A cluster of multidrug-resistant Mycobacterium tuberculosis among patients arriving in Europe from the Horn of Africa: a molecular epidemiological study

Abstract

SummaryBackgroundThe risk of tuberculosis outbreaks among people fleeing hardship for refuge in Europe is heightened. We describe the cross-border European response to an outbreak of multidrug-resistant tuberculosis among patients from the Horn of Africa and Sudan.MethodsOn April 29 and May 30, 2016, the Swiss and German National Mycobacterial Reference Laboratories independently triggered an outbreak investigation after four patients were diagnosed with multidrug-resistant tuberculosis. In this molecular epidemiological study, we prospectively defined outbreak cases with 24-locus mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) profiles; phenotypic resistance to isoniazid, rifampicin, ethambutol, pyrazinamide, and capreomycin; and corresponding drug resistance mutations. We whole-genome sequenced all Mycobacterium tuberculosis isolates and clustered them using a threshold of five single nucleotide polymorphisms (SNPs). We collated epidemiological data from host countries from the European Centre for Disease Prevention and Control.FindingsBetween Feb 12, 2016, and April 19, 2017, 29 patients were diagnosed with multidrug-resistant tuberculosis in seven European countries. All originated from the Horn of Africa or Sudan, with all isolates two SNPs or fewer apart. 22 (76%) patients reported their travel routes, with clear spatiotemporal overlap between routes. We identified a further 29 MIRU-VNTR-linked cases from the Horn of Africa that predated the outbreak, but all were more than five SNPs from the outbreak. However all 58 isolates shared a capreomycin resistance-associated tlyA mutation.InterpretationOur data suggest that source cases are linked to an M tuberculosis clone circulating in northern Somalia or Djibouti and that transmission probably occurred en route before arrival in Europe. We hypothesise that the shared mutation of tlyA is a drug resistance mutation and phylogenetic marker, the first of its kind in M tuberculosis sensu stricto.FundingThe Swiss Federal Office of Public Health, the University of Zurich, the Wellcome Trust, National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), the Medical Research Council, BELTA-TBnet, the European Union, the German Center for Infection Research, and Leibniz Science Campus Evolutionary Medicine of the Lung (EvoLUNG).

A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic

“…1), which is associated with ETH resistance [57], a drug widely used in second-line treatment regimens. Interestingly, a similar observation was made in an MDR-TB outbreak originating in the Horn of Africa, where a capreomycin resistance conferring tlyA mutation was found to be present in otherwise susceptible progenitors [58]. While it is possible that the ethA mutation simply arose by chance, ETH was used in the past (since the 1960s) in nonstandardised therapy, including first-line therapy [59,60], which may explain the early acquisition and therefore deeply rooted evolution of this resistance marker.…”

Haemoptysis and fever in a young refugee from Somalia

“…In recent years, TB in migrants has represented a major public health challenge for low TB incidence countries such as Italy (Lönnroth et al, 2017;Sotgiu et al, 2017a). Incidence rates in foreign-born populations coming from high TB burden areas (e.g., Somalia) are higher than those recorded in the native European population; furthermore, migrants show a higher probability of developing the disease from latent TB infection acquired in the country of origin or on the route to Europe (Sotgiu et al, 2017a;Walker et al, 2018).…”

Computational Pan-genome Mapping and pairwise SNP-distance improve Detection of Mycobacterium tuberculosis Transmission Clusters

“…In recent outbreak investigations WGS was an indispensable tool of outbreak detection and transmission analysis and is replacing genotyping (mycobacterial interspersed repetitive unit -variable number tandem repeat, MIRU-VNTR) as method of choice in low incident countries like most West-European countries [9][10][11]. WGS can validate participation of individuals to a common transmission event and thus associate TB cases that do not have a clear epidemiological link or vice versa [9,12,13]. With its high resolution WGS outperforms other molecular typing methods as MIRU-VNTR, Spoligotyping or RFLP [14].…”