Whole-Genome and Social-Network Analysis of a Tuberculosis Outbreak in Canada

In the Canadian province of British Columbia, the 2007 incidence of 6.4 cases of Mycobacterium tuberculosis per 100,000 population exceeded the Canadian national average of 4.7 cases per 100,000 population. Between May 2006 and December 31, 2008, there were a total of 41 cases of tuberculosis identified in a small area of the province, resulting in an incidence rate of 72 cases per 100,000 population in the region. The British Columbia Centre for Disease Control (BCCDC) initiated an epidemiologic investigation that determined that all cultured isolates showed an identical pattern of mycobacterial interspersed repetitive unit–variable-number tandem repeats (MIRUVNTRs), suggesting a clonal origin. Despite this, traditional contract tracing did not identify a source. To understand the outbreak with more clarity, the BCCDC used whole-genome sequencing and social-network analysis to identify key individuals, places, and behaviors that contributed to the dynamics of the outbreak.

In its report [N Engl J Med. 2011;364(8):730-739], the center defined laboratory-confirmed cases of tuberculosis as those with M tuberculosis complex present on culture. Clinical cases were those without M tuberculosis culture but that were characterized by a radiologic, pathologic, or therapeutic response consistent with active tuberculosis. Using short-read sequencing, the investigators sequenced the entire genome of 32 M tuberculosis outbreak isolates and 4 historical isolates from the same region. As part of the social-network analysis, the investigators developed a social-network questionnaire (SNQ) to identify shared socialization settings and to prioritize case findings. The SNQ focused on drug and alcohol use, residential and travel history, places of social aggregation, and identification of contacts in the context of high-risk behaviors and locations. The SNQ was administered in the form of an open-ended interview and was used retrospectively to examine 9 of the 11 cases diagnosed before October 31, 2006. The social-network analysis was completed in November 2006. The 41 cases of tuberculosis in the British Columbia region represented a >10-fold increase in the annual incidence of the disease in the region. The majority of patients were adults (mean age, 36 years), who presented with pulmonary tuberculosis (68%) or pleural tuberculosis (24%).

There were 2 pediatric cases, including 1 in an infant. Outcomes were recorded through December 31, 2009, with a minimum of 12 months of follow-up for all patients. The majority of patients had favorable outcomes, with 35 patients (85%) meeting the World Health Organization criteria for “cure or treatment completed.” One patient (2%) did not complete treatment, and 1 patient (2%) had a relapse of pulmonary tuberculosis. Four deaths (10% of patients) were recorded during the followup period, including 1 death from complications of disseminated tuberculosis and 1 death from hepatic failure during receipt of antituberculosis medication. Two patients died from unrelated causes (motor vehicle accident and drug overdose). The results of the social-network analysis showed that 1 case (MT0001, the fifth case identified in the outbreak) was the most likely source case. The patient was an adult with cavitary, smear-positive pulmonary tuberculosis that had been symptomatic and untreated for at least 8 months before the detection of the first case. MT0001 was connected to all but 2 early cases through direct contact or a shared social setting. Use of the SNQ improved subsequent case-finding efforts by revealing previously unreported social interactions and identifying several locations frequented by infectious patients, including 2 hotels, a meal center, 2 community centers, and a series of crack houses.

The whole-genome data revealed 2 genetically distinct lineages of M tuberculosis with identical MIRU-VNTR genotypes. Both lineages had been present in the area for at least 5 years before the outbreak. When the genomic data and the social-network data were integrated and analyzed, MT0001 acted as a “superspreader,” probably causing 6 cases within lineage A. In lineage B, 2 cases, MT0010 and MT0011, were most likely to have been responsible for 4 and 3 subsequent cases, respectively. The investigators said that the outbreak, which came from a simultaneous appearance of 2 extant strains of tuberculosis, was most likely due to social or environmental factors rather than a genetic change in the organism. A surge in crack use in the area, which peaked in 2006, during this period could be the major factor, the investigators added.