Latent Tuberculosis Infection

Posted by • May 29th, 2015

About one third of the world population has latent M. tuberculosis infection. A new review explains the approach to patients with latent infection, including an update on the risks and benefits of treatment and assessment of the likelihood of progression to active disease.

Studies suggest that active tuberculosis will develop in 5 to 15% of persons with latent infection during their lifetimes.

Clinical Pearls

Describe the pathogenesis of latent Mycobacterium tuberculosis infection.

The natural history of tuberculosis begins with the inhalation of Mycobacterium tuberculosis organisms. A period of bacterial replication and dissemination ensues, followed by immunologic containment of viable bacilli. The result of this process is asymptomatic latent tuberculosis infection, which is defined as a state of persistent bacterial viability, immune control, and no evidence of clinically manifested active tuberculosis.

Who is most at risk for progression of latent infection to active clinical tuberculosis disease?

The likelihood of progression of latent infection to active clinical tuberculosis disease is determined by bacterial, host, and environmental factors. It has been postulated that there are differences in the ability of various strains of M. tuberculosis to cause disease, but little clinical or epidemiologic data support this theory. The initial bacterial load, inferred by the severity of disease in an index case and the closeness of the contact, is directly associated with the risk of development of the disease. Disease develops at a higher rate among infants and very young children who have latent infection than among older children with latent infection; after a child reaches approximately 5 years of age, age appears to have little correlation with the risk of disease. Suppression of cellular immunity by human immunodeficiency virus (HIV) infection, tumor necrosis factor alpha inhibitors, glucocorticoids, and organ or hematologic transplantation increases the risk of progression of latent infection substantially. End-stage renal disease confers an increased likelihood of progression to active tuberculosis. Silicosis and exposure to silica dust are also associated with increased rates of progression, and the combination of HIV and silicosis in South African miners has contributed to an explosive epidemic of tuberculosis in this population.

Table 1. Incidence of Active Tuberculosis and Prevalence of Latent Tuberculosis Infection in Selected High-Risk Groups, According to Published Studies.

Morning Report Questions

Q: What are limitations of the tuberculin skin test and the interferon-gamma release assay (IGRA) for the detection of latent tuberculosis?

A: The tuberculin skin test is widely used and inexpensive, but it has poor specificity in populations vaccinated with bacille Calmette-Guerin (BCG), is subject to cross-reactivity with environmental nontuberculosis mycobacteria, and has poor sensitivity in immunocompromised persons. There are also logistic drawbacks, including the need for a return visit in 2 to 5 days to read the amount of induration, since self-reading is associated with a high error rate. Furthermore, there is a worldwide shortage of tuberculin, attributed to market forces. IGRAs (the QuantiFERON-TB Gold In-Tube assay [Cellestis] and the T-SPOT.TB assay [Oxford Immunotec] measure in vitro responses of T cells or peripheral-blood mononuclear cells to M. tuberculosis antigens that are not found in BCG and most nontuberculous mycobacteria, and thus specificity for M. tuberculosis is higher than with the tuberculin skin test. However, recent studies involving serially tested health care workers in the United States have shown that false conversions (from a negative to a false positive result) and reversions (from a positive to a false negative result) are more common with IGRAs than with tuberculin skin tests. In addition, IGRAs are more costly and require more work in the laboratory.

Q: What options are available for the treatment of latent tuberculosis?

A: The aim of the treatment of latent tuberculosis infection is the prevention of progression to active clinical disease. In the absence of controlled clinical trials comparing isoniazid with placebo, the

9-month isoniazid regimen has been recommended as adequate treatment; however, a meta-analysis of 11 isoniazid trials involving 73,375 HIV-uninfected persons showed that, as compared with placebo, the risk of progression to active tuberculosis at 6 months is similar to that at 12 months. Other effective regimens are daily rifampin for 3 or 4 months, daily isoniazid and rifampin for 3 months, and isoniazid (900 mg) and rifapentine (900 mg) once weekly for 12 weeks. In a multicenter, randomized clinical trial, a regimen of daily rifampin for 4 months was associated with fewer serious adverse events and better adherence and was more cost-effective than a 9-month regimen of isoniazid. A fixed-dose combination of rifapentine (300 mg) and isoniazid (300 mg) is expected to be marketed soon in tablet form, which will facilitate treatment. The 3-month isoniazid-rifapentine regimen may be a cost-effective alternative to the 9-month isoniazid regimen, particularly if the cost of rifapentine decreases and the treatment is self-administered. Currently, the 3-month isoniazid-rifapentine regimen is not recommended for children younger than 2 years of age, persons with HIV infection who are receiving antiretroviral therapy, and women who are pregnant. A few small studies have explored treatment of latent tuberculosis infection in contacts (both children and adults) of persons with multidrug-resistant tuberculosis on the basis of the results of drug-susceptibility testing of the source patient. However, evidence is lacking on the best treatment approach. Rather, strict observation and monitoring for at least 2 years for the development of active tuberculosis disease are the preferred clinical measures.

Table 2. Regimens for Latent Tuberculosis Treatment, According to Pooled Efficacy, Risk of Hepatotoxicity, Adverse Events, and Drug Interactions.

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