Whole genome sequencing of recurrent tuberculosis in Stockholm County 1996–2016

Background: Recurrence of infection after completed antibiotic treatment is reported to occur in around 2% of tuberculosis (TB) patients, in TB-low-endemic settings. Whether these recurrent cases represent relapse of infection or reinfection from another TB strain can be evaluated with molecular typing. The aim of this study was to analyze the frequency of TB-recurrence in Stockholm Country and to use whole genome sequencing (WGS) to separate recurrent cases caused by relapse from those caused by reinfection as an evaluation of current treatment strategies and treatment control. Methods: In this population-based cohort study all 2,552 patients diagnosed with culture verified TB between 1996 and 2016, at the Karolinska University Hospital in Stockholm County were eligible and followed until TB recurrence, or end of study period (end of 2017). The median follow-up time was 10.2 years (IQR, 5.6–16.2 years). WGS of the Mycobacterium tuberculosis (M.tb) strains from the two TB episodes separated relapse and reinfection. Results: Culture confirmed TB recurrence, more than 180 days after successful treatment completion was seen in 24 (0.7%) patients. With WGS analysis of paired M.tb samples from 17 patients, 12 (71%) cases were classified as relapse and five (29%) were regarded as reinfection, resulting in a relapse frequency of 0.5%, corresponding to an annual risk of relapse of 0.06%. Drug resistance was present at the first TB episode in 6 (50%) of the cases with TB relapse. No additional mutations for drug resistance were detected at the second TB episode in patients with relapse. Conclusions: The relapse frequency in Stockholm County is low, indicating a well-functioning TB-care. WGS is a useful tool to distinguish relapse from reinfection. A high proportion of resistant TB strains in patients with relapsing infection indicates a need of improved treatment control in this group.