Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure

Abstract

The absence of a gold standard to determine when antibiotics have induced sterilizing cure confounds the development of new approaches to treat pulmonary tuberculosis (PTB). We detected PET-CT imaging response patterns consistent with active disease along with the presence of Mycobacterium tuberculosis mRNA in sputum and bronchoalveolar lavage samples in a substantial proportion of adult, HIV-negative PTB patients after standard 6-month treatment plus one year follow-up, including patients with a durable cure and others who later developed recurrent disease. The presence of MTB mRNA in the context of non-resolving and intensifying lesions on PET-CT might indicate ongoing transcription, suggesting that even apparently curative PTB treatment may not eradicate all organisms in most patients. This suggests an important complementary role for the immune response in maintaining a disease-free state. Sterilizing drugs or host-directed therapies and better treatment response markers are likely needed for the successful development of improved and shortened PTB treatment strategies.

Effect of previous treatment and sputum quality on diagnostic accuracy of Xpert® MTB/RIF

“…28 Finally, a recent study that used advanced imaging techniques found that persistent Xpert positivity at end of treatment, even when clinical and microbiological cure was achieved, was a risk factor for TB relapse. 29 In this study, 82% of presumptive TB patients with discordant cultureÀ, Xpertþ results had mucosalivary samples, suggesting that these sample types may be negatively impacting the yield of MGIT culture. If this finding is reproduced in other studies, discordant results might be better explained by inter-and intra-sample variability in sensitivity between culture and Xpert rather than non-viable bacillary populations, as they would be expected to be uniformly present in all samples, regardless of rheological characteristics.…”

A novel blood test for tuberculosis prevention and treatment

“…A blood-based triage test that allows targeted investigation of individuals with active and sub-clinical TB disease, including asymptomatic individuals at highest risk of progression from latency to disease, could help to shorten the time to treatment start, or even prevent incipient disease before symptoms emerge. [6,7] The vision of a TB blood test to identify high-risk individuals for targeted preventive or curative therapy is within reach.…”

Interplay of human macrophages and Mycobacterium tuberculosis phenotypes

“…This could lead to local monotherapy, or to suboptimal drug concentrations in certain regions of lesions, facilitating Mtb persistence and the emergence of genetic drug resistance. Furthermore, the lesions within one individual receiving TB treatment are heterogeneous, with some lesions responding to treatment while others do not decrease in size or activity [369]. These differences have been attributed to differential immune responses at the lesional level, although this is hypothetical.…”

“…In line with that, a recent study provided evidence for 'active persisters' in TB patients. Employing 18 FDG-PET-CT scanning to monitor lesion activity during antibiotic treatment, many granulomas were found to abate and resolve, but still one third of patients showed intensified and new lesions [369]. Even if lesions intensified due to killed bacteria triggering local immune responses, the emergence of new lesions is hard to explain if not by ongoing infection.…”

“…In the same study, sputum and BAL samples were analyzed and -although culture negative -often contained Mtb DNA and mRNA. The stable DNA molecules but not the rather instable mRNA could originate from dead and lysed bacilli, suggesting a non-culturable but viable Mtb population or at least bacilli with active transcription remaining in lesions after successful completion of TB treatment [369]. Under the assumption that emergence and increase of lesions during treatment reflects growing bacteria, it could indicate that different lesions contain different phenotypes, with for example non-culturable bacilli in cavitary lesions but growing Mtb in contained granulomas.…”