Mycobacterium tuberculosis

Clinical Background

Mycobacteria belong to the family Mycobacteriaceae and the order Actinomycetales. Mycobacterium tuberculosis as well as other non-tuberculosis species can be infectious agents in humans.

Mycobacterium tuberculosis

Epidemiology
- Prevalence
  - 8-9 million new cases occur per year
  - 3-4 million cases of infectious pulmonary disease (smear positive)
Organism
- Mycobacterium tuberculosis - rod-shaped aerobic bacterium with acid-fast staining properties
- Mycobacterium tuberculosis complex (MTB) - M. tuberculosis, M. bovis, M. africanum M. microti and others
  - Transmission is via inhalation of droplet nuclei
Risk factors
- Once the patient has been infected, the risks for developing active tuberculosis (TB) for the development of active TB include:
  - Comorbidity present (AIDS, immunosuppression, fibrotic lung disease, chronic renal failure, diabetes mellitus)
  - Recent tuberculosis infection (<1 year)
  - Malnutrition, alcoholism
  - Fibrotic lesions on chest X-ray
Clinical Presentation
- Primary disease
  - Ranges from mild, self-limited illness to severe disseminated disease
- Post primary disease
  - Reactivation of latent infection
  - Moderate to severe, progressive and often fatal disease
- Extrapulmonary TB
  - Gastrointestinal disease
  - Genitourinary
  - Lymphadenitis
  - Meningitis, central nervous system tuberculoma
  - Miliary
  - Pericarditis
  - Pleural disease
  - Skeletal (Pott disease)
- TB in patients with HIV
  - Extrapulmonary disease is common
  - Atypical chest X-ray findings
  - Delays in diagnosis and treatment are common
  - Increased risk of reactivation of latent disease and rapid progression of newly acquired infection

Nontuberculous (atypical) mycobacteria

Epidemiology
- Transmission via cutaneous, inhalation, or parenteral routes
  - Widely distributed in water, soil and animal species
Organisms
- Nontuberculous organisms
  - M. avium complex, M. kansasii, M. fortuitum, M. abscessus, M. chelonae, M. marinum, M. haemophilum
- Rare new organisms
  - M.nebraskerise, M. parmense, M. saskat-chewanense, M. arupense, M. caprae, M. colombiense, M. florentium, M. montefiorense
- Pathogenicity and clinical significance vary with species and host
  - Asymptomatic infections are common
Clinical Presentation
- Cutaneous - M. fortuitum, M. abscessus, M. chelonae, M. marinum, M. haemophilum
  - Nodular or ulcerating chronic lesions that fail to respond to standard antimicrobial therapy
  - Lymphadenitis - M. avium complex, especially in children
- Pulmonary - M. avium complex, M. kansasii, M. abscessus
  - Immunocompromised and immunocompetent hosts
  - Increased in elderly and patients with underlying pulmonary disease
  - Bronchiectatic, nodular or cavitary disease
- Disseminated
  - Weight loss, fever, fatigue, lymphadenopathy, hepatosplenomegaly, gastrointestinal complaints
  - Usually immunocompromised patients (advanced HIV, transplant)
- Other (catheter-related, skeletal)

See Also

Acromegaly

Actinomycoses and Nocardia Infections

Sarcoidosis - Angiotensin Converting Enzyme

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: AFB Culture (Includes AFB Stain 0060151)

ARUP #: 0060152

Methodology: Standard reference procedures for stain and culture. Identification of AFB is ordered and billed separately. DNA probes are available for M. tuberculosis complex and M. avium-intracellulare complex as indicated. DNA sequencing and other molecular techniques are used for identification of other mycobacteria species. For drug susceptibilities, refer to Antimicrobial Susceptibility - AFB Mycobacteria (0060217).

Use:

Gold standard, most sensitive test for diagnosing mycobacteria

Use for detection in sputum, tissues, urine and other body fluids

Limitations:

Time to detection (mycobacteria are slow growing organisms)

Follow-up:

DNA probes are available for M. tuberculosis complex and M. avium-intracellulare complex as indicated. DNA sequencing and other molecular techniques are used for identification of other mycobacteria species.
For drug susceptibilities, refer to Antimicrobial Susceptibility - AFB Mycobacteria (0060217)

Test name: Mycobacterium tuberculosis Amplified Direct Detection

ARUP #: 0060095

Methodology: Transcription Mediated Amplification (Gen-Probe®)

Use:

Order as adjunct to AFB culture in untreated patients with smear-positive and smear-negative respiratory samples

Rapid,sensitive and specific detection of MTB complex from respiratory specimens

Limitations:

AFB culture should always be ordered with this test

Low level false-positive results can occur in specimens with high concentration of Mycobacteria other than M. tuberculosis

