Tuberculosis super-spreading due to interterritorial mobility and prolonged diagnostic delay: A call for an integrated and enhanced analysis

Whole genome sequencing has revolutionised the precision with which we can delineate tuberculosis (TB) transmission. However, the majority of genomic epidemiology surveillance in TB is restricted to the analysis of geographically limited populations, which impairs the identification of cross-regional transmission. In this study, we delineate a complex transmission event in Spain involving 13 cases, characterised by the convergence of i) interterritorial transmission due to the mobility of migrant cases, ii) superspreading due to an undiagnosed advanced TB case resulting from a prolonged diagnostic delay, iii) extensive exposures attributable to substantial social gatherings, iv) involvement of 6 different nationalities and autochthonous cases, and iv) two independent populations where the majority of cases were exposed or diagnosed, respectively. The final understanding of this transmission event was only possible following the integration of sequencing data obtained from different populations, the refinement of interviews with patients to cover social networks at both the diagnostic and exposure populations, the design of tailored laboratory assays to fast-track new cases based on targeted sequencing of the strain marker single-nucleotide polymorphisms (SNPs) and the evolutionary analysis of the SNPs identified in the cluster. This study may serve as an illustration of the integrative efforts and simultaneous strategic, methodological and analytical improvements that are required to address the numerous novel challenges arising for a proper surveillance of TB transmission in our current, increasingly complex, epidemiological scenario.