At a Glance

Tuberculosis is a globally distributed infectious disease caused by Mycobacterium tuberculosis. “Tuberculosis” refers specifically to M tuberculosis infections, even though many members of the genus Mycobacterium can cause human disease. Mycobacteria are aerobic, rod-shaped, nonspore forming bacteria containing high concentrations of cell wall lipids/waxes. Mycobacterial cell wall composition is responsible for so-called “acid fastness,” a feature characterized by resistance to common bacterial stains (e.g., Gram) and the inability of acid-alcohol solutions to effectively decolorize organisms that have been stained with dyes, such as carbol fuchsin.

The clinical manifestations of tuberculosis are extraordinarily varied. The majority of clinically overt cases of tuberculosis occur following late reactivation of localized primary pulmonary or extrapulmonary infections. A minority of patients develop disseminated infections on first exposure. Patients within this group tend to be relatively immunosuppressed (i.e., young; elderly; overtly immunosuppressed due to infection, such as HIV-1; or therapy, such as anti-TNF alpha). Classic tuberculosis is suggested by cough, night sweats, fatigue, and weight loss. It is important to emphasize the protean nature of tuberculosis (e.g., meningitis, osteomyelitis) It is estimated by the World Health Organization (WHO) that as many as one-third of the world’s population harbors latent tuberculosis.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Traditionally, the diagnosis of tuberculosis has been based on the direct demonstration of acid-fast bacilli in relevant specimens (e.g., sputum) collected from a clinically suspect patient. Culture, isolation, and definitive bacteriologic identification of M tuberculosis is slow (2-6 weeks), expensive, and requires specialized facilities. This has led to the development of more rapid methods.

The tuberculin (or purified protein derivative, PPD) skin test is falsely negative in up to 25% of infected patients and requires appropriate controls and administration.

Interferon-gamma (IFN-gamma) release assays using either whole blood or purified mononuclear cells entail in vitro cell activation with specific selected mycobacterial antigens. These assays are somewhat more sensitive and specific than skin tests but are expensive and labor-intensive.

Classic acid-fast stains include the Ziehl-Neelson and Kinyoun methods; the most commonly used modified-acid-fast method employs auramine 0, a fluorescence dye easily visible when excited with an appropriate ultraviolet light source. Each of these staining methods requires expertise, and none is absolutely specific, as other mycobacteria and some nonmycobacterial organisms can be interpreted as positive. Nonetheless, they offer the advantage of rapidity.

As noted, isolation and bacteriologic identification is definitive but slow. Turnaround times have been reduced through the use of a variety of rapid cultivation and identification techniques.

Nucleic acid amplification techniques offer excellent specificity and 1-3 day turnaround times. There have been cases in which nonviable mycobacterial nucleic acid yields a false-positive nucleic acid amplification result.

The key to diagnosis in tuberculosis is clinical suspicion, particularly in the case of an unusual presentation. Direct tests, such as acid-fast staining, can be helpful, because they are rapid but with the caveat that there is a significant false-negative rate. Skin testing and IFN-gamma release assays both exhibit significant false-negative rates and are, thus, more helpful when positive. Interpretation of skin tests and IFN-gamma tests are complicated by remote exposure (e.g., latent infection or BCG vaccination). A useful approach is to pursue direct testing methods in advance of definitive nucleic acid and bacteriologic methods.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Because of the paucity of organisms, identification of Mycobacterium tuberculosis in specimens from infected extrapulmonary sites (e.g., CSF, plural fluid) is difficult when direct staining methods (e.g., Ziehl-Neelson) are used.

The diagnosis of tuberculosis in patients infected by HIV-1 can be hampered by the presence of low CD4-positive T lymphocyte counts. Both tuberculin (PPD) skin tests and IFN-gamma release assays are more likely suppressed in patients with low CD4-positive T lymphocyte counts.

What Lab Results Are Absolutely Confirmatory?

Definitive diagnosis of tuberculosis requires bacteriologic identification of Mycobacterium tuberculosis. An added advantage of a diagnostic isolote is antimicrobial susceptibility testing. However, it is appropriate to begin treatment on the basis of a rapid clinical assay, such as an acid-test stain.