The End of the Binary Era: Revisiting the Spectrum of Tuberculosis

Abstract

Human Mycobacterium tuberculosis infection was thought to result in either active symptomatic tuberculosis (TB) or latent asymptomatic infection. It is now clear that this binary classification is insufficient to describe the myriad of infection outcomes. In active TB, symptomatic disease can be mild to severe, with a range of lung and thoracic lymph node involvement or extrapulmonary manifestations. Most humans control the infection and develop latent TB infection, with differential risks of reactivation to active TB. However, some frequently exposed persons appear to be resistant to infection, whereas others may initially become infected yet subsequently eliminate all bacilli. The immunologic factors influencing these varied outcomes are still not clear, but likely involve a range of different responses. In this article, we review the data supporting the spectrum of M. tuberculosis infection in humans as well as data in nonhuman primates that allow dissection of the immune responses leading to the varied outcomes of infection.

Figure 1.

Caseous granuloma from the lung of an M. tuberculosis-infected macaque.

Figure 2.

The outcome of M. tuberculosis infection includes a host of outcomes and clinical manifestations. Those with severe outcomes are often highly symptomatic (e.g., weight loss, chills, night sweats, fevers, cough) with a positive skin test or interferon gamma release assay (IGRA), chest x-ray (CXR) with substantial TB disease and growth of M. tuberculosis on sputum culture. In contrast, some individuals may have been infected in the past (with or without a positive IGRA/skin test) and have cleared the infection resulting in the absence of symptoms, negative sputum culture and normal chest x-ray. While the greatest proportion of infected individuals are able to control infection (LTBI), the exact distribution of outcomes depicted here is not known. PPD= Purified Protein Derivative Tuberculin Skin Test.

Figure 3.

Granulomas are independent and dynamic by PET CT during M. tuberculosis infection in macaques. Top row: Between 6 and 16 weeks after infection, one granuloma increases in size but maintains the same FDG avidity (yellow arrow), while the other granuloma increases in size and FDG avidity (orange arrow) in the accessory lobe. Bottom row: This same animal has a granuloma in the right lower lobe that has decreased in size and FDG avidity (blue arrow) at the same time points. Black line = 1 cm

Figure 4.

The hypothetical spectrum of granuloma types is seen in any infected individual with each granuloma associated with a range of immune control and bacterial burden. A granuloma that has lost its overall structure and function (“progressive” and “disseminating” granulomas) is associated with poor immune control and high bacterial burden. In contrast, fibrotic granulomas are often sterile reflecting a robust immune response.