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Shakir

Tuberculosis (TB) is an airborne infection caused by the bacterium Mycobacterium tuberculosis. The infection can be noncontagious and asymptomatic, which is known as a latent infection, or progress to active TB, which is both contagious and symptomatic. Active TB can develop shortly after initial exposure but may not develop for months or years, or may never manifest, depending on individual risk factors. Despite being both preventable and curable, TB remains a leading cause of death from infectious diseases worldwide. Although the United States maintains one of the lowest TB incidence rates globally, case numbers began increasing in 2021. Timely identification of individuals infected with M. tuberculosis and accurate diagnosis of active TB are critical for effective patient care, public health surveillance, and outbreak control. Immunologic tests, which detect the host immune response to TB antigens, are used to diagnose infection. However, these tests cannot differentiate between latent infection and active TB disease. Therefore, clinical evaluation and further diagnostic testing are essential to confirm TB and assess potential drug resistance. Laboratory methods to diagnose and confirm active TB may include acid-fast bacilli (AFB) smear microscopy, nucleic acid amplification tests (NAATs), and culture.
Quick Answers for Clinicians
Individuals at highest risk for Mycobacterium tuberculosis infection include those who share a household with, or have had recent contact with, someone with active tuberculosis (TB). Other high-risk groups include foreign-born persons and travelers from countries with high TB prevalence, residents and staff of high-risk congregate settings such as correctional facilities, nursing homes, or shelters for individuals experiencing homelessness, as well as employees of healthcare facilities or mycobacteriology laboratories.
Individuals with weakened immune systems, including those with HIV/AIDS and those receiving immunosuppressive drugs such as chemotherapy, high-dose corticosteroid therapy, or medications to prevent organ transplant rejection, and those with certain medical conditions, including Hodgkin disease, lymphoma, diabetes mellitus, chronic renal failure, and malnutrition, are at increased risk for progression to active tuberculosis (TB). In addition, children younger than 5 years and postpubertal adolescents are at greater risk of developing active TB after infection.
Individuals at increased risk for drug-resistant tuberculosis (TB) include those who have been treated for TB in the past and experienced treatment failure or relapse due to incorrect treatment or poor drug compliance. Others at risk are close contacts of someone with drug-resistant TB, foreign-born persons, and individuals who travel frequently to areas where drug-resistant TB is common.
Nontuberculous mycobacteria (NTM) comprise a diverse group of mycobacterial species, a subset of which (e.g., Mycobacterium avium complex, M. abscessus, and M. kansasii) can cause pulmonary disease that presents similarly to tuberculosis (TB). Unlike TB infections, which are transmitted by individuals with active TB, NTM infections are primarily acquired from environmental sources. Due to the similarity in clinical and radiologic presentation and the difficulty in differentiating NTM from M. tuberculosis using smear microscopy, misdiagnosis of NTM infections can occur and lead to delayed or inappropriate treatment. Because NTM infections do not respond to standard anti-TB drugs, accurate diagnosis with species-level identification is essential. Laboratory methods such as culture, nucleic acid amplification tests (NAATs), DNA probes, matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry, and DNA sequencing are used to identify the causative species and guide appropriate treatment.
Tuberculosis (TB) is one of the leading causes of death among people with HIV worldwide. Individuals with HIV and latent TB infection are at significantly increased risk of developing active TB compared with those without HIV, particularly during the first year after TB infection. Guidelines recommend all individuals with HIV infection be evaluated for latent TB infection, regardless of their epidemiologic risk for exposure to Mycobacterium tuberculosis. Annual testing for latent TB infection is recommended for individuals with HIV who are at high risk for exposure and have a negative test history. Individuals with advanced HIV who test negative for latent TB and for whom latent TB treatment is not clinically indicated should be retested for latent TB after starting antiretroviral therapy (ART) to confirm their TB status.
Indications for Testing
Risk of Latent Infection
Individuals who are at increased risk for M. tuberculosis exposure should undergo testing for latent TB infection. Many institutions also require TB testing as a condition of employment or enrollment. Otherwise, testing is not recommended for individuals with a low risk for infection.
Suspected Active Tuberculosis
Determining whether individuals should undergo diagnostic testing for active TB is based on whether they present with symptoms and/or show radiographic signs of disease.
Pulmonary TB symptoms include a cough lasting longer than 3 weeks, hemoptysis, chest pain, and shortness of breath.
Extrapulmonary TB may or may not present with classic symptoms of pulmonary TB and is characterized by symptoms affecting organs other than the lungs. Depending on the site(s) of infection, symptoms may include blood in the urine, headache or confusion, back pain, hoarseness, swollen glands, and swollen joints.
Laboratory Testing
Tests for Latent Infection
Latent TB infection testing indirectly detects the presence of M. tuberculosis by evaluating an individual’s immune response to specific antigens, either through an interferon-gamma release assay (IGRA) or a tuberculin skin test (TST). ,
Interferon-Gamma Release Assay Blood Test
An IGRA is a blood test that detects M. tuberculosis infection by measuring the immune response in a blood sample to polypeptides resembling TB antigens. These antigens are selected based on their presence in the M. tuberculosis complex but absence from the Bacille Calmette-Guérin (BCG) vaccine and most nontuberculous mycobacteria.
When available and accessible, the IGRA is the preferred test for individuals 5 years and older, particularly those who have received the BCG vaccine and/or are unlikely to return for the TST interpretation.
Mantoux Tuberculin Skin Test
A TST is administered by injecting tuberculin, a protein derived from M. tuberculosis, into the skin of the lower forearm. The injection site is examined 48 to 72 hours later for induration, which is then measured for interpretation. Clinical interpretation is based on the size of the induration and the individual’s risk for TB exposure and disease progression.
A positive TST result suggests M. tuberculosis infection and warrants prompt clinical and radiographic evaluation. A negative result makes infection less likely. However, a negative TST result does not rule out latent infection or active TB, as factors such as young age, malnutrition, immunosuppression, viral infections, and extrapulmonary TB can reduce TST reactivity. Notably, some children with culture-confirmed TB may initially have a negative TST. Additionally, individuals who have received a BCG vaccine may have a false-positive TST due to cross-reactivity.
Historically, TST was generally preferred in individuals 5 years or younger. However, IGRA is considered an acceptable alternative in children 2 years and older and in those who may not return for TST readings.
Tests for Active Tuberculosis
A definitive diagnosis of active TB requires bacteriologic confirmation.
For pulmonary TB, the preferred sample type is freshly expectorated sputum. For adult patients who are not spontaneously producing sputum, induced sputum is acceptable. Bronchoalveolar lavage fluids are also alternative samples. For children and adolescents who are not spontaneously producing sputum, early-morning gastric aspiration is preferred over sputum induction, as the latter requires specialized expertise. Nasopharyngeal aspirates and stool samples may be acceptable alternatives when preferred specimen types are difficult to obtain, although they may have lower sensitivity.
For extrapulmonary TB, samples such as body fluids, tissue biopsies, or aspirates should be collected from the sites of suspected infection.
For a complete and accurate medical evaluation, samples should be tested with a combination of the tests described in the following sections. These tests are generally ordered concurrently.
Acid-Fast Bacilli Smear
For all patients with suspected pulmonary TB, performing an acid-fast-bacilli (AFB) smear on three different sputum specimens collected at different time points is recommended. A positive AFB smear can indicate TB disease but does not confirm TB infection. This is because a positive AFB result cannot differentiate M. tuberculosis from other mycobacteria. AFB smears are rapid first-line tests, but species identification requires positive culture or NAAT results. ,
Nucleic Acid Amplification Tests
Performing a NAAT on the initial respiratory specimen in all patients with suspected pulmonary TB is recommended. NAATs are rapid and highly specific, although they may be less sensitive than culture. A NAAT, unlike an AFB smear, can distinguish M. tuberculosis from other mycobacteria. A positive NAAT result with or without a positive AFB smear is considered sufficient evidence for TB diagnosis.
NAATs and other molecular tests (such as sequencing) are also used to detect drug resistance. , In individuals with positive AFB and/or NAAT results and risk factors for drug-resistant TB, molecular testing for drug resistance and susceptibility should be ordered immediately to inform timely treatment.
Although NAATs continue to advance and are increasingly used in the diagnostic evaluation of TB, it is important to recognize that a negative result alone does not rule out TB or drug resistance. This is because the detection capabilities of NAATs depend on known genetic markers and the technical limitations of each assay.
Culture
Mycobacterial culture is recommended for all individuals with suspected TB disease, as culture enables a definitive diagnosis and yields isolates that may be needed for further testing and public health evaluation. , Additional testing includes phenotypic drug susceptibility testing, genotyping, rapid molecular detection of drug-resistance genes, and precise species identification within the M. tuberculosis complex. However, because of the relatively long turnaround time (up to 10 weeks with solid media and 1 to 6 weeks with liquid media), more rapid tests such as NAATs are often ordered concurrently to guide timely clinical decisions.
ARUP Laboratory Tests
Semi-Quantitative Chemiluminescent Immunoassay (CLIA)/Semi-Quantitative Enzyme-Linked Immunosorbent Assay (ELISA)
Semi-Quantitative Chemiluminescent Immunoassay (CLIA)/Semi-Quantitative Enzyme-Linked Immunosorbent Assay (ELISA)
Stain/Culture/Matrix-Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF) Mass Spectrometry/16SrDNA Sequencing/Polymerase Chain Reaction/Broth Microdilution
Matrix-Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF) Mass Spectrometry/Polymerase Chain Reaction/Sequencing
Continuous Monitoring Blood Culture/Culture
Stain/Culture/16S rDNA Sequencing/ Broth Microdilution/Polymerase Chain Reaction/ Matrix-Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF) Mass Spectrometry
Qualitative Polymerase Chain Reaction (PCR)
Methods may include biochemical, mass spectrometry, or sequencing.
Susceptibility Testing
Broth Macrodilution/Broth Microdilution
Broth Macrodilution
Auramine O Stain
Continuous Monitoring Blood Culture/Culture
References
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