High resolution imaging and five-year tuberculosis contact outcomes

Abstract

Background: The evolution of tuberculosis (TB) disease during the clinical latency period remains incompletely understood.

Methods: 250 HIV-uninfected, adult household contacts of rifampicin-resistant TB with a negative symptom screen underwent baseline ¹⁸F-Fluorodeoxyglucose positron emission and computed tomography (PET/CT), repeated in 112 after 5-15 months. Following South African and WHO guidelines, participants did not receive preventive therapy. All participants had intensive baseline screening with spontaneous, followed by induced, sputum sampling and were then observed for an average of 4.7 years for culture-positive disease. Baseline PET/CT abnormalities were evaluated in relation to culture-positive disease.

Results: At baseline, 59 (23.6%) participants had lung PET/CT findings consistent with TB of which 29 (11.6%) were defined as Subclinical TB, and 30 (12%) Subclinical TB-inactive. A further 83 (33.2%) had other lung parenchymal abnormalities and 108 (43.2%) had normal lungs. Over 1107-person years of follow-up 14 cases of culture-positive TB were diagnosed. Six cases were detected by intensive baseline screening, all would have been missed by the South African symptom-based screening strategy and only one detected by a WHO-recommended chest X-Ray screening strategy. Those with baseline Subclinical TB lesions on PET/CT were significantly more likely to be diagnosed with culture-positive TB over the study period, compared to those with normal lung parenchyma (10/29 [34.5%] vs 2/108 [1.9%], Hazard Ratio 22.37 [4.89-102.47, p<0.001]).

Conclusions: These findings challenge the latent/active TB paradigm demonstrating that subclinical disease exists up to 4 years prior to microbiological detection and/or symptom onset. There are important implications for screening and management of TB.

Figure 1.. Study flow diagram

Shows number of individuals screened, excluded, consented and followed up. Cult= culture, micro=microscopy

Figure 2.. Difference in TB diagnosis according to different screening and follow-up approaches and PET/CT images of those diagnosed.

Panels A to D show diagrammatic representation of the cohort by previous TB history and radiographic evidence of subclinical TB showing proportion with confirmed TB with different screening and follow-up approaches: (Panel A) South African guideline: Sputum investigation only if TB symptoms; (Panel B) WHO recommended approach using CXR with spontaneous sputum investigation only x-ray abnormal or symptoms; (Panel C) Intensive sputum investigation at baseline with 3x sputum (induced if needed); (Panel D) Intensive sputum investigation at baseline with follow-up over 5 years. Each of the 250 participants is represented by a circle with outline colour showing baseline PET/CT grouping (Subclinical – orange, Subclinical-inactive – yellow, no/other lesions – black). The circle is filled when TB is confirmed. The proportion with positive a Quantiferon test (QFT+) (i.e. with a clinical diagnosis of latent TB) and the proportion with previous TB is also represented. Cult+ = culture positive, f/u = follow-up. Panel E shows axial sections of fused FDG-PET/CT of the 6 culture positive participants at baseline. Panel F shows axial sections of fused FDG-PET/CT at baseline (top row), second PET/CT after 6-12 months (middle row) and at TB diagnosis (bottom row) of 2 participants finally diagnosed with TB at 32 (left) and 34 (right) months. Outline colour denotes; Black = baseline, Green = lesion improves or no change, Red = lesion worsens.

Figure 3.. Survival curves for culture positive TB diagnosis according QuantiFERON or PET/CT findings

Survival curves showing development of TB over time by QuantiFERON status inducing (Panel A) or excluding (Panel B) those with no previous history of TB. Survival curves showing development of TB over time by nature of baseline radiography inducing (Panel C) or excluding (Panel D) those with no previous history of TB. Survival curves showing development of any treated TB (Panel E) or any treated TB and untreated Xpert-positive TB (Panel F) over time by nature of baseline radiography inducing those with no previous history of TB.