Early Changes by (18)Fluorodeoxyglucose positron emission tomography coregistered with computed tomography predict outcome after Mycobacterium tuberculosis infection in cynomolgus macaques

Abstract

Cynomolgus macaques infected with low-dose Mycobacterium tuberculosis develop both active tuberculosis and latent infection similar to those of humans, providing an opportunity to study the clinically silent early events in infection. (18)Fluorodeoxyglucose radiotracer with positron emission tomography coregistered with computed tomography (FDG PET/CT) provides a noninvasive method to measure disease progression. We sought to determine temporal patterns of granuloma evolution that distinguished active-disease and latent outcomes. Macaques (n = 10) were infected with low-dose M. tuberculosis with FDG PET/CT performed during infection. At 24 weeks postinfection, animals were classified as having active disease (n = 3) or latent infection (n = 6), with one "percolator" monkey. Imaging characteristics (e.g., lesion number, metabolic activity, size, mineralization, and distribution of lesions) were compared among active and latent groups. As early as 3 weeks postinfection, more pulmonary granulomas were observed in animals that would later develop active disease than in those that would develop latent infection. Over time, new lesions developed in active-disease animals but not in latent animals. Granulomas and mediastinal lymph nodes from active-disease but not latent animals consistently increased in metabolic activity at early time points. The presence of fewer lesions at 3 weeks and the lack of new lesion development in animals with latent infection suggest that innate and rapid adaptive responses are critical to preventing active tuberculosis. A greater emphasis on innate responses and/or rapid recruitment of adaptive responses, especially in the airway, should be emphasized in newer vaccine strategies.

FIG 1

Serial FDG PET/CT images showing a disseminating and stable pattern of granuloma evolution during the course of early infection. (Top row) Primary lesions (blue arrows) were first established at 3 weeks postinfection, while new lesions developed adjacent to existing lesions (red arrows) or in new sites (yellow arrows). Animals that would later develop active TB developed more lesions during the course of infection. (Bottom row) Primary lesions (blue arrows) of latent animals usually remained stable, with few new granulomas developing through the course of infection. wks PI, weeks postinfection.

FIG 2

Granuloma number and metabolic activity during M. tuberculosis infection. (A) Active-disease animals (squares) had more lung granulomas (Lung Gran) than latently infected animals (circles) as early as 3 weeks after infection and throughout infection. (B) Active-disease animals had more new lesions develop between 3 and 6 weeks postinfection than did latently infected animals. Each dot represents the number of granulomas for a single animal. Bars indicate medians. P = 0.06 (§) and P < 0.05 (*) by Mann-Whitney test.

FIG 3

Metabolic activity of lung lesions differs between active and latent animals during early infection. (A) Individual granulomas from active-disease animals had a significant increase in metabolic activity (measured as standard uptake volume ratio [SUV]) between 3 and 6 weeks after infection. (B) Metabolic activity among individual granulomas from latent animals between 3 and 6 weeks postinfection is variable. (C) The change in metabolic activity between latent and active animals was compared. Active-disease animals had an overall increase in metabolic activity between 3 and 6 weeks. (D) Active-disease animals had an overall increase in metabolic activity between 3 and 24 weeks postinfection. Each dot represents a granuloma. Latent groups are colored gray, and active-disease groups are in black. The Wilcoxon rank-sum test was used to analyze data from panels A and B. For panels C and D, P < 0.001 (***) by Mann-Whitney test.

FIG 4

Mediastinal lymph nodes between active-disease and latent animals differ in metabolic activity. (A) Metabolic activity (measured as SUV) among active and latent groups during infection. The median SUV among lymph nodes at 6, 8, and 12 weeks postinfection was higher among active-disease animals than latently infected animals. Each dot represents a granuloma. (B) Median change in SUV between 3 and 6 weeks postinfection was higher in active-disease animals than latently infected animals. Each dot represents an animal. Latent groups are colored gray, and active-disease groups are in black. P = 0.06 (§), P < 0.05 (*), and P < 0.001 (***) by Mann-Whitney test.