contact investigations, testing during pregnancy, in addition to screening of health care workers, and others undergoing serial evaluation for M. tuberculosis infection.
• In spite of the indication of a preference, the use of the alternative test (FDA-approved IGRA or TST) are approved medical and public health practice.
• We should be alert in interpretation when testing particular populations due to limited data on the use of IGRAs

• Populations in which IGRAs are preferred for testing:

• Individuals who received BCG (either as a vaccine or for cancer therapy)
• Individuals from groups that historically have less chances of coming back for TST reading.

• TST is better than IGRAs for children less than 5 years of age.
• As with TST, IGRAs generally should not be used for testing individuals who have a low risk of infection and a low risk of tuberculosis disease.

Routine testing with TST and IGRA is not recommended, but results from both tests may be useful in the following conditions:

When the initial test is negative and:	When the initial test is positive and:
The risk for infection, the risk for progression to active disease, and the risk for a bad outcome are high (e.g., HIV-infected individuals or children under 5 years of age who are exposed to an individual with infectious TB). Presence of clinical suspicion for TB disease (e.g., signs, symptoms, and/or radiographic evidence suggestive of TB disease) and confirmation of M. tuberculosis infection is needed. Getting a positive result from a second test as evidence of infection increases detection sensitivity of the test.	Another evidence of infection is needed to encourage acceptance and adherence (e.g., foreign-born healthcare workers who believe their positive TST is due to BCG). A positive IGRA may necessitate greater acceptance of treatment for LTBI as compared with a positive TST alone. The individual has a low risk of both infection as well as progression from infection to TB disease. Requiring a positive result from the second test as evidence of infection increases the probability that the test reflects infection. An alternative is to suppose, without additional testing, that the initial result is a false positive or that the risk for the disease does not need additional evaluation or treatment, regardless of test results.
Table adapted from CDC

• Moreover, repeating an IGRA or doing a TST may be of value when the initial IGRA result is indeterminate, borderline, or invalid and a reason for testing persists.
• Several negative results from any combination of these tests do not exclude M. tuberculosis infection. We should take some steps to minimize unnecessary and misleading testing of individuals at low risk.
• Choosing the best test or combination of tests for detection of M. tuberculosis infection should be made according to the causes and the context for testing, test availability, and overall cost of testing.