A negative result does not exclude M. tuberculosis infection

Test name: QuantiFERON®-TB Gold In Tube

ARUP #: 0051729

Methodology: Cell Culture/Enzyme-Linked Immunosorbent Assay

Use:

Detect latent TB infections among persons who are at increased risk for TB

Specific for M. tuberculosis, not nontuberculous mycobacteria or the BCG vaccine

Limitations:

Diagnosing or excluding tuberculosis disease and assessing the probability of latent tuberculosis infection require a combination of epidemiological, historical, medical, and diagnostic findings that should be taken into account when interpreting the results of this test

Test name: QuantiFERON®-TB Gold (Local Clients Only)

ARUP #: 0051231

Methodology: Cell Culture/Enzyme-Linked Immunosorbent Assay

Use:

Detect latent TB infections among persons at increased risk for TB

Specific for M. tuberculosis; not nontuberculous mycobacteria or the BCG vaccine

Limitations:

Time sensitive test

The ability of the QuantiFERON®-TB Gold assay to predict the progression of latent tuberculosis infection to active tuberculosis has not been evaluated

Test name: Mycobacterium tuberculosis Complex Speciation

ARUP #: 0060771

Methodology: Polymerase Chain Reaction

Use:

Identify species of the M. tuberculosis complex (M. tuberculosis, M. bovis, M. bovis BCG-vaccine strain, M. africanum, M. microti, M. caprae) to species level by comparing genomic deletion patterns

Limitations:

Non-tuberculous mycobacteria may have indeterminate patterns of the genomic deletions used as targets in this assay

Changes in DNA sequence at the primer annealing sites may affect genomic deletion pattern determination and speciation

Test name: Mycobacterium tuberculosis Antibody, IgG by ELISA

ARUP #: 0051698

Methodology: Enzyme-Linked Immunosorbent Assay

Use:

Order this rapid serologic assay when clinical symptoms and the possibility of exposure indicate MTB infection

Detect IgG antibodies against MTB in patients with active infection

Monitor the success of therapeutic intervention

Differentiate active and latent cases of TB

Can also be used in previously BCG vaccinated individuals since the antigens utilized are not present in Mycobacterium bovis

Limitations:

Not intended for use as a screening assay

Results should be interpreted in conjunction with PPD or QuantiFERON® testing as well as the complete history of the patient

Assay has not been validated for use on patients with HIV/TB co-infection and is not recommended for this population

Test name: AFB Culture (Includes AFB Stain 0060151) with Reflex to Mycobacterium tuberculosis Amplified Direct Detection (0060095)

ARUP #: 0060738

Use:

Single order test incorporating culture and stain with reflex to amplified testing for MTB complex when smear positive

Limitations:

Available for respiratory specimens only

Low-level false-positive results can occur in specimens with high concentration of mycobacteria other than M. tuberculosis

A negative result does not exclude M. tuberculosis

Test name: Blood Culture, AFB

ARUP #: 0060060

Methodology: Bactec® 9240, continuous monitoring systems. Standard reference procedures for identification of positive cultures.

Use:

Order for AFB culture of blood or bone marrow specimen

Limitations:

Follow-up:

Test name: Mycobacterium tuberculosis Amplified Detection , CSF

ARUP #: 0060063

Methodology: Transcription Mediated Amplification (Gen-Probe®)

Use:

Amplified test offers rapid and specific detection of MTB complex from cerebrospinal fluid (CSF)

Limitations:

AFB culture should always be ordered with test
The Mycobacterium tuberculosis Amplified Direct test does not differentiate among members of the MTB complex

Low level false-positive results can occur in specimens with high concentration of mycobacteria other than M. tuberculosis (rare in CSF)

Limited sensitivity

A negative result does not exclude the possibility of isolating MTB from the specimen (e.g. culture)

Follow-up:

Test name: AFB Identification with Reflex to Susceptibility

ARUP #: 0060997

Methodology: Standard reference procedures for identification and susceptibility testing of AFB. DNA probes available for M. tuberculosis complex and M. avium-intracellulare complex. DNA sequencing and other molecular techniques are used for other mycobacteria species.

Use:

Identification of acid-fast organisms (AFB) isolated in pure culture with reflex susceptibility testing if indicated

Limitations:

Susceptibility testing may not be performed on all isolates (varies by species)

Follow-up:

Test name: Antimicrobial Susceptibility - AFB/Mycobacteria

ARUP #: 0060217

Methodology: Varies with organism identification

Use:

Availability:
a. M. tuberculosis primary panel
b. M. avium complex panel
c. Rapidly Growing Nontuberculous Mycobacteria panel
d. Atypical Mycobacteria panel

Limitations:

Follow-up:

Additional Tests Available

Test name: AFB Stain Only

ARUP #: 0060151

Methodology: Auramine O Stain

Comments: Monitor respiratory specimens on previously diagnosed patientsShould not be ordered without culture in previously undiagnosed patients

Test name: AFB Identification

ARUP #: 0060999

Methodology: Standard reference procedures for identification of AFB. DNA probes available for M. tuberculosis complex and M. avium-intracellulare complex. DNA sequencing and other molecular techniques are used for other mycobacteria species.

