Routine survey of Mycobacterium tuberculosis isolates reveals nosocomial transmission

Abstract

Control of Mycobacterium tuberculosis transmission in high-income healthcare settings and in low tuberculosis (TB) prevalence countries remains a public health priority given the constant changes in M. tuberculosis epidemiology worldwide. Though Europe is a low prevalence area [1], TB burden among precarious and migrant populations contributes to this evolving landscape, as addressed by the action framework towards TB elimination [2]. At the core of the national healthcare system, tertiary care hospitals manage both patients with greater susceptibility to TB, and patients with complex and/or advanced TB disease. Key measures for TB control rely on enabling linkage of cases and identification of transmission chains, often supported by molecular survey tools [3,4]. This is achieved by highlighting matched genotypes through a population-based systematic molecular TB survey in order to uncover outbreaks, even between apparently unrelated cases [5]. On that basis, further investigations can be triggered to understand the circumstances of transmission. In case of healthcare-related transmission, the origin of TB exposure is difficult to track as clinical disease develops months or years after patient discharge [6]. Therefore, understanding nosocomial TB transmission is essential for implementing control measures preventing such events. Herein, we bring evidence of the usefulness of molecular survey programmes to detect unsuspected TB transmission events among highly susceptible populations, and from a multidrug-resistant (MDR)-TB patient to a community-based individual. Subsequent corrective interventions implemented to prevent further nosocomial TB transmission are also described.Since 2008, the laboratory of the Lyon University Hospital has implemented a prospective population-based survey by systematic genotyping of M. tuberculosis isolates from the surrounding geographic districts (ORAM: Observatoire Rhône-Alpes des Mycobactéries), to facilitate the reporting of clinical microbiology results from TB laboratories to an operational network including TB management and control centres, and a centralised regional health agency [7]. In addition to spoligo-and MIRU-VNTR15-typing performed as described [7], from 2016 onwards, whole genome sequencing (WGS) was implemented as previously reported [5]. Sampling and testing were performed upon diagnosis and in accordance with the French bioethics laws. Contact-tracing was conducted as recommended by the French guidelines [8].From 2008 to 2018, 3230 cases of microbiologically proven TB were recorded; 20.5% of these cases were clustered, representing 662 patients distributed in 217 clusters. Among 96 clusters (341 cases) with confirmed transmission ( patients knew each other), four were healthcare-related (transmission occurring in hospital area), representing eight patients, including a single MDR-TB transmission event (figure 1a). Among them, three cases in lung transplant recipients resulted from nosocomial transmission of drug-susceptible TB. All index cases were men aged fro...

Mycobacterium tuberculosis genetic features associated with pulmonary tuberculosis severity

“…The median [interquartile range (IQR)] age of the study population was 35 [25-58] years, and a majority were male (66.2%). Most of the patients originated from Europe or Africa, which is consistent with the local epidemiology 19,20 . No difference was found in terms of comorbidities according to severity group ( Table 1 ).…”

“…Most of the patients originated from Europe or Africa, which is consistent with the local epidemiology 19,20 . No difference was found in terms of comorbidities according to severity group (Table 1).…”

“…1 and Extended Data Fig. 1 ) reflected the local epidemiology 20 . No difference was observed between groups regarding Mtb resistance profile ( Table 2 ).…”

Within-host genetic micro-diversity ofMycobacterium tuberculosisand the link with tuberculosis disease features

“…As WGS is performed in routine practice in our lab, as well as in other TB diagnosis lab, it could be envisioned as an all-in-one solution, to detect antibiotic resistance 37 , to infer Mtb transmission chains and to perform epidemiological monitoring 38,39 and now as a prognosis tool. In the frame of cancer and microbiological research, calling algorithm for low frequency variants were developed [40][41][42] and may be adapt to Mtb WGS data.…”

“…In this retrospective study, a total of 355 Mtb clinical isolates were included, from 311 patients diagnosed with microbiologically proven TB at the Lyon University Hospital. We included all Mtb clinical isolates for which WGS was performed in routine practice at the Lyon University Hospital from January 2017 to January 2020 and significant isolates of our collection (MDR Mtb, representative strains of large previously identified clusters, samples from patients with both pulmonary and extra-pulmonary TB) which were captured and implemented in the database during sequencing development in the lab 38,39 . It should be noted that we excluded pleural TB as depending of the clinical presentation it can be considered as PTB or EPTB.…”