Standard genotyping overestimates transmission of Mycobacterium tuberculosis among immigrants in a low incidence country.

Immigrants from high tuberculosis (TB) incidence regions are a risk group for TB in low-incidence countries such as Switzerland. In a previous analysis of a nationwide collection of 520 Mycobacterium tuberculosis isolates from 2000-2008, we identified 35 clusters comprising 90 patients based on standard genotyping (24-loci MIRU-VNTR and spoligotyping). Here, we used whole genome sequencing (WGS) to revisit these transmission clusters. Genome-based transmission clusters were defined as isolate pairs separated by ≤12 single nucleotide polymorphisms (SNPs). WGS confirmed 17/35 (49%) MIRU-VNTR clusters; the other 18 clusters contained pairs separated by >12 SNPs. Most transmission clusters (3/4) of Swiss-born patients were confirmed by WGS, as opposed to 25% (4/16) of clusters involving only foreign-born patients. The overall clustering proportion using standard genotyping was 17% (90 patients, 95% confidence interval [CI]: 14-21%), but only 8% (43 patients, 95% CI: 6-11%) using WGS. The clustering proportion was 17% (67/401, 95% CI: 13-21%) using standard genotyping and 7% (26/401, 95% CI: 4-9%) using WGS among foreign-born patients, and 19% (23/119, 95% CI: 13-28%) and 14% (17/119, 95% CI: 9-22%), respectively, among Swiss-born patients. Using weighted logistic regression, we found weak evidence for an association between birth origin and transmission (aOR 2.2, 95% CI: 0.9-5.5, comparing Swiss-born patients to others). In conclusion, standard genotyping overestimated recent TB transmission in Switzerland when compared to WGS, particularly among immigrants from high TB incidence regions, where genetically closely related strains often predominate. We recommend the use of WGS to identify transmission clusters in low TB incidence settings.