Comments: Identification of acid-fast organisms (AFB) isolated in pure culture

Test name: Blood Culture, AFB & Fungal

ARUP #: 0060024

Methodology: Bactec® 9240, continuous monitoring systems. Standard reference procedures for identification of positive cultures.

Comments:

Test name: Adenosine Deaminase, Body Fluid

ARUP #: 0098115

Methodology: Spectrophotometry

Comments:

Test name: Chylomicron Screen, Body Fluid

ARUP #: 0098457

Methodology: Electrophoresis

Comments:

Additional Information

The laboratory should be notified when the presence of Mycobacterium genavense is suspected as this organism will not grow on media routinely used for Mycobacterial isolation.

References

Guidelines

Controlling tuberculosis in the United States. Recommendations from the American Thoracic Society, CDC, and the Infectious Diseases Society of America. American Thoracic Society - Medical Specialty Society. Centers for Disease Control and Prevention - Federal Government Agency [U.S.] Infectious Diseases Society of America - Medical Specialty Society. 2005 Nov 4. 81 pages. NGC:004660

Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. Centers for Disease Control and Prevention - Federal Government Agency [U.S.]. 2005 Dec 30. 142 pages.

Jereb JA. Progressing toward tuberculosis elimination in low-incidence areas of the United States. Recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR Recomm Rep. 2002;51(RR-5):1-14.

Diagnostic Standards and Classification of Tuberculosis in Adults and Children. This official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999. This statement was endorsed by the Council of the Infectious Disease Society of America, September 1999. Am J Respir Crit Care Med. 2000;161(4 Pt 1):1376-1395.

General References

Dinnes J, Deeks J, Kunst H, Gibson A, Cummins E, Waugh N, Drobniewski F, Lalvani A. A systematic review of rapid diagnostic tests for the detection of tuberculosis infection. Health Technol Assess. 2007;11(3):1-196.

Goto,M., Noguchi,Y., Koyama,H., Hira,K., Shimbo,T., Fukui,T. Diagnostic value of adenosine deaminase in tuberculous pleural effusion: a meta-analysis. Ann Clin Biochem. 2003;40(Pt 4):374-81.

Harries AD, Dye C. Tuberculosis. Ann Trop Med Parasitol. 2006;100(5-6):415-431.

Havlir DV, Barnes PF. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med. 1999;340(5):367-373.

Jasmer RM, Nahid P, Hopewell PC. Clinical practice. Latent tuberculosis infection. N Engl J Med. 2002;347(23):1860-1866.

Kanaujia GV, Lam PK, Perry S, Brusasca PN, Catanzaro A, Gennaro ML. Integration of microscopy and serodiagnostic tests to screen for active tuberculosis. Int J Tuberc Lung Dis.. 2005;9(10):1120-6.

Lalvani A. Diagnosing tuberculosis infection in the 21st century: new tools to tackle an old enemy. Chest. 2007;131(6):1898-1906.

Maartens G, Wilkinson RJ. Tuberculosis. Lancet. 2007;370(9604):2030-2043.

Marais BJ, Graham SM, Cotton MF, Beyers N. Diagnostic and management challenges for childhood tuberculosis in the era of HIV. J Infect Dis. 2007;196 Suppl 1:S76-S85.

Palomino JC. Newer diagnostics for tuberculosis and multi-drug resistant tuberculosis. Curr Opin Pulm Med. 2006;12(3):172-178.

Perkins MD, Cunningham J. Facing the crisis: improving the diagnosis of tuberculosis in the HIV era. J Infect Dis. 2007;196 Suppl 1:S15-S27.

Quast TM, Browning RF. Pathogenesis and clinical manifestations of pulmonary tuberculosis. Dis Mon. 2006;52(11-12):413-419.

Richeldi L. An update on the diagnosis of tuberculosis infection. Am J Respir Crit Care Med. 2006;174(7):736-742.

Sharma SK, Mohan A, Sharma A, Mitra DK. Miliary tuberculosis: new insights into an old disease. Lancet Infect Dis. 2005;5(7):415-430.

Small PM, Fujiwara PI. Management of tuberculosis in the United States. N Engl J Med. 2001;345(3):189-200.

Stout JE. Evaluation and management of patients with pulmonary nontuberculous mycobacterial infections. Expert Rev Anti Infect Ther. 2006;4(6):981-993.

Tortoli E. The new mycobacteria: an update. FEMS Immunol Med Microbiol. 2006;48(2):159-178.

Yew WW, Leung CC. Update in tuberculosis 2006. Am J Respir Crit Care Med. 2007;175(6):541-546.

