During June 2017–April 2018, active tuberculosis with Beijing SIT1 isolates was diagnosed in 14 persons living in 4 distant cities in France. Whole-genome sequencing indicated that these patients belonged to a single transmission chain. Whole-genome sequencing–based laboratory investigations enabled prompt tracing of linked cases to improve tuberculosis control.

Mycobacterium tuberculosis (Mtb) infections result in a wide spectrum of clinical presentations but without proven Mtb genetic determinants. Herein, we hypothesized that the genetic features of Mtb clinical isolates, such as specific polymorphisms or microdiversity, may be linked to tuberculosis (TB) severity. A total of 234 patients with pulmonary TB (including 193 drug-susceptible and 14 monoresistant cases diagnosed between 2017 and 2020 and 27 multidrug-resistant cases diagnosed between 2010 and 2020) were stratified according to TB disease severity, and Mtb genetic features were explored using whole genome sequencing, including heterologous single-nucleotide polymorphism (SNP), calling to explore microdiversity. Finally, we performed a structural equation modeling analysis to relate TB severity to Mtb genetic features. The clinical isolates from patients with mild TB carried mutations in genes associated with host-pathogen interaction, whereas those from patients with moderate/severe TB carried mutations associated with regulatory mechanisms. Genome-wide association study identified an SNP in the promoter of the gene coding for the virulence regulator espR, statistically associated with moderate/severe disease. Structural equation modeling and model comparisons indicated that TB severity was associated with the detection of Mtb microdiversity within clinical isolates and to the espR SNP. Taken together, these results provide a new insight to better understand TB pathophysiology and could provide a new prognosis tool for pulmonary TB severity.

Appropriate tuberculosis (TB) management requires anti-TB drugs resistance detection. We assessed the performance of rapid resistance detection assays and their impact on treatment adaptation, focusing on isoniazid resistant (Hr) TB. From 2016 to 2022, all TB cases enrolled in 3 hospitals were reviewed for phenotypic drug susceptibility testing (p-DST) and genotypic DST (g-DST) performed by rapid molecular testing, and next generation sequencing (NGS). Clinical characteristics, treatment and outcome were collected for Hr-TB patients. The concordance between g-DST and p-DST results, and delay between treatment initiation and results of g-DST and p-DST were respectively recorded to assess the contribution of DST results on Hr-TB management. Among 654 TB cases enrolled, 29 were Hr-TB. Concordance between g-DST by rapid molecular methods and p-DST was 76.9 %, whilst concordance between NGS-based g-DST and p-DST was 98.7 %. Rapid resistance detection significantly fastened Hr-TB treatment adaptation (median delay between g-DST results and treatment modification was 6 days). It consisted in fluoroquinolone implementation for 17/23 patients; outcome was favourable except for 2 patients who died before DST reporting. Rapid resistance detection fastened treatment adaptation. Also, NGS-based g-DST showed almost perfect concordance with p-DST, thus providing rapid and safe culture-free DST alternative.