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 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.

Aerosolization of viable Mycobacterium tuberculosis bacilli by tuberculosis clinic attendees independent of sputum-Xpert Ultra status

“…The ability of the aerosol phenotype of Mtb to persist in bioaerosols during and after TB therapy poses a previously under-recognized challenge to TB eradication within an individual. Furthermore, the isolation of viable Mtb from individuals not reaching a clinical threshold for TB diagnosis and treatment potentially expands the cohort of subclinical TB in the community—reinforcing very recent observations suggesting that subclinical disease might exist as long as 4 y prior to TB symptom onset ( 25 ). However, whether these organisms are transmissible to other hosts and have the capacity to revert to disease-causing phenotypes remains to be determined.…”

“…Current approaches to TB control are predicated on tenets which are increasingly being questioned as improved technologies enable insights into mycobacterial pathogenicity and the TB disease cycle that were previously inaccessible to investigation ( 24 , 25 ). Among these are the reliance on sputum Mtb positivity as a marker of patient infectiousness ( 26 ), and the dependence on coughing as sole vehicle for aerosol Mtb release ( 4 , 10 , 14 ).…”

“…Our understanding of any disease is dependent on the assays and tools which are available to study it. New technologies such as FDG-PET/CT imaging are changing our perspective of within-host TB pathology ( 25 ), and developments in noninvasive bioaerosol sampling, such as modified facemasks ( 13 ) and our RASC sampling system, are revealing insights into the natural history of TB infection and disease. Applying these technologies longitudinally and to a wide spectrum of at-risk individuals can help to elucidate the complex interactions between the pathogen and the host throughout the human lifespan.…”

Mathematical modeling suggests heterogeneous replication ofMycobacterium tuberculosisin rabbits

“…n); rates of replication and death may vary between sub-populations and/or with time since infection t (eqn. (7)).…”

“…Studying TB progression in humans is difficult as most exposed individuals do not develop the disease, and thus, it requires dedicated long-term cohort studies (e.g., [5,7]). Most of what we know about within-host Mtb replication early after infection comes from animal studies [8][9][10][11].…”