References from the ARUP Institute for Clinical and Experimental Pathology Research®

Aldous WK, Pounder JI, Cloud JL, Woods GL. Comparison of six methods of extracting Mycobacterium tuberculosis DNA from processed sputum for testing by quantitative real-time PCR. J Clin Microbiol. 2005;43(5):2471-2473.

Cloud JL, Carroll KC, Cohen S, Anderson CM, Woods GL. Interpretive criteria for use of AccuProbe for identification of Mycobacterium avium complex directly from 7H9 broth cultures. J Clin Microbiol. 2005;43(7):3474-3478.

Cloud JL, Hoggan K, Belousov E, Cohen S, Brown-Elliott BA, Mann L, Wilson R, Aldous W, Wallace RJ Jr, Woods GL. Use of the MGB Eclipse system and SmartCycler PCR for differentiation of Mycobacterium chelonae and M. abscessus. J Clin Microbiol. 2005;43(8):4205-4207.

Cloud JL, Meyer JJ, Pounder JI, Jost KC Jr, Sweeney A, Carroll KC, Woods GL. Mycobacterium arupense sp. nov., a non-chromogenic bacterium isolated from clinical specimens. Int J Syst Evol Microbiol. 2006;56(Pt 6):1413-1418.

Cloud JL, Neal H, Rosenberry R, Turenne CY, Jama M, Hillyard DR, Carroll KC. Identification of Mycobacterium spp. by using a commercial 16S ribosomal DNA sequencing kit and additional sequencing libraries. J Clin Microbiol. 2002;40(2):400-406.

Cloud JL, Shutt C, Aldous W, Woods G. Evaluation of a modified gen-probe amplified direct test for detection of Mycobacterium tuberculosis complex organisms in cerebrospinal fluid. J Clin Microbiol. 2004;42(11):5341-5344.

Cooksey RC, de Waard JH, Yakrus MA, Toney SR, Da Mata O, Nowicki S, Sohner K, Koch E, Petti CA, Morey RE, Srinivasan A. Mycobacterium cosmeticum, Ohio and Venezuela. Emerg Infect Dis. 2007;13(8):1267-1269.

Neal H, Cloud JL, Pounder JI, Page SR, Woods GL. Sequence variant for internal transcribed spacer region of Mycobacterium abscessus. J Clin Microbiol. 2005;43(12):6214-.

Odell ID, Cloud JL, Seipp M, Wittwer CT. Rapid species identification within the Mycobacterium chelonae-abscessus group by high-resolution melting analysis of hsp65 PCR products. Am J Clin Pathol. 2005;123(1):96-101.

Pounder JI, Aldous WK, Woods GL. Comparison of real-time polymerase chain reaction using the Smart Cycler and the Gen-Probe amplified Mycobacterium tuberculosis direct test for detection of M. tuberculosis complex in clinical specimens. Diagn Microbiol Infect Dis. 2006;54(3):217-222.

Simmon KE, Pounder JI, Greene JN, Walsh F, Anderson CM, Cohen S, Petti CA. Identification of an emerging pathogen, Mycobacterium massiliense, by rpoB sequencing of clinical isolates collected in the United States. J Clin Microbiol. 2007;45(6):1978-1980.

Taggart EW, Hill HR, Ruegner RG, Litwin CM. Evaluation of an in vitro assay for interferon gamma production in response to the Mycobacterium tuberculosis-synthesized peptide antigens ESAT-6 and CFP-10 and the PPD skin test. Am J Clin Pathol. 2006;125(3):467-473.

Taggart EW, Hill HR, Ruegner RG, Martins TB, Litwin CM. Evaluation of an in vitro assay for gamma interferon production in response to Mycobacterium tuberculosis infections. Clin Diagn Lab Immunol. 2004;11(6):1089-1093.

Wallace RJ Jr, Brown-Elliott BA, Brown J, Steigerwalt AG, Hall L, Woods G, Cloud J, Mann L, Wilson R, Crist C, Jost KC Jr, Byrer DE, Tang J, Cooper J, Stamenova E, Campbell B, Wolfe J, Turenne C. Polyphasic characterization reveals that the human pathogen Mycobacterium peregrinum type II belongs to the bovine pathogen species Mycobacterium senegalense. J Clin Microbiol. 2005;43(12):5925-5935.

Medical Reviewers

Carney, Heather, M.D. Assistant Medical Director, Transfusion Services at ARUP Laboratories; Pathology, University of Utah

Litwin, Christine, M.D. Medical Director, Immunology at ARUP Laboratories; Professor, Clinical Pathology, University of Utah

Petti, Cathy A., M.D. Medical Director, Infectious Diseases at ARUP Laboratories; Assistant Professor, Pathology and Medicine, University of Utah

Comprehensive Review: September 2008
Last Update: September 2008