New approaches in the diagnosis and treatment of latent tuberculosis infection

Abstract

With nearly 9 million new active disease cases and 2 million deaths occurring worldwide every year, tuberculosis continues to remain a major public health problem. Exposure to Mycobacterium tuberculosis leads to active disease in only ~10% people. An effective immune response in remaining individuals stops M. tuberculosis multiplication. However, the pathogen is completely eradicated in ~10% people while others only succeed in containment of infection as some bacilli escape killing and remain in non-replicating (dormant) state (latent tuberculosis infection) in old lesions. The dormant bacilli can resuscitate and cause active disease if a disruption of immune response occurs. Nearly one-third of world population is latently infected with M. tuberculosis and 5%-10% of infected individuals will develop active disease during their life time. However, the risk of developing active disease is greatly increased (5%-15% every year and ~50% over lifetime) by human immunodeficiency virus-coinfection. While active transmission is a significant contributor of active disease cases in high tuberculosis burden countries, most active disease cases in low tuberculosis incidence countries arise from this pool of latently infected individuals. A positive tuberculin skin test or a more recent and specific interferon-gamma release assay in a person without overt signs of active disease indicates latent tuberculosis infection. Two commercial interferon-gamma release assays, QFT-G-IT and T-SPOT.TB have been developed. The standard treatment for latent tuberculosis infection is daily therapy with isoniazid for nine months. Other options include therapy with rifampicin for 4 months or isoniazid + rifampicin for 3 months or rifampicin + pyrazinamide for 2 months or isoniazid + rifapentine for 3 months. Identification of latently infected individuals and their treatment has lowered tuberculosis incidence in rich, advanced countries. Similar approaches also hold great promise for other countries with low-intermediate rates of tuberculosis incidence.

Figure 1

Natural progression of events and outcome in an immunocompetent individual following exposure of human subjects (contacts of TB patients) to droplet nuclei containing M. tuberculosis expectorated by a source case of sputum smear-positive pulmonary TB. Every year, ~50 million people worldwide are infected with M. tuberculosis. Complete elimination of tubercle bacilli is achieved in ~10% individuals only while in ~90% of infected individuals, bacterial growth is stopped but some bacilli survive and persist leading to latent M. tuberculosis infection (LTBI). The waning of dormant bacilli in persons with LTBI can be accelerated by therapy with isoniazid for 9 months (denoted by *). The vaccines currently in clinical trials are designed to prevent or delay the reactivation of latent infection in persons with LTBI (denoted